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Golgi Glycosylation and Human Inherited Diseases

Hudson H. Freeze and Bobby G. Ng

Genetic Disease Program, Sanford Children’s Health Research Center, Sanford-Burnham Medical Research Institute, La Jolla, California 92037 Correspondence: [email protected]

The Golgi factory receives custom glycosylates and dispatches its cargo to the correct cellular locations. The process requires importing donor substrates, moving the cargo, and recycling machinery. Correctly glycosylated cargo reflects the Golgi’s quality and efficiency. Genetic disorders in the specific equipment (enzymes), donors (nucleotide sugar transporters), or equipment recycling/reorganization components (COG, SEC, golgins) can all affect glyco- sylation. Dozens of human glycosylation disorders fit these categories. Many other genes, with or without familiar names, well-annotated pedigrees, or likely homologies will join the ranks of glycosylation disorders. Their broad and unpredictable case-by-case phenotypes cross the traditional medical specialty boundaries. The gene functions in patients may be elusive, but their common feature may include altered glycosylation that provide clues to Golgi function. This article focuses on a group of human disorders that affect protein or lipid glycosylation. Readers may find it useful to generalize some of these patient-based, translational observations to their own research.

argo sorting and glycosylation are the major remains on those that affect Golgi composition, Cjobs of the Golgi apparatus. Because 1%– structure, and homeostasis. The glycan biosyn- 2% of the translated genome affects glycan thetic pathways are described briefly here; other (sugar chain) biosynthesis and/or binding, it articles cover them in more detail. is not surprising that humans have mutations Human glycosylation disorders assume in genes involved in glycan synthesis covering many guises and their phenotypic expression known pathways (Eklund and Freeze 2006). in model systems and humans is not easy to Here we focus on glycosylation disorders mostly predict based on cell biology alone; they often discovered within the last 10–12 years (Lowe assault multiple organ systems. Recent meetings 2005; Freeze 2006; Jaeken and Matthijs 2007; identified areas of consensus and controversy Clement et al. 2008; Coman et al. 2008; Foulqu- in the Golgi field (Donaldson and McPherson ier 2009; Freeze and Schachter 2009; Guillard 2009; Emr et al. 2009). Add an assurance that et al. 2009). Many disorders that result from many Golgi-related genetic disorders will be biosynthetic defects in the endoplasmic reticu- identified in the near future. Discoveries will lum (ER) also require mention, but the focus confirm, extend, and modify our current

Editors: Graham Warren and James Rothman Additional Perspectives on The Golgi available at www.cshperspectives.org Copyright # 2011 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a005371 Cite this article as Cold Spring Harb Perspect Biol 2011;3:a005371

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H.H. Freeze and B.G. Ng

concepts of Golgi function with new hypothe- glycosphingolipid glycosylation (SIAT9-CDG, ses, controversies, and, in time, consensus. An Amish infantile epilepsy) and two defects in gly- understanding of glycosylation will benefit cosylphosphatidylinositol anchor biosynthesis basic scientists in many biological disciplines, (PIGM-CDG, and PIGV-CDG, glycosylphos- but more importantly for patients, it may sug- phatidylinositol deficiency). A common feature gest disease markers and potential therapies. of all Golgi glycosylation pathways is that nucleotide sugar donors must be transported into the Golgi using a series of transporters OVERVIEW OF GLYCOSYLATION with different sugar preferences. Not surpris- PATHWAYS ingly, defects in these carriers can affect multiple There are seven major ER-Golgi glycan biosyn- glycosylation pathways. Table 1 summarizes the thetic pathways each defined by the nature of ER-Golgi pathway glycans and their general the sugar-protein or sugar-lipid bond. Human functions. disorders occur in each of them. By far, the majority is in the N-glycosylation pathway ER LOCATION (GlcNAc-Asn), especially those defects found in the ER. Protein O-glycosylation is more Monosaccharide substrates are activated through diverse. Ser/Thr residues are linked to glycans a series of sugar specific pathways involving ki- through N-acetylgalactosamine, xylose, man- nases, epimerases, and mutases that eventually nose, or fucose (GalNAc, Xyl, Man, and Fuc, generate multiple high-energy nucleotide sugar respectively). Each of these has pathway-specific donors (Freeze and Elbein 2009) that can be glycosyltransferases that extend the chains. In used directly when acceptor proteins, lipids, or many cases, terminal sugars are added by glycans face the cytoplasm. When they face the more promiscuous transferases that service Golgi lumen, the activated donors require different pathways (Stanley and Cummings protein-mediated transport into the Golgi. 2009). Glycosphingolipids link glucose (Glc) N-linked glycosylation begins in the ER by to membrane-embedded ceramide and the a step-wise assembly of a 14-sugar glycan glycan chain is then extended using pathway Glc3Man9GlcNAc2 on a PP-dolichol precursor. specific enzymes. Glycophosphatidylinositol Initially, the half-completed precursor (Man5 (GPI) anchors are initially made in the ER GlcNAc2-PP-dolichol) faces the cytoplasm, transferred to protein and remodeled in the but it flips to the luminal side using a flippase. Golgi. Both glycosphingolipids and GPI The glycan is completed therein using Dol-P- anchors are enriched in detergent-insoluble, Man and Dol-P-Glc before oligosaccharyl cholesterol-containing lipid rafts initially transferase directs en bloc transfer of the com- assembled in the Golgi and later found on the pleted glycan to the polypeptide chain emerg- plasma membrane (Kinoshita et al. 2008; Fujita ing from the ribosome into the ER lumen. et al. 2009; Westerlund and Slotte 2009). The protein-bound glycan is then trimmed. Recently, defects have been identified in Two outermost glucose residues are removed

Table 1. Classification of the major glycan–protein linkages Glycan type Linkage Typical proteins Cell type N-linked GlcNAc-b-Asn Cell surface receptors and All cell types secreted proteins O-linked GalNAc-a-Ser/Thr Secreted and cell surface mucins Cell surface, gastrointestinal and reproductive tracts O-linked Man-a-Ser/Thr a-Dystroglycan Muscle tissue, nerve cells O-linked Xyl-b-Ser Chondroitin/dermatan sulfate Extracellular matrix, cartilage & heparan sulfate/heparin

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Golgi Glycosylation and Human Inherited Diseases

quickly and the third is used as a quality control N-LINKED PATHWAY assurance check. Following its permanent removal, a single Man unit is cleaved clearing Glycan trimming and reconstruction are unique the protein for movement to the Golgi. This to the N-glycosylation pathway as discussed in brief description harbors 18 distinct human Stanley (2011). Mutations in the first a-glucosi- glycosylation disorders even prior to the traffic dase (glucosidase I) prevent the removal of the reaching the Golgi (Freeze 2006; Jaeken and first glucose, but a backup cis- to medial Golgi Matthijs 2007; Haeuptle and Hennet 2009). endo-a-mannosidase is up-regulated (Volker Specific chaperones in the ER help escort et al. 2002) and cleaves an intact tetrasaccharide proteins into the Golgi and genetic disorders from the glycoproteins. This allows further have been found in a few of these as well. processing to occur, and in contrast to many One, called COSMC, escorts an O-GalNAc other N-glycosylation disorders, the typical pathway-specific b-galactosyltransferase to its serum glycoprotein structures such as those site of action in the Golgi (Ju et al. 2008). A seen on transferrin are not altered. In fact, the combined loss of coagulation factors V and disorder was only identified from the accumu- VIII results from mutations in a transmem- lation of the tetrasaccharide (Glca1,2Glca1, brane mannose-binding lectin in the ER- 3Glca1,3Mana1,2) in the urine. The enzyme is Golgi intermediate compartment (ERGIC-53), transported from ER to Golgi in COP II vesicles. and multiple coagulation factor deficiency 2 (Torossi et al. 2010). (MCFD2) its soluble calcium-binding protein Given the multiple glycosyltransferases partner (Spreafico and Peyvandi 2009; Nishio involved in N-glycan processing and branching, et al. 2010). this portion of the pathway might be expected O-fucosylation of selected proteins that to show many defects. Surprisingly, only two carry tandem EGF modules such as Notch or are known. One (CDG-IIa) results from essen- others with thrombospondin type I repeats tially total loss of b-1,2-N-acetylglucosaminyl- occurs in the ER, and may have both chaperone transferase (MGAT2) function. This enzyme is and glycan initiating roles (Leonhard-Melief and required for formation of multiantennary gly- Haltiwanger 2010; Takeuchi and Haltiwanger cans and further processing into complex 2010). The different protein modules select N-glycans. The few patients with this N-glycan- which of two fucosyltransferases to use and specific deficiency have severe psychomotor and which glycan extensions occur in the Golgi. growth retardation along with distinct abnor- Glycosphingolipid synthesis begins in the mal facial features and thoracic deformity ER with the synthesis of GlcbCer and all subse- (Schachter and Jaeken 1999). The other defect quent extensions occur in the Golgi. Mannose- (CDG-IId) is caused by mutation in b1,4 rich GPI-anchors are also constructed in the ER galactosyltransferase-I. The single patient had where they are transferred to proteins. Their severe neurologic disease, myopathy, and clot- lipid remodeling may be a signal for their export ting defects (Hansske et al. 2002). A series of to the Golgi (Bonnon et al. 2010; Rivier et al. other known b1,4 galactosyltransferases with 2010). different substrate preferences were insufficient to overcome this lesion, pointing to this enzyme as the major one required for N-glycan process- GENETIC DISORDERS IN THE MACHINERY ing. This transferase is also responsible for We define the glycosylation machinery as those extending GlcNAcb1,3Fuc glycans necessary proteins that participate in the assembly of gly- for fringe modulation of Notch signaling, men- cans of one or more pathways. Like most other tioned below (Chen et al. 2001). This example glycosylation disorders, these are nearly all underscores that mutations in a single transfer- autosomal recessive. The defective genes are ase can affect multiple glycosylation pathways. divided by pathway and listed in Table 2. A special case of a Golgi transferase defi- Selected ones are highlighted below. ciency is I-cell disease or Mucolipidosis II,

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Table 2. Golgi-related glycosylation disorders Gene function Gene OMIM Clinical presentation N-glycan disorders MGAT2-CDG N-acetylglucosaminyltransferase MGAT2 212066 Mental retardation, (CDG-IIa)a II dysmorphism, seizures I-cell disease GlcNAc-1-P transferase GNPTA 252500 Severe developmental abnormalities Multiple pathway disorders SLC35C1-CDG GDP-fucose transporter FUCT1 266265 Severe psychomotor (CDG-IIc)a retardation, hypotonia, elevated peripheral neutrophils B4GALT1-CDG b1,4-galactosyltransferase B4GALT1 607091 Hypotonia, spontaneous (CDG-IId)a hemorrhage, Dandy– Walker malformation COG7-CDG (CDG-IIe)a Conserved oligomeric Golgi COG7 608779 Early death, dysmorphism, subunit 7 hypotonia, seizures, hepatomegaly, recurrent infections, cardiac failure, excessive skin SLC35A1-CDG CMP-sialic acid transporter SLC35A1 605634 Normal transferrin, (CDG-IIf )a thrombocytopaenia, abnormal platelet glycoproteins COG1-CDG (CDG-IIh)a Conserved oligomeric Golgi COG1 606973 Mild MR, hypotonia, subunit 1 growth retardation, progressive microcephaly, hepatosplenomegaly COG8-CDG Conserved oligomeric Golgi COG8 611182 MR, hypotonia, subunit 8 encephalopathy COG5-CDG Conserved oligomeric Golgi COG5 — Moderate mental subunit 5 retardation with cerebellar atrophy, hypotonia COG4-CDG Conserved oligomeric Golgi COG4 — Mild mental retardation, subunit 4 mild dysmorphia, epilepsy, recurrent respiratory infections, mild ataxia COG6-CDG Conserved oligomeric Golgi COG6 — Early fatality, severe subunit 6 neurological impairment, seizures, vomiting, intracranial bleeding, ATP6V0A2-CDG Golgi pH regulator ATP6V0A2 219200 Cutis laxa, wrinkly skin, connective tissue weakness, large fontanelle, variable mental retardation Continued

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Golgi Glycosylation and Human Inherited Diseases

Table 2. Continued Gene function Gene OMIM Clinical presentation Achondrogenesis type 1A Golgi structure GMAP210 200600 Soft skull bones, short ribs that fracture easily, extremely short limbs, and lack normal ossification in the spine and pelvis Gerodermia Golgi structure SCYL1BP1 231070 Wrinkley lax skin, Osteodysplastica osteoporosis, variable growth retardation Congenital ER-Golgi protein trafficking SEC23B 224100 Anemia, jaundice, dyserythropoietic splenomegaly, gall anemia (CDA II) bladder disease Cranio-lenticulo-sutural ER-Golgi protein trafficking SEC23A 607812 Facial dysmorphisms, dysplasia (CLSD) sutural cataracts and skeletal defects O-mannose disorders (dystroglycanopathy) Walker–Warburg O-mannosyltransferase POMT1, 268870 Death in infancy, severe syndrome POMT2 muscle weakness, diminished psychomotor development, abnormal neuronal migration ocular abnormalities Muscle–eye–brain O-mannosyl GlcNAc transferase POMGnT1 253280 Severe muscle weakness, disease (MEB) mental retardation, epilepsy, neuronal migration disorder, ocular abnormalities Fukuyama-type Putative glycosyltransferase Fukutin 253800 Severe proximal and axial congenital muscular weakness, mental dystrophy (FCMD) retardation, epilepsy and abnormal neuronal migration Congenital muscular Fukutin-related protein, a FKRP 606612 Hypotonia, impaired dystrophy type 1C putative glycosyltransferase motor development (MDC1C) with respiratory muscle weakness Congenital muscular Putative glycosyltransferase LARGE 608840 Muscular dystrophy with dystrophy type 1D severe mental (MDC1D) retardation

Glycophosphatidyl inositol disorders Autosomal Recessive GPI 1st mannosyltransferase in PIGM 610273 Venous thrombosis and Anchor Deficiency GPI biosynthesis seizures Hyperphosphatasia 2nd mannosyltransferase in PIGV 239300 Hyperphosphatasia, mental retardation GPI biosynthesis mental retardation, and (HPMR) syndrome distinct facial characteristics Continued

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H.H. Freeze and B.G. Ng

Table 2. Continued Gene function Gene OMIM Clinical presentation Glycosphingolipid disorders Amish infantile epilepsy Sia2,3Galb1,4Glc-Cer synthase SIAT9 609056 Neurological decline with (GM3) tonic-clonic seizures and arrested development Glycosaminoglycan synthesis disorders (O-xylose) Multiple hereditary Heparan sulfate copolymerase EXT1, 133701 Bony outgrowths exostoses EXT2 Ehlers–Danlos Xylosylprotein B4GALT7 604327 Connective tissue syndrome progeroid b-1,4-galactosyltransferase 130070 abnormalities with form loose skin, hypotonia and developmental delay Diastrophic dysplasia Anion (sulfate) transporter DTDST 600972 Premature calcification, achondrogenesis 606718 scoliosis, club foot Spondylo- 30-phosphoadenosine- ATPSK2 603005 Abnormal skeletal epimetaphyseal 50-phosphosulphate synthase development and linear dysplasia (PAPS) growth Spondylo- Chondroitin CHST3 143095 Normal intelligence, epimetaphyseal 6-O-sulfotransferase 608637 reduced adult height, dysplasia (Omani progressive type) kyphoscoliosis, joint dislocations, cardiac involvement, mild brachydactyly, camptodactyly, and microdontia Macular corneal GlcNAc-6-sulfotransferase CHST6 605294 Progressive corneal dystrophy opacity. Adducted N-acetylgalactosamine CHST14 601776 Congenital contractures of thumb-clubfoot 4-O-sulfotransferase 1 thumbs and feet with syndrome joint instability, facial clefting, coagulopathy, abnormal skin, heart, kidney, or intestinal defects Schneckenbecken UDP-GlcA / UDP-GalNAc Golgi SLC35D1 610804 Severely shortened long dysplasia transporter bones with bowing of limb bones and unossified vertebral bodies O-GalNAc disorders Familial tumoral GalNAc transferase GALNT3 211900 Large calcium deposits in calcinosis both skin and tissue Tn syndrome Chaperone of b1,3GalT COSMC 230430 Hematological abnormalities including anemia, leucopenia, thrombocytopaenia Continued

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Golgi Glycosylation and Human Inherited Diseases

Table 2. Continued Gene function Gene OMIM Clinical presentation O-fucose disorders Peters plus syndrome b-1,3 glucosyltransferase specific B3GALTL 261540 Mental retardation with for O-fucose on prenatal growth delay, thrombospondin type 1 short stature, repeats brachymorphism, short limbs, and eye abnormalities aData adapted from Jaeken et al. 2009.

which can arguably be called the first N- binding to modify glycan chain. Even simple glycosylation-specific disorder to be solved in mannose derivatives can serve as an acceptor 1981 (Reitman et al. 1981; Kollmann et al. for GlcNAc-1-P transferase reaction using this 2010). It was categorized as a “lysosomal storage enzyme, but with 1000-fold lower efficiency disorder” because cells accumulated inclusions (Lang et al. 1985). of undegraded material, but in contrast to most such disorders with single enzyme defi- TRANSPORTERS OF ACTIVATED DONORS ciencies, the patients’ cells lacked multiple lyso- somal enzymes. Instead, patients’ plasma or The activated nucleotide sugars made in the media from cultured cells accumulated multiple cytoplasm (or nucleus for CMP-sialic acid) mislocalized, lysosomal enzymes suggesting must be transported into the Golgi lumen to a shared deficiency in localization. Although glycosylate proteins and lipids. A series of lysosomal enzymes share little sequence homol- membrane embedded, non-energy-dependent ogy, they contain features that allow recognition transporters are antiporters that import the by an oligomeric protein complex that transfers nucleoside diphosphates and return the spent GlcNAc-1-P from UDP-GlcNAc to selected nucleoside monophosphates back to the cyto- mannose units on high mannose type glycans plasm (Liu et al. 2010). The transporters are on those enzymes (Kornfeld 1992). Subse- present from yeast to mammalian cells, and quently a specific a-N-acetylglucosaminidase, are mostly localized to the Golgi. They can be an “uncovering enzyme,” cleaves that phospho- highly substrate specific or show selectivity for diester bond to generate one or two terminal a limited series of substrates for multiple glyco- mannose-6-P residues, which are ligands for sylation pathways (Hiraoka et al. 2007; Caffaro Man-6-P receptors in the Golgi. This recogni- et al. 2008). tion marker allows for the delivery of the Congenital disorder of glycosylation-IIc is enzymes to the lysosome and the pH-depend- caused by mutations in the GDP-Fucose trans- ent dissociation of the receptor and its recycling porter. Patients have severe retardation and to the Golgi. Two receptors with different chronic infections. Some N- and O-glycans binding specificities can recognize the phos- were hypofucosylated, but loss of a fucosylated phorylated enzymes and with some preference glycan, sialyl LewisX, results in high levels of for their different protein ligands. I-cell disease circulating neutrophils even in the absence of results from mutations in the GlcNAc-1-P infections (Marquardt et al. 1999; Yakubenia phosphotransferase, not the “uncovering en- et al. 2008). This glycan is required for leukocyte zyme” (Kollmann et al. 2010). rolling prior to their extravasation into the tis- This is the best example of protein-specific sues. For some patients, supplementing their glycosylation that relies on structural features diet with fucose corrected this deficiency. It is of the protein acceptor to allow high-affinity likely that another fucose transporter exists,

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H.H. Freeze and B.G. Ng

but this has not been shown (Hellbusch et al. transferase (POMGNT1). Mutations in these 2007). It is possible that another known trans- genes decrease or eliminate enzyme activity. porter also uses GDP-fucose, but less efficiently Mutations in fukutin (FKTN) and fukutin (Liu et al. 2010). related protein (FKRP) also cause muscular A defect in the CMP-sialic acid transporter dystrophy. These proteins have features and sig- was reported in one patient who showed devel- natures of glycosyltransferases, but the specific opmental delay and giant megakaryocytes reactions and acceptor substrates are unknown. (Martinez-Duncker et al. 2005). Another protein called “Large” (because of its Schneckenbecken dysplasia is caused by size) has two glycosyltransferase domains, but, mutations in the dual substrate Golgi transporter again, the donor and acceptors are unknown for UDP-glucuronic acid and UDP-N-acetylga- (Barresi et al. 2004; Kanagawa et al. 2004). lactosamine that provides precursors for chon- Besides the glycosyltransferase homology, a droitin sulfate synthesis (see below) (Hiraoka key tool in grouping these disorders is a set of et al. 2007). Surprisingly, this protein appears to monoclonal antibodies that recognize an unde- be localized in the ER. Loss-of-function muta- fined O-mannose-based glycan (Martin 2007). tions cause severe skeletal dysplasia with very All of these disorders decrease the apparent short long bones (Hiraoka et al. 2007). molecular weight of aDG to the same extent and abolish antibody reactivity. An important insight into the glycan O-MANNOSE PATHWAY structure and, therefore, genes and possible bio- For years, clinicians characterized mutations synthetic enzymes was that LARGE-dependent that cause Duchenne and Becker muscular dys- antibody-reactive glycans contain Man-6-P in trophies. They also identified a set of rare mus- a diester linkage to an unknown molecule. In cular dystrophies with variable clinical severity the absence of LARGE-dependent modification that often involved neurological abnormalities of the glycan, Man-6-P exists as a monoester and eye defects, while other patients were neu- (Yoshida-Moriguchi et al. 2010). Why is this rologically normal (Jimenez-Mallebrera et al. significant? Addition of Man-6-P to aDG 2005; Muntoni et al. 2008; Chandrasekharan does not use the lysosomal enzyme pathway and Martin 2010). This broad spectrum of dis- that employs high-mannose type glycan accep- orders is caused by defects in a recently appreci- tors. Here Mannose-O-Thr/Ser glycans are the ated glycosylation pathway that is primarily acceptors. This glycan can be further extended focused on a-dystroglycan (aDG), a peripheral with GalNAc or with Gal and Sia (Yoshida- membrane component of the dystrophin–gly- Moriguchi et al. 2010). The latter can also be coprotein complex (DGC) located in muscle, branched. O-mannose glycans account for nerve, heart, and brain. Relatively little work one-third of all O-linked species in the brain has been performed in studying the Golgi in (Yuen et al. 1997), but the majority is probably muscular dystrophies, but see review by Percival on other proteinsbecausebrain-specificablation and Froehner (2007). of aDG has little effect on the amount of these The severe muscular dystrophies including glycans. One study suggests that LARGE may muscle–eye–brain (MEB) disease, Fukuyama- act on the O-mannose, complex N-glycans, type congenital muscular dystrophy (FCMD), and mucin O-GalNAc glycans of aDG (Aguilan Walker–Warburg syndrome, and limb–girdle et al. 2009), so the story may be more complex. muscular dystrophy, (Table 2). These mutations also appear to affect neuronal migration in the O-XYL PATHWAY: developing brain, thus accounting for the com- GLYCOSAMINOGLYCANS bined effects on muscle and brain development. The first sugar, Mannose-a-Ser/Thr, is added Xylb-serine-linked glycans on selected pro- in the ER by POMT1/POMT2 complex and it teins produce glycosaminoglycans (GAG) is elongated in the Golgi by a b1,2 GlcNAc that share a common core tetrasaccharide

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Golgi Glycosylation and Human Inherited Diseases

GlcAb1,3Galb1,3Galb1,4Xylb. These linkage Disorders in Chain Elongation—Hereditary glycans are elongated into either chondrotin- Multiple Exostosis and dermatan-sulfate composed of alternating (GalNAcb1,4GlcAb1,3) disaccharides or into The most common and well-studied GAG- heparan sulfate and heparin with alternating related disorder is hereditary multiple exo- (GlcNAca1,4GlcAb1,4). Both polymers are stosis (HME), caused by mutations in the variably sulfated and glucuronic acid (GlcA) synthetic machinery used for heparan sulfate units are epimerized to iduronic acid (HS). It is one of the few autosomal dominant (IdU). The polymerization and modification diseases and has a prevalence of about occurs exclusively in the Golgi. Disorders in 1:50,000 (Schmale et al. 1994). More specifi- these pathways often cause skeletal- and cally, HME is caused by missense or frameshift chondrodysplasias. mutations in either gene EXT1 or EXT2 that encode HS polymerases (Zak et al. 2002). HME patients develop bony outgrowths at Substrate Limitation the growth plates of the long bones. Normally Sulfate ions must be imported into the cell the growth plates contain well-ordered chon- because sulfate is not salvaged from degraded drocytes in various stages of development, glycans. Several allelic clinical chondrodys- embedded in a collagen-chondroitin sulfate plasias (diastrophic dysplasia, achondrogenesis containing matrix (Zak et al. 2002). In HME type IB, neonatal osseous dysplasia I, and auto- patients, the outgrowths are composed of disor- somal recessive multiple epiphyseal dysplasia), ganized chondrocytes that must be surgically result from defective sulfation because of muta- removed. These patients are at higher risk to tions in the sulfate ion transporter, encoded by develop osteosarcomas (Schmale et al. 1994) DTDST (also known as SLC26A2) (Dawson and and some are diagnosed on the autistic spec- Markovich 2005). In spondyloepimetaphyseal trum (Li et al. 2002). dysplasia (SEMD), mutations occur in gene is EXT1 and EXT2 appear to form a protein ATPSK2, encoding the 30-phosphoadenosine complex in the Golgi. Partial loss of one allele 50-phosphosulfate (PAPS) synthase (Sugahara of either gene appears sufficient to cause and Schwartz 1979), the activated donor sub- MHE, which is unusual because most glycan strate for sulfation. A mouse model of this dis- biosynthetic enzymes are produced in excess. ease shows reduced limb length and axial Loss of HS synthesis, and the concurrent skeletal size. In SEMD, there is progressive decrease in tissue HS, probably leads to an reduction in the size of the columnar and hyper- abnormal distribution of HS-binding growth trophic zones in the epiphyseal growth plates (ul factors. These include several members of the Haque et al. 1998). FGF family, and morphogens, such as hedgehog (Hh), decapentaplegic (Dpp), and wingless (Wg) (Esko and Selleck 2002). In Drosophila, Disorders in Chain Initiation loss of HS disrupts Hh, Wg, and Dpp pathways Mutations in B4GALT7 cause the progeria var- (Bornemann et al. 2004). Embryonic lethality iant of Ehlers–Danlos syndrome. The gene and failure to gastrulate occur in mice that are product (b1,4-Galactosyltransferase) (Okajima null for either Ext gene (Lin et al. 2000; Stickens et al. 1999) adds the first Gal residue to xylose et al. 2005). However, Ext2 heterozygous ani- to the linkage region of GAG chains (Lindahl mals are viable. These develop a single visible 1966) and only a few patients have been exostosis on the ribs in about a third of the lit- described (Quentin et al. 1990; Okajima et al. ters (Stickens et al. 2005). Hh signaling in these 1999; Faiyaz-Ul-Haque et al. 2004; Gotte and animals is normal because no difference was Kresse 2005). A dermatan sulfate proteoglycan detected in the protein distribution based on from one patient’s fibroblasts contained only immunohistochemistry, thus not explaining xylose (Quentin et al. 1990). the phenotype. Ext1 heterozygotes also develop

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H.H. Freeze and B.G. Ng

exostoses, but the penetrance is strain-depend- (Kozma et al. 2006; Sato et al. 2006). Later, ent, also seen within different families who Hess et. al. determined that B3GALTL was carry the same mutations, suggesting a pro- involved in the addition of a glucose to O-linked found modifier gene effect. fucose to form glucose-b1,3-fucose disaccha- Macular corneal dystrophy is caused by a ride associated specifically with thrombospon- deficiency in a tissue-specific sulfotransferase din type-1 repeats (Hess et al. 2008). (CHST6), corneal N-acetylglucosamine-6-sul- Thrombospondin type-1 repeats (TSRs) are fotransferase (GlcNAc6ST), which is responsi- a class of protein motifs similar to epidermal ble for the production of corneal keratan growth factor-like (EGF) repeats and are com- sulphate (Akama et al. 2000). Unsulfated kera- prised of a cysteine rich domain 40–60 amino tan chains are poorly soluble and their eventual acids involved in several biological processes precipitation disrupts the collagen network, such as proper coagulation, cell migration, neu- leading to thinning and loss of transparency of rogenesis, and angiogenesis (Tucker 2004). the corneal stroma. Although TSRs are structurally and function- Mutations in another sulfotransferase gene ally similar to EGF repeats, separate and distinct (CHST14) are responsible for the addition of enzymes carry out the modification. Addition 4-O-sulfate to GalNAc residues in dermatan of fucose to an EGF repeats, as in the case of sulfate (DS) (Dundar et al. 2009). Its loss causes NOTCH, is performed solely by protein O-fuco- facial dysmorphism, adducted thumbs, clubbed syltransferase1 (POFUT1).Whereasfucose mod- feet, joint instability, short stature, and coagu- ification of TSR is only performed by protein lopathy. Several patients died of respiratory O-fucosyltransferase 2 (POFUT2) and further insufficiency. Patient fibroblasts were missing extended by B3GALTL to yield a unique disac- highly flexible DS chains, but had an overabun- charide glucose-b1,3-fucose (Luo et al. 2006). dance of less flexible chondroitin sulfate (CS), It is suggested that O-fucosylation of TSR- which likely affected collagen bundle formation containing proteins regulates the proper folding or maintenance. The first biosynthetic step of of secreted proteins and dysfunction would lead converting CS to DS is the epimerization of glu- to accumulation of misfolded proteins and curonic acid in CS to iduronic acid, and it is diminished secretion (Ricketts et al. 2007). Anal- easily reversible. The sulfotransferase appears ysis of several TSRs containing proteins from to “lock in” the commitment toward DS synthe- Peters plus patients revealed a complete lack of sis, but without it, reverse epimerization regen- O-fucosylation,supporting Petersplussyndrome erates CS (Miyake et al. 2010). This discovery as a glycosylation disorder (Hess et al. 2008). stresses the importance of dermatan sulfate in human development and matrix maintenance. O-GALNAC DISORDERS Familial tumoral calcinosis (FTC) is an auto- O-FUCOSE DISORDERS somal recessive disorder characterized by Mutations in the b1,3-glucosyltransferase, painfully large calcium deposits, hyperphos- B3GALTL, result in the autosomal recessive dis- phatemia, and debilitating secondary side order Peters plus syndrome that is characterized affects such as recurrent infection. Genome by developmental delay, short stature, craniofa- wide marker analysis of two large unrelated cial defects and most frequently by anterior eye- families helped to identify the glycosyltransfer- chamber abnormalities (Lesnik Oberstein et al. ase, GALNT3, as the causative gene mutated in 2006). When the genetic defect for Peters plus FTC (Topaz et al. 2004). syndrome was identified, the precise function GALNT3 belongs to a large family of UDP- for B3GALTL was unknown. Based on protein GalNAc transferase localized to the cis-Golgi sequence homology the protein was hypothe- and catalyzes the transfer of N-acetylgalactos- sized to be a galactosyltransferase, but shown amine to a serine or threonine residue allowing experimentally to be a glucosyltransferase for the initiation of mucin O-glycosylation.

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Golgi Glycosylation and Human Inherited Diseases

Although there are several genes with high GM3 precursors and lacked downstream GM3- sequence homology, it appears GALNT3 pos- dependent products. Interestingly, GM3 syn- sesses a unique acceptor substrate specificity thase null mice do not duplicate the human not seen in other family members which can disorder because of an alternative biosynthetic clearly be seen in its ability to glycosylate both pathway (Yamashita et al. 2003). fibronectin and HIV gp120 (Matsuura et al. 1988; Bennett et al. 1999). GLYCOSYLPHOSPHATIDYLINOSITOL Mutations in the O-glycosylated protein, ANCHOR DISORDERS Fibroblast growth factor 23 (FGF23), result in another form of FTC. Two separate groups Inherited GPI deficiency (IGD) is characterized identified cases in which GALNT3 was normal, byvenousthrombosis inadditiontoseizuresand but potential O-glycosylated serine residues is caused by a mutation in the mannosytransfer- in FGF23 were mutated. They subsequently ase PIGM that is required for the addition of the showed that mutagenesis of either serine resi- first mannose to the core glycosylphosphatidyl- due dramatically impaired O-glycosylation inositol (GPI) (Maeda et al. 2001). In two unre- and for the first time proved certain mutations lated consanguineous families, Almeida and in FGF23 resulted in FTC (Larsson et al. 2005; colleagues identified a shared promoter muta- Bergwitz et al. 2009). tion in a key SP1 transcription factor binding Another O-GalNAc deficiency is the rare site that dramatically reduced the expression of autoimmune disease, Tn syndrome. It is caused PIGM leading toadefectin GPIanchor synthesis by somatic mutations in the X-linked gene, (Almeida et al. 2006). COSMC and is characterized by various hema- In a follow-up paper involving the same tological abnormalities (Crew et al. 2008). patients, Almeida and colleagues showed COSMC is a chaperone for b1,3 galactosyl- patient lymphoblast treated with sodium transferase and is necessary for the formation butyrate completely restored normal PIGM of the glyco-structure, T-antigen (Ju and transcript level as well as cell surface GPI expres- Cummings 2002). T-antigen is an O-linked sion. More importantly, treating the patient Galb1,3GalNAc that acts as a precursor for with sodium phenylbutyrate, a histone deacety- most mucin O-glycans and can be further lase inhibitor, resulted in a dramatic improve- extended into several other structures. Muta- ment after only two weeks, as measured by a tions in COSMC result in the formation of a lack of seizure activity and improved motor truncated structure known as Tn Antigen that skills (Almeida et al. 2007). is simply an O-linked linked GalNAc (Ju and Mutations in PIGV that encode the second Cummings 2005; Ju et al. 2008). mannosyltransferase of GPI anchors cause hyperphosphatasia mental retardation syn- drome (a.k.a. Mabry syndrome, OMIM GLYCOSPHINGOLIPID DISORDERS 239300, Rasmussen 1975; Krawitz et al. 2010). Autosomal recessive Amish infantile epilepsy is Patients with these mutations have greatly associated with developmental delay, seizures, increased plasma alkaline phosphatase, a GPI- and blindness. Linkage analysis of a large Amish anchored protein, along with unusual facial family identified a nonsense mutation in SIAT9 features, variable seizures, and muscular hypo- resulting in a stop codon and consequently tonia (Horn et al. 2010). Surface expression of truncated protein (Simpson et al. 2004). SIAT9 GPI-anchors themselves and anchored proteins is a sialyltransferase that makes ganglioside were reduced in patients’ leukocytes. PIGV- GM3 (Siaa2,3Galb1,4Glc-ceramide) from lac- deficient CHO cells can be complemented tosylceraminde (Galb1,4Glc-ceramide). Hence, with wild-type human allele, but not with the it is not surprising that patients with the mutant. truncated SIAT9 showed accumulation of non- Somatic mutations in PIGA limit the first sialylated plasma glycosphingolipids, and of step of GPI synthesis resulting in partial or

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H.H. Freeze and B.G. Ng

complete loss of GPI-linked membrane pro- alteration and identifies a mechanism. Serum teins and are the underlying cause of Paroxys- proteins (hepatocyte and plasma cell-derived) mal nocturnal hemoglobinuria (PNH), an are convenient markers, but they may not always acquired hematopoietic disorder characterized indicate defective glycosylation. Impairments by unusual blood cell populations and intravas- may only appear in selected tissues where the cular hemolysis (Takeda et al. 1993). “glycosylation demand” is high.

FACTORY ORGANIZATION, SHIPPING, COGs AND GLYCOSYLATION AND RECEIVING Conserved oligomeric Golgi (COG) complex is It is not surprising that mutations in the glyco- composed of eight individual subunits, COG1– sylation hardware disrupt patients’ glycosyla- 8. Mutations are known for six subunits, mak- tion pathways. Some enzymes in glycosylation ing it the best known of the trafficking defects pathways form complexes in the Golgi (Opat (Ungar 2009). The complex exists in two lobes et al. 2000; Pinhal et al. 2001; Sprong et al. or subcomplexes. Lobe A (COG1–4) and 2003; Young 2004; Maccioni 2007; Hassinen Lobe B (COG 5–8) are bridged by a COG1/ et al. 2010), which presumably increases effi- COG8 heterodimer that links the different ciency of substrate modification. However, lobes. COG1 and COG2 were identified as the mutations in genes that disrupt Golgi organiza- defective genes in ldlB and ldlC mutant CHO tion, structure, and trafficking of either cargo or lines, respectively, that were defective in the sur- resident proteins also cause disorders that affect face localization of the LDL receptor. These lines glycosylation. Perhaps this should be expected had incomplete N- and O-linked glycans and because drugs that alter Golgi integrity and abnormal Golgi architecture. The COG com- protein trafficking also alter glycosylation. plex localizes to the cis- and medial Golgi and Therefore, altered glycosylation may be a surro- is found at the tips and along the rims of the cis- gate indicator of the functional importance of a ternae and on vesicles, making it a likely tether- Golgi-related protein. Many disease-causing ing factor (Vasile et al. 2006). See Figure 1. mutations in specific proteins (Howell et al. The COG complex is found from yeast to 2006) cause protein misfolding, retention in mammalsandinteractswithothertrafficking the ER, and proteasomal degradation. Examples proteins. For instance, COG3 coprecipitates include, a1-antitrypsin deficiency, autosomal with b-COPI and in yeast, COG2 interacts with dominant polycystic kidney disease, cystic fi- gCOPI. When COG3 is depleted using siRNA brosis,Charcot-Marie-Toothdisease,congenital knockdown, vesicles containing glycosylation sucrase-isomaltase deficiency, Fabry’s disease, enzymes, GPP130 (cis-Golgi) and the SNAREs familial hypercholesterolemia, and osterogene- GS15 and GS28 accumulate. COGs appear to be sis imperfecta (Vogt et al. 2005; Howell et al. important for retrograde trafficking because 2006). An unusually high proportion (1.4%) COG depletion cannot move cell surface bound of such mutations in proteins traveling the bacterial toxins (e.g., Shiga and AB) through the ER/Golgi circuit actually create inappropriate Golgi to the ER (Smith et al. 2009). N-glycosylation sites. Some of these are patho- SM (SEC1/MUNC18) protein, Sly1, inter- logical. Their delivery to the membrane is nor- acts directly with (COG4) which also inter- mal (Vogt et al. 2005; Vogt et al. 2007), but the acts with Syntaxin5 using different binding presence of the glycan actually impairs function. sites. Blocking COG4-Sly1 interaction impairs Alternatively, the mutations may prevent the pairing of SNAREs involved in intra-Golgi assembly into multisubunit complexes such as transport thereby markedly attenuating Golgi- in the case of fibrillin1 in Marfan’s syndrome to-ER retrograde transport (Laufman et al. (Raghunath et al. 1995; Lonnqvist et al. 1996). 2009). The interaction between p115 and It is more challenging to find the appropri- COG2 is essential for Golgi ribbon reformation ate cell/tissue or specific protein that shows the after the disruption of the ribbon by p115

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Golgi Glycosylation and Human Inherited Diseases

Plasma membrane Golgi glycosylation proteins Trans Medial

Cis 3 2 1 6 4 8 5 7

3 2 1 6 ER 4 8 5 7 COG-dependent vesicles 3 2 1 3 4 6 2 1 6 8 5 3 4 8 5 7 2 1 7 4 8 5 6 7

3 2 1 6 4 8 5 7

Figure 1. Role of the conserved oligomeric Golgi (COG) complex in Golgi localized retrograde transport. In focus is how the COG complex transports various mislocalized Golgi glycosylation proteins back to their proper destinations and then returns after redirecting the vesicles.

siRNA knockdown or brefeldin A treatment et al. 2007). One patient with a different splice (Sohda et al. 2007). site mutation had no dysmorphic features and In a broad screen of Rab binding factors prolonged survival (Zeevaert et al. 2009a). A mammalian COG6 bound to GTP-restricted COG1-deficient patient was identified with Rab1, Rab6, and Rab41 and COG4 preferen- generalized hypotonia, but with normal tially interacts with Rab30-GTP (Fukuda et al. strength, failure to thrive, small hands and 2008). feet, and short stature (Foulquier et al. 2006) The first sib patients with a COG-based Cerebellar and cerebral abnormalities were trafficking disorder showed defective N- and milder than in COG7 patients. The mutation O-glycosylation caused by splice mutations in eliminated the carboxy-terminal 80 amino COG7 (Wu et al. 2004). The patients had peri- acids. Two other COG1-deficient patients were natal asphyxia, feeding problems, growth retar- found with costovertebral dysplasia in cerebro- dation, hypotonia, enlarged cholestatic liver, costomandibular syndrome (CCMS) and in epileptic seizures, cerebral atrophy, and severely cerebrofaciothoracic dysplasia and spondylo- shortened limbs with absence of long bone epi- costal dysostosis (Zeevaert et al. 2009b). pheses. Another curious feature was an accumu- Two patients were identified with COG8 lation of excessive, wrinkled, doughy-like skin. mutations. One with a truncating mutation Both patients died of infections and cardiac that eliminated 76-carboxy-terminal amino insufficiency. Six additional COG7-deficient acids had a normal neonatal and infancy, but patients with this mutation showed similar later developed mental retardation and ataxia severe phenotypes (Morava et al. 2007; Ng from cerebellar atrophy/hypoplasia (Foulquier

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H.H. Freeze and B.G. Ng

et al. 2007). The other patient had a splice site Little is known about how the COG com- mutation and a deletion that truncated the pro- plex maintains proper glycosylation, homeosta- tein (Kranz et al. 2007). This patient is severely sis, and structural integrity of the Golgi. Recent retarded and has a near absence of muscle that analysis suggests that the amino-terminal por- resembles malnutrition, but no dysmorphic tion of Cogs1–4 are required for assembly of a features. COG5-deficient patient had a splicing core complex, whereas the carboxy-terminal mutation that caused exon skipping and severe domains form “elongated legs” that interact reduced expression of the COG5 protein, but with other glycosylation related proteins. with mild psychomotor retardation, delayed Carboxy-terminal domain of COG1 is required motor and language development (Paesold- for interaction with the COG 5–8 subunit Burda et al. 2009). complex (Lees et al. 2010). Another study shows COG4 deficiency (Reynders et al. 2009; that small interfering RNA knockdown of lobe Richardson et al. 2009) in one patient with a A (Cogs1–4) subunits alter Golgi structure, missense mutation and small deletion caused whereas loss of Lobe B (Cogs 5–8) subunits only mild phenotype. Its loss decreased the decreased stability of both B4GALT1 and expression or stability of the other Lobe A sub- ST6GAL1 (Peanne et al. 2010) used for serum units, but stability of the complex was still seen glycoprotein synthesis. COG patients show defi- in the cytoplasm at lower levels. Another patient ciencies in both galactosylation and sialylation. with a COG4 defect had a fatal outcome (Ng Other genetic disorders will likely arise from et al. 2011). A patient has also been identified defects in proteins that directly interact with the with lethal mutations in COG6 that caused COG complex. neurologic disease, seizures, and intracranial bleeding (Lubbehusen et al. 2010). VACUOLAR ATPase Fibroblasts from all COG patients show a three to fourfold slower rate of brefeldin A– Autosomal recessive cutis laxa (ARCL) is asso- induced Golgi dissociation, while postwashout ciated with a progeroid appearance, lax and Golgi reassembly is normal. This is consistent wrinkled skin, osteopenia, and mental retarda- with COG’s role in retrograde transport from tion (Morava et al. 2008). One of the major Golgi to ER. In all cases except COG4, expres- diagnostic criteria is abnormal elastin fibers sion of the normal allele in patients’ cells (Morava et al. 2009), but the genetic deficiencies normalizes BFA response (Foulquier 2009; of many cutis laxa patients were unknown. Reynders et al. 2009). Mutations in ATP6V0A2, the a2 subunit of the The very broad spectrum of clinical presen- vacuolar Hþ-ATPase (V-ATPase) were shown tations among COG patients may seem puz- to affect N- and O-glycosylation and alter Golgi zling, and although it may be lumped into the trafficking as determined by BFA treatment “genetic background” explanation, other issues (Guillard et al. 2009; Kornak et al. 2008). Cells may cloud predictions or interpretations. As from patients had distended Golgi cisternae with most glycoyslation disorders, the mutated with accumulation of abnormal lysosomes alleles are hypomorphic, not null. Also, patient and multivesicular bodies. Tropoelastin (TE) fibroblasts are convenient, but probably not accumulated in the Golgi and in large, abnor- reflective of the pathology in other cells or mal intracellular and extracellular aggregates. tissues. This is especially important because siRNA knockdown of ATP6V0A2 showed COG mutations frequently involve splice sites similar phenotype. The delayed secretion and that can show variable penetrance. Finally, increased intracellular retention of TE in the understanding of COG cell biology is in an early Golgi and reduced extracellular deposition of stage, and it is clear that COGs function in mature elastin increased apoptosis of elasto- intra-Golgi as well as Golgi to ER transport, genic cells (Hucthagowder et al. 2009). It is but it is not known if all the components are likely that the vacuolar ATPase maintains required for each role. correct pH in lysosomes, synaptic vesicles,

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Golgi Glycosylation and Human Inherited Diseases

endosomes, secretory granules, and the Golgi proteins such as type II collagen and aggrecan apparatus (Saroussi and Nelson 2009). Another were correctly localized, but perlecan, a large candidate disease gene could be the Golgi pH heparan sulfate proteoglycan accumulated in regulator (GPHR) that shows a voltage-depend- the ER. This argued that GMAP210 deficiency ent anion-channel activity and alters glycosyla- caused a selective protein trafficking defect in tion (Maeda et al. 2008). a tissue that carried a heavy demand for glyco- sylation of proteoglycans. Early death seemed to result from lung compression caused by an GOLGINS underdeveloped skeleton rather than a defect Golgins bind to the cytoplasmic side of cis- and in the primary cilium assembly and localiza- trans-Golgi and can act as tethers using their tion. There is evidence that golgins can play a coiled coil domains that project from the cister- specific role in cargo protein selection (Drin nae as long thin fibers (Ramirez and Lowe 2009; et al. 2008; Ungar 2009). This example is impor- Sztul and Lupashin 2009; Goud and Gleeson tant because it points out the difficulty of pre- 2010). They interact with small GTPases, and dicting which proteins, organ systems, or time some bind to the cytoskeletal elements. Golgin frames will be affected by mutations in Golgi GMAP210 recruits g tubulin complexes to trafficking proteins. form Golgi ribbons and also interacts with Gerodermia osteodysplastica is a genetic Arf1 (Drin et al. 2008; Cardenas et al. 2009). disorder that causes premature wrinkly skin GMAP210 binds to highly curved membranes and osteoporosis, defining it as a progeroid dis- and is thought to tether tubules or vesicles to order (Al-Gazali et al. 2001). Mapping studies the cis-Golgi (Drin et al. 2008). Overepression localized the defect to SCYL1BP1 loss-of- induces Golgi fragmentation and disturbs ER function mutations. The protein is highly ex- to Golgi trafficking (Ramirez and Lowe 2009). pressed in those locations and it increases It is widely expressed and may be redundant during osteoblast differentiation (Hennies et al. because deficient mouse embryos have a normal 2008). Immunofluorescence localized it to the Golgi. This protein anchors the cilia component Golgi, and yeast two-hybrid pull down showed of IFT20 to the Golgi and these cells from the it interacted with RAB6, in its GTP-activated mutants have shorter primary cilia, suggesting state. The protein contained coiled coil do- that it plays some role in the sorting of mem- mains, localized to the Golgi, and bound brane components to the cilia (Follit et al. RAB6, identifying it as a golgin. These results 2008). This conclusion matched the known reinforce the relation of the secretory pathway data, but did not explain why GMAP210-defi- in selected tissues with age-related changes in cient mice died soon after birth, apparently of connective tissues (Hennies et al. 2008). Addi- heart and complex lung defects (Follit et al. tional patients had similar phenotypes and 2009). The answer emerged from a forward mutations in this gene, but transferrin glycosy- genetic screen focused on determining the lation was normal (Al-Dosari and Alkuraya genes responsible for neonatal lethal skeletal 2009). As seen with GMAP210 mutations that defects in mice (Smits et al. 2010). The target cause achondrogenesis type Ia, the effects on gene Trip11 encoded GMAP210 and the mouse glycosylation may be protein selective and tissue phenotype resembled that of a human disorder specific. achondrogenesis type Ia (Smits et al. 2010). Subsequent analysis of patients showed muta- SEC PROTEINS tions in TRIP11. The phenotype could not have been predicted from the cell biology, espe- Another example showing unpredictable func- cially because GMAP210 is widely expressed. tional consequences is also seen in two disor- Chondrocytes from mutant mice show im- ders caused by mutations in the family of paired differentiation, distended ER, and al- COPII coat protein complexes, SEC23A and tered glycosylation. Many of the large matrix SEC23B (Lang et al. 2006; Bianchi et al. 2009).

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H.H. Freeze and B.G. Ng

Mutations in SEC23A cause the cranio-lentic- suggesting the presence of a subclinical haplo- ulo-sutural dysplasia syndrome and affect facial insufficiency (Zdebska et al. 2002). development (Boyadjiev et al. 2006). In zebra- fish, positional cloning mapped the defect of a LIPID HOMEOSTASIS AND TRAFFICKING malformed craniofacial skeleton, kinked pec- toral fins and a short body length to the homo- Lipid and glycolipid trafficking also involve the log of sec23b. The mutant fish also showed Golgi together with other compartments in the accumulation of ECM components including cell (Lev 2006; Chandran and Machamer 2008; type II collagen in the ER (Lang et al. 2006). van Meer et al. 2008). Recent proposed explan- Mice mutated in the transcription factor ations for the organization, dynamics, and flux BBF2H7 that activates Sec23A transcription of both proteins and lipids through the Golgi have a similar phenotype to GMAP210-defi- are based primarily on their physical properties, cient mice including abnormal chondrogenesis and sites of synthesis/depletion to construct and accumulation of collagen II and cartilage membranes of different compositions, dimen- oligomeric matrix protein in the ER. Introduc- sions, and curvatures (Lippincott-Schwartz tion of Sec23A into chondrocytes normalized and Phair 2010). Lipid and protein sorting are the secretion of matrix components (Stagg interwoven and interdependent in this attrac- et al. 2008; Saito et al. 2009). tive, but unproven model (Emr et al. 2009; The mutant form of SEC23A poorly recruits Gong et al. 2010). However, it provides a setting the SEC13-SEC31 complex, inhibiting vesicle to discuss the possibility that altered glycosyla- formation. Surprisingly, this effect is modulated tion may be a useful marker or play a role in by the SAR1 GTPase paralog used in the reac- pathophysiology of the disorders. These include tion, indicating distinct affinities of the two various disorders of cholesterol trafficking human SAR1 paralogs for the SEC13–SEC31 such as Niemann–Pick type C (Urano et al. complex. Patient cells accumulate numerous 2008; Lloyd-Evans and Platt 2010). Defects in tubular cargo-containing ER exit sites devoid this protein of still unknown function also affect of observable membrane coat, likely represent- the esterification of dolichol (Turunen and ing an intermediate step in COPII vesicle for- Schedin-Weiss 2007) and glycosylation of ApoE mation (Fromme et al. 2007). in mouse models (Chua et al. 2010). Surpris- In contrast, SEC23B mutations cause a ingly, study of lipid storage and trafficking completely different glycosylation disorder models in Drosophila, shows that cholesterol called congenital dyserythropoietic anemia or storage alters the trafficking of a glycolipid HEMPAS (Schwarz et al. 2009). These patients from the biosynthetic to the degradative endo- have poor erythropoiesis generating bi- and lysosomal pathway and cholesterol depletion multinucleated erythroblasts in bone marrow, eliminates glycolipid recycling. Lactosyl cera- suggesting abnormal cytokinesis (Denecke and mide diverts a neutral cargo (dextran) away Marquardt 2009). In peripheral red blood cells, from the lysosome (Hortsch et al. 2010). proteins and glycolipids are incompletely gly- cosylated (Fukuda 1990). This leads to a pro- PERSPECTIVES AND CONCLUSIONS gressive splenomegaly, gallstones, and iron overload potentially with liver cirrhosis or car- Current and emerging gene sequencing tech- diac failure. Knockdown of SEC23B via shRNA nology as well as falling costs (Ng et al. 2009; mimics the defective cytokinesis, and zebrafish Horn et al. 2010; Roach et al. 2010) will reveal morphants have abnormal enrythrocyte devel- new inherited disorders in the near future. opment (Bianchi et al. 2009; Schwarz et al. The examples in this article show that 2009). Surprisinglyanalysis of one family showed Golgi-associated disorders that affect glycosyla- that heterozygous parents had detectable abnor- tion will be well represented. Protein homology malities in erythrocyte membrane glycans, but predictions may not produce accurate predic- a healthy child was completely normal, thus tions of patients’ phenotypes (e.g., compare

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SEC23A and SEC23B or PIGM vs. PIGV). caused by distinct mutations in a new sulphotransferase Forward genetic screens in model organisms gene. Nat Genet 26: 237–241. (GMAP210 causing lethal achondrogensis) Al-Dosari M, Alkuraya FS. 2009. A novel missense mutation in SCYL1BP1 produces geroderma osteodysplastica phe- may help identify interacting pathways and pro- notype indistinguishable from that caused by nullimor- tein binding partners. Some of the defective phic mutations. Am J Med Genet A 149A: 2093–2098. genes will be familiar, others will have unknown Al-Gazali LI, Sztriha L, Skaff F, Haas D. 2001. Gerodermia functions or be poorly annotated making their osteodysplastica and wrinkly skin syndrome: Are they the same? Am J Med Genet 101: 213–220. physiological function difficult to unravel. In Almeida AM, Murakami Y, Layton DM, Hillmen P, Sellick some cases, biochemical confirmation of altered GS, Maeda Y, Richards S, Patterson S, Kotsianidis I, glycosylation can be a quality control indicator Mollica L, et al. 2006. Hypomorphic promoter mutation that implicates the Golgi in the physiological in PIGM causes inherited glycosylphosphatidylinositol functions of defective genes (Nilsson et al. deficiency. Nat Med 12: 846–851. Almeida AM, Murakami Y, Baker A, Maeda Y, Roberts IA, 2009). Genetic defects commonly associated Kinoshita T, Layton DM, Karadimitris A. 2007. Targeted with various medical specialties will require therapy for inherited GPI deficiency. N Engl J Med 356: increased interaction and cooperation with 1641–1647. basic cell biologists and biochemists to explain Barresi R, Michele DE, Kanagawa M, Harper HA, Dovico SA, Satz JS, Moore SA, Zhang W,Schachter H, Dumanski and translate these genetic errors into physiol- JP, et al. 2004. LARGE can functionally bypass a-dystro- ogy and potential treatments. glycan glycosylation defects in distinct congenital muscu- lar dystrophies. Nat Med 10: 696–703. Bennett EP, Hassan H, Mandel U, Hollingsworth MA, Aki- SUMMARY sawa N, Ikematsu Y,Merkx G, van Kessel AG, Olofsson S, Clausen H. 1999. Cloning and characterization of a close The Golgi apparatus sorts, organizes, and homologue of human UDP-N-acetyl-a-D-galactosa- traffics intracellular protein and lipid cargos. It mine:polypeptide N-acetylgalactosaminyltransferase-T3, glycosylates cargo and maintains factory organ- designated GalNAc-T6. Evidence for genetic but not functional redundancy. J Biol Chem 274: 25362–25370. ization for efficient pickups and deliveries Bergwitz C, Banerjee S, Abu-Zahra H, Kaji H, Miyauchi A, between the ER and final destinations (plasma Sugimoto T, Juppner H. 2009. Defective O-glycosylation membrane or endocytic organelles). Impaired due to a novel homozygous S129P mutation is associated performance by mutated Golgi resident pro- with lack of fibroblast growth factor 23 secretion and teins creates severe and highly variable pa- tumoral calcinosis. J Clin Endocrinol Metab 94: 4267– 4274. thologies. Emerging developments in patients’ Bianchi P, Fermo E, Vercellati C, Boschetti C, Barcellini W, genetic analysis should identify new Golgi com- Iurlo A, Marcello AP, Righetti PG, Zanella A. 2009. ponents/processes, in which glycosylation is a Congenital dyserythropoietic anemia type II (CDAII) is good indicator of Golgi and the patients’ health caused by mutations in the SEC23B gene. Hum Mutat 30: 1292–1298. or pathology. Bonnon C, Wendeler MW, Paccaud JP, Hauri HP. 2010. Selective export of human GPI-anchored proteins from the endoplasmic reticulum. J Cell Sci 123: 1705–1715. ACKNOWLEDGMENTS Bornemann DJ, Duncan JE, Staatz W, Selleck S, Warrior R. The authors are supported by grant no. 2004. Abrogation of heparan sulfate synthesis in Droso- phila disrupts the Wingless, Hedgehog and Decapenta- R01DK55615, The Rocket Williams Fund, and plegic signaling pathways. Development 131: 1927–1938. the Sanford Children’s Health Research Center. Boyadjiev SA, Fromme JC, Ben J, Chong SS, Nauta C, Hur H.H.F. is a Sanford Professor. DJ, Zhang G, Hamamoto S, Schekman R, Ravazzola M, et al. 2006. Cranio-lenticulo-sutural dysplasia is caused by a SEC23A mutation leading to abnormal endo- REFERENCES plasmic-reticulum-to-Golgi trafficking. Nat Genet 38: 1192–1197. Aguilan JT, Sundaram S, Nieves E, Stanley P. 2009. Muta- Caffaro CE, Luhn K, Bakker H, Vestweber D, Samuelson J, tional and functional analysis of Large in a novel CHO Berninsone P, Hirschberg CB. 2008. A single Caenor- glycosylation mutant. Glycobiology 19: 971–986. habditis elegans Golgi apparatus-type transporter of Akama TO, Nishida K, Nakayama J, Watanabe H, Ozaki K, UDP-glucose, UDP-galactose, UDP-N-acetylglucos- Nakamura T,Dota A, Kawasaki S, Inoue Y,Maeda N, et al. amine, and UDP-N-acetylgalactosamine. Biochemistry 2000. Macular corneal dystrophy type I and type II are 47: 4337–4344.

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Golgi Glycosylation and Human Inherited Diseases

Hudson H. Freeze and Bobby G. Ng

Cold Spring Harb Perspect Biol 2011; doi: 10.1101/cshperspect.a005371 originally published online June 27, 2011

Subject Collection The Golgi

Structure of Golgi Transport Proteins Golgi and Related Vesicle Proteomics: Simplify to Daniel Kümmel and Karin M. Reinisch Identify Joan Gannon, John J.M. Bergeron and Tommy Nilsson Golgi Biogenesis Organization of SNAREs within the Golgi Stack Yanzhuang Wang and Joachim Seemann Jörg Malsam and Thomas H. Söllner Golgi Glycosylation and Human Inherited Golgi during Development Diseases Weimin Zhong Hudson H. Freeze and Bobby G. Ng Models for Golgi Traffic: A Critical Assessment Entry and Exit Mechanisms at the cis-Face of the Benjamin S. Glick and Alberto Luini Golgi Complex Andrés Lorente-Rodríguez and Charles Barlowe Architecture of the Mammalian Golgi COPI Budding within the Golgi Stack Judith Klumperman Vincent Popoff, Frank Adolf, Britta Brügger, et al. Evolution and Diversity of the Golgi Mechanisms of Protein Retention in the Golgi Mary J. Klute, Paul Melançon and Joel B. Dacks David K. Banfield Evolutionary Forces Shaping the Golgi The Golgin Coiled-Coil Proteins of the Golgi Glycosylation Machinery: Why Cell Surface Apparatus Glycans Are Universal to Living Cells Sean Munro Ajit Varki Golgi Positioning Signaling at the Golgi Smita Yadav and Adam D. Linstedt Peter Mayinger

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