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Carbohydrate-De¢Cient Glycoprotein Syndrome Type II

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Carbohydrate-De¢Cient Glycoprotein Syndrome Type II View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Biochimica et Biophysica Acta 1455 (1999) 179^192 www.elsevier.com/locate/bba Review Carbohydrate-de¢cient glycoprotein syndrome type II Harry Schachter a;*, Jaak Jaeken b a Department of Biochemistry, University of Toronto Medical School, and Department of Structural Biology and Biochemistry, Hospital for Sick Children, 555 University Avenue, Toronto, Ont. M5G 1X8, Canada b Center for Metabolic Disease, University of Leuven, Leuven, Belgium Received 8 February 1999; accepted 3 May 1999 Abstract The carbohydrate-deficient glycoprotein syndromes (CDGS) are a group of autosomal recessive multisystemic diseases characterized by defective glycosylation of N-glycans. This review describes recent findings on two patients with CDGS type II. In contrast to CDGS type I, the type II patients show a more severe psychomotor retardation, no peripheral neuropathy and a normal cerebellum. The CDGS type II serum transferrin isoelectric focusing pattern shows a large amount (95%) of disialotransferrin in which each of the two glycosylation sites is occupied by a truncated monosialo-monoantennary N-glycan. Fine structure analysis of this glycan suggested a defect in the Golgi enzyme UDP-GlcNAc:K-6-D-mannoside L-1,2-N-acetylglucosaminyltransferase II (GnT II; EC 2.4.1.143) which catalyzes an essential step in the biosynthetic pathway leading from hybrid to complex N-glycans. GnT II activity is reduced by over 98% in fibroblast and mononuclear cell extracts from the CDGS type II patients. Direct sequencing of the GnT II coding region from the two patients identified two point mutations in the catalytic domain of GnT II, S290F (TCC to TTC) and H262R (CAC to CGC). Either of these mutations inactivates the enzyme and probably also causes reduced expression. The CDG syndromes and other congenital defects in glycan synthesis as well as studies of null mutations in the mouse provide strong evidence that the glycan moieties of glycoproteins play essential roles in the normal development and physiology of mammals and probably of all multi- cellular organisms. ß 1999 Elsevier Science B.V. All rights reserved. Keywords: Carbohydrate-de¢cient glycoprotein; N-Acetylglucosaminyltransferase; N-Glycan synthesis; Golgi; Transferrin glycoform; Psychomotor retardation Contents 1. Introduction .......................................................... 180 2. Clinical presentations of CDGS ............................................ 180 3. The analysis of serum transferrin glycoforms in CDGS ........................... 181 4. Clinical biochemistry . ................................................. 182 5. Complex N-glycan synthesis within the Golgi apparatus . ....................... 183 * Corresponding author. 0925-4439 / 99 / $ ^ see front matter ß 1999 Elsevier Science B.V. All rights reserved. PII: S0925-4439(99)00054-X BBADIS 61859 15-9-99 180 H. Schachter, J. Jaeken / Biochimica et Biophysica Acta 1455 (1999) 179^192 6. The genetic defect in CDGS II ............................................ 184 7. The diagnosis of CDGS II ................................................ 186 8. The function of complex N-glycans in development . ............................ 186 Acknowledgements . ...................................................... 187 References ............................................................... 187 1. Introduction transferrin pattern have been described (designated types Ia, Ib and Ic). The enzymatic and genetic de- At least 0.5^1% of the transcribed human genome fects in these variants have been determined and it is is devoted to the production of proteins involved in clear that there are other CDGS type I patients with the synthesis, degradation and function of glycocon- as yet undetermined metabolic defects. CDGS types jugates [1]. It is therefore not surprising that there III [5] and IV [6] cases are very rare and nothing is are many congenital diseases with defects in these known about the biochemical defects in these pa- pathways. Table 1 lists eight autosomal recessive dis- tients. eases in which there is a defect in the synthesis of Asn-linked glycans (N-glycans) proving that these structures are essential for normal human develop- 2. Clinical presentations of CDGS ment. Some of these diseases are discussed in other chapters of this volume. This chapter will focus on CDGS I occurs world-wide and a¡ects both sexes carbohydrate-de¢cient glycoprotein syndrome type II equally [4,7]. The patients show moderate to severe (CDGS II). neurological disease (cerebellar ataxia and marked The carbohydrate-de¢cient glycoprotein syn- psychomotor retardation), a characteristic dysmor- dromes are a group of congenital multi-systemic dis- phy and variable involvement of other organs. Feed- eases characterized by defective glycosylation of N- ing problems, vomiting and diarrhea may occur re- glycans. The discovery of this disease was based on sulting in severe developmental delay and failure to the observation by Jaeken et al. [2] of decreased se- thrive [8,9]. Infants may show a distinctive lipodys- rum thyroxine-binding globulin and increased aryl- trophy (peculiar distribution of subcutaneous fat), sulfatase A activity in two patients with familial psy- nipple retraction and hypogonadism. After infancy, chomotor retardation. In 1984, Jaeken et al. [3] retinitis pigmentosa [10,11], joint contractures, skel- reported sialic acid de¢ciency in serum and cerebro- etal deformities [12], stroke-like episodes, epilepsy spinal £uid transferrin from identical twin-sisters and peripheral neuropathy may develop. About with demyelinating disease and thereby ¢rst showed 20% of the patients die within the ¢rst year. Lan- that this new syndrome was due to defective protein guage and motor development are severely delayed glycosylation. There were about 280 patients with and walking without support is rarely achieved. The this disease world-wide as of October, 1998 [4]. Until IQ ranges from 40 to 60 and the children usually recently, four variants of CDGS were recognized have an extroverted and cheerful disposition. Com- (called types I^IV) based primarily on the quantita- puterized tomography (CT), nuclear magnetic reso- tive analysis of serum transferrin glycoforms either nance imaging (MRI) and postmortem studies of the by isoelectric focusing or chromatofocusing. Varia- brain of CDGS I patients often show olivopontocer- tions in the pattern of transferrin glycoforms re£ect ebellar atrophy (OPCA) and a small brain stem [13^ di¡erences in negative charge due to abnormal sialyl- 20]. ation of protein-bound N-glycans (described in more Two CDGS patients, designated as CDGS II, have detail below). Within the last 3 years, at least three been described who di¡er from the classic picture of distinct variants of CDGS associated with a type I CDGS I described above, an Iranian girl (patient A) BBADIS 61859 15-9-99 H. Schachter, J. Jaeken / Biochimica et Biophysica Acta 1455 (1999) 179^192 181 [21] and a Belgian boy (patient B) [22,23]. In contrast 1^7%; S3, 4^17%; S4, 46^73%; S5, 10^30%; S6, 0^ to CDGS I, both CDGS II patients had a more 9%; S7, traces. The corresponding values for CDGS severe psychomotor retardation, no peripheral neu- sera showing a type 1 pattern [3,20,31,33,36^38] are: ropathy and a normal cerebellum on MRI. Both pa- S2, 14^37%; S3, 6^19%; S4, 18^57%; S5, 5^17%; S6, tients had a similar dysmorphy particulary of the 0^6%. In addition, CDGS I sera show appreciable face (coarse features, low-set ears), widely spaced amounts of S0 (2^29%), a glycoform not usually de- nipples, a ventricular septal defect, a striking stereo- tected in normal sera. In other words, CDGS I sera typic behavior (tongue thrusting, hand washing and show dramatic reductions in S4 and S5 and dramatic other movements), generalized hypotonia and limb increases in S0 and S2 (Fig. 1). Data from many weakness, and normal deep tendon re£exes. Patient laboratories indicate an `all-or-none' situation in A was lost from follow-up after the age of 3 years. which each glycosylation site on transferrin is either Patient B's speech was limited to a few monotonous occupied by a normal N-glycan or is not occupied sounds at 10 years. He su¡ered from frequent infec- suggesting that the addition of oligosaccharide to tions in infancy and epilepsy developed at 6 years. Asn is the defective step (Fig. 1) [13,35,39^42]. The diagnosis of CDGS was not made until patient The CDGS II serum transferrin isoelectric focus- B was 9.5 years old when an investigation of bleeding ing pattern di¡ers markedly from that in CDGS I gums revealed a typical CDGS coagulopathy. Radio- (Fig. 1) in that there are no or minimal amounts of logical examination showed osteopenia and other asialo-, tetrasialo-, pentasialo- and hexasialo-trans- skeletal abnormalities. MRI revealed absence of cer- ferrrins, low amounts of monosialo-transferrin, a ebellar atrophy, but showed delayed myelination and moderate amount (about 4%) of trisialo-transferrin global cortical atrophy. and a large amount (95%) of disialo-transferrin [23,28,29]. Electrospray-mass spectrometry analysis of both 3. The analysis of serum transferrin glycoforms in normal and CDGS II puri¢ed serum transferrin CDGS showed seven glycoform peaks (I^VII) with molecu- lar masses ranging from 79 265 to 80 369 Da for nor- The basic defect in CDGS is defective N-glycosyl- mal transferrin and 77 958 to 79 130 Da for CDGS II ation of glycoproteins
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