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V12a18-Klintworth Pgmkr Molecular Vision 2006; 12:159-76 <http://www.molvis.org/molvis/v12/a18/> ©2006 Molecular Vision Received 13 October 2005 | Accepted 8 March 2006 | Published 10 March 2006 CHST6 mutations in North American subjects with macular corneal dystrophy: a comprehensive molecular genetic review Gordon K. Klintworth,1,2 Clayton F. Smith,2 Brandy L. Bowling2 Departments of 1Pathology and 2Ophthalmology, Duke University Medical Center, Durham, NC Purpose: To evaluate mutations in the carbohydrate sulfotransferase-6 (CHST6) gene in American subjects with macular corneal dystrophy (MCD). Methods: We analyzed CHST6 in 57 patients from 31 families with MCD from the United States, 57 carriers (parents or children), and 27 unaffected blood relatives of affected subjects. We compared the observed nucleotide sequences with those found by numerous investigators in other populations with MCD and in controls. Results: In 24 families, the corneal disorder could be explained by mutations in the coding region of CHST6 or in the region upstream of this gene in both the maternal and paternal chromosome. In most instances of MCD a homozygous or heterozygous missense mutation in exon 3 of CHST6 was found. Six cases resulted from a deletion upstream of CHST6. Conclusions: Nucleotide changes within the coding region of CHST6 are predicted to alter the encoded protein signifi- cantly within evolutionary conserved parts of the encoded sulfotransferase. Our findings support the hypothesis that CHST6 mutations are cardinal to the pathogenesis of MCD. Moreover, the observation that some cases of MCD cannot be explained by mutations in CHST6 suggests that MCD may result from other subtle changes in CHST6 or from genetic heterogeneity. Macular corneal dystrophy (MCD; OMIM 217800), a polysaccharidoses [18], and analyses of sulfated GAGs pro- rare inherited disorder first described in 1890 by Groenouw duced by organ cultures of corneas with MCD led to the dis- [1], has been identified throughout the world. MCD is most covery that corneal tissue with MCD does not synthesize KS prevalent in India [2-4] and Saudi Arabia [5]. In some coun- [19] or normal KS containing proteoglycans (PGs) because of tries, this disease accounts for a high percentage (10-75%) of defective sulfation [20,21]. Immunochemical studies using an the corneal dystrophies requiring keratoplasty [6,7]. Clinically, antibody that recognizes antigenic KS (AgKS) disclosed het- MCD is characterized by a cloudiness of the cornea and ir- erogeneity among cases of MCD based on the reactivity of regularly shaped superficial opacities of both eyes that pro- corneal tissue with the antibody [22]. Subsequently this led to gressively extend through the entire thickness of the central the recognition of three immunophenotypes that are clinically and peripheral corneal stroma. The corneal stroma is thinner and histopathologically indistinguishable from each other than normal [8-10]. In 1938, its autosomal recessive mode of [5,22-24]. Most often neither the serum nor the corneal tissue inheritance became appreciated [11]. More than two decades contain AgKS (MCD type I), but sometimes AgKS is absent later Jones and Zimmerman [12,13] differentiated MCD his- in the corneal stroma and the serum but can be detected in the topathologically from the other two major stromal corneal keratocytes (MCD type IA). A third immunophenotype (MCD dystrophies known as granular and lattice corneal dystrophy. type II) is characterized by the presence of AgKS in corneal Histopathologically, MCD is typified by an intracellular stor- tissue and detectable serum levels of AgKS that are often age of glycosaminoglycans (GAGs) within keratocytes and present in normal amounts. MCD type I corneas have been the corneal endothelium combined with an extracellular depo- found to synthesize an abnormal KS-PG with sition of similar material in the corneal stroma and Descemet’s lactosaminoglycan side chains that lack sulfate. In sharp con- membrane [5,14]. Guttae are common on Descemet’s mem- trast, an MCD type II cornea produced a normal ratio of KS- brane [15]. In 1964, because of similarities to the systemic PG to dermatan sulfate-PG, but the net synthesis of PGs was mucopolysaccharidoses, Klintworth and Vogel [16] suggested below normal [25]. However, the chondroitin/dermatan sul- MCD might be a mucopolysaccharidosis localized to the cor- fate side chains on decorin were sulfated. Subsequently, fluo- nea. A metabolic defect in keratan sulfate (KS), the major cor- rochrome-assisted carbohydrate electrophoresis disclosed that neal GAG [17], was suspected because of the histochemical the KS chain size within the cornea and cartilage in MCD attributes of the corneal accumulations and that the cornea type I was reduced and chain sulfation was absent [26]. In a was the only site of overt abnormalities. Cell culture studies cornea with MCD type II, the sulfation of N-acetylglucosamine disclosed differences from the systemic muco- and galactose was significantly reduced and the chain size was also reduced, but to a lesser degree than in MCD type I [26]. Correspondence to: Gordon K. Klintworth, MD, PhD, Duke Univer- The absence or paucity of sulfate in KS and KS-contain- sity Medical Center, Box 3802, Durham, NC, 27710; Phone: (919) ing PGs in corneas with MCD suggested that patients with 684-3550; FAX: (919) 684-9225; email: [email protected] MCD were deficient in a carbohydrate sulfotransferase that 159 Molecular Vision 2006; 12:159-76 <http://www.molvis.org/molvis/v12/a18/> ©2006 Molecular Vision catalyzes the transfer of sulfate groups from 3'- Because the gene responsible for MCD was suspected of phosphoadenosine 5'-phosphosulfate (PAPS) to KS in a man- encoding for a carbohydrate sulfotransferase and had been fine ner comparable to which sulfate esters are put on other en- mapped to the same region as CHST5 and CHST6, these genes dogenous and exogenous substrates (PAPS + R-OH ->PAP + became logical suspects for the MCD disease gene. In 2000, R-OSO3). An analysis of the serum in patients with MCD type Akama et al. [33] discovered mutations in CHST6 in MCD I disclosed normal levels of enzymatic activity for sulfating at and also found insertional or deletional defects in the region least one of the two sugars present in KS and an enzyme defi- between CHST5 and CHST6 in some cases. Subsequently, cient for sulfating N-acetylglucosamine (GlcNAc) was thought several laboratories confirmed these observations [2-4,39-52]. to be present [27]. Because the serum KS is considered to be This report documents an analysis of CHST6 in 57 pa- derived from cartilage, the discovery of undetectable levels of tients from 31 families from the United States with MCD, and AgKS in the serum of individuals with MCD type I suggested reviews these findings with all previously documented muta- that the KS sulfotransferase deficiency was not restricted to tions. the cornea. Direct evidence of cartilage involvement was ob- tained later in cartilage from the nose and ear in MCD type I METHODS [26,28]. Cartilage lacks abnormal accumulations comparable Subjects: We analyzed CHST6 in 141 individuals (57 affected to those in the cornea, but the chondrocytes and extracellular patients, 57 carriers [parents or children], and 27 normal blood matrix do not contain AgKS and the KS content of cartilage is related family members) from 31 families with MCD. In all at least 800 times lower than normal [28]. instances, the diagnosis of MCD was made on a combination Using families from Iceland, where MCD was the most of the characteristic clinical features together with the typical frequent indication for penetrating keratoplasty [7], the gene histopathologic findings in the corneal tissue obtained follow- for MCD type I was mapped to chromosome 16 (16q22) and ing a penetrating keratoplasty in one or both eyes. All patients linkage data hinted that MCD type II was also at this locus were born in the United states and some ancestral lines could [29]. Fine mapping refined the location of the MCD gene. be traced to England, Ireland, Germany, Holland, Northern Two candidate genes (TAT and LCAT) in that part of chromo- Ireland, Scotland, Switzerland, and Norway. Nonmolecular some 16 were excluded [30-32]. genetic studies have been previously reported on some of these A sulfotransferase suspected of being defective in MCD cases [14,16,18,19,53-56]. This study was approved by the would belong to the galactose/N-acetylgalactosamine/N- Internal Review Board of Duke University and conformed to acetylglucosamine 6-O-sulfotransferase family of carbohy- the tenets of the declaration of Helsinki. Written informed drate sulfotransferases. This family of enzymes catalyzes 6- consent was obtained from all participants. To evaluate the O-sulfation on the 6-hydroxyl of GlcNAc, galactose (GAL), CHST6 gene in 11 deceased or unavailable patients from five or N-acetylgalactosamine (GalNAc) [33]. All known families with MCD, we analyzed the DNA of surviving sib- sulfotransferases contain highly conserved regions [34], in- lings, parents, and children to establish which mutations had cluding a 5'-PSB (phosphosulfate-binding) and a 3'-PB (3'- been transmitted to the carriers. We also analyzed DNA from phosphate binding domain) [35]. The carbohydrate 50 control specimens from the United States and DNA from sulfotransferases in different species possess marked sequence 10 normal spouses who married into these families. similarities at the amino acid level particularly in their cata- Determination of MCD immunophenotypes: Prior to mo- lytic domains and, with the exception of CHST3 (also known lecular genetic studies, the immunophenotypes had been de- as GST-0), the coding sequences of the open reading frames termined in 32 of the 57 subjects with MCD by ascertaining (ORFs) for all CHST genes are within a single exon [36]. The the presence or absence of sulfated epitopes in KS in the cor- galactose/N-acetylgalactosamine/N-acetylglucosamine 6-O- neal tissue and/or serum.
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