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Identification of Novel Mutations in the Carbohydrate Sulfotransferase Gene

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Identification of Novel Mutations in the Carbohydrate Sulfotransferase Gene Identification of Novel Mutations in the Carbohydrate Sulfotransferase Gene (CHST6) Causing Macular Corneal Dystrophy Mohamed F. El-Ashry,1,2,3 Mai M. Abd El-Aziz,1 Simon Wilkins,4 Michael E. Cheetham,4 Susan E. Wilkie,1 Alison J. Hardcastle,1 Stephanie Halford,1 Ahmed Y. Bayoumi,2 Linda A. Ficker,3 Stephen Tuft,3 Shomi S. Bhattacharya,1 and Neil D. Ebenezer1 PURPOSE. Macular corneal dystrophy (MCD) is a rare corneal phies that require penetrating keratoplasty, depending on the dystrophy that is characterized by abnormal deposits in the population.3,4 The disease becomes evident in the first decade corneal stroma, keratocytes, Descemet’s membrane, and endo- of life, defined by fine, diffuse, superficial clouding in the thelium, accompanied by progressive clouding. It has been central stroma that extends to the periphery and usually in- classified into three immunophenotypes—MCD types I, IA, and volves the entire thickness of the cornea by the second decade II—according to the serum level of sulfated keratan sulfate (KS) of life. These opacities are more superficial and prominent in and immunoreactivity of the corneal tissue. Recently, muta- the central cornea and are deeper and more discrete in the tions in a new carbohydrate sulfotransferase gene (CHST6) periphery. encoding corneal glucosamine N-acetyl-6-sulfotransferase (C- MCD has been classified into three immunophenotypes—I, GlcNac-6-ST) have been identified as the cause of MCD. Muta- IA, and II—based on measurement of the serum level of sul- tion screening of the CHST6 gene has been undertaken to fated keratan sulfate (KS) by enzyme-linked immunosorbent identify the underlying mutations in five unrelated British fam- assay (ELISA)5 and an immunohistochemical evaluation of the ilies with MCD. corneal tissue.6 In MCD type I, neither the cornea nor the ETHODS serum contains appreciable levels of sulfated KS, whereas in M . DNA was extracted from venous blood obtained 7 from all participants, and the coding region of CHST6 was MCD type II, there is detectable KS in the cornea and serum. amplified by polymerase chain reaction (PCR). The PCR prod- The third subtype, IA, in which sulfated KS is absent in the cornea and the serum but can be detected in the keratocytes, ucts were analyzed by direct sequencing and restriction en- 8 zyme digestion. Enzyme-linked immunosorbent assay (ELISA) has been identified in subjects from Saudi Arabia. All three was performed to assess the presence of KS in serum from the immunohistochemical subtypes have the same clinical pheno- probands of MCD-affected families participating in the study. type. Histologically, MCD is characterized by accumulation of RESULTS. Six novel missense mutations—four homozygous and glycosaminoglycans between the stromal lamellae, underneath two compound heterozygous—were identified in the CHST6 the epithelium, and within the keratocytes and endothelial gene. The ELISA showed that the disease in all patients partic- cells.9,10 An abnormality in the metabolism of KS has been ipating in the study was of MCD type I, including the sub- implicated in the pathogenesis of MCD11 and has been attrib- type IA. uted to an error in a specific sulfotransferase involved in the CONCLUSIONS. These novel mutations are thought to result in sulfation of KS.12–14 loss of corneal sulfotransferase function, which would account MCD types I and II had previously been linked to chromo- for the MCD phenotype. (Invest Ophthalmol Vis Sci. 2002;43: some 16 (16q22).15–17 Recently, mutations in a new carbohy- 377–382) drate sulfotransferase gene (CHST6) encoding corneal glu- cosamine N-acetyl-6-sulfotransferase (C-GlcNac-6-ST) have acular corneal dystrophy (MCD, On-line Mendelian Inher- been identified as the cause of MCD.18 A number of missense Mitance in Man (OMIM) 217800; provided in the public mutations were described in patients with MCD type I18–20 or domain by the National Center for Biotechnology Information, type IA.20 In MCD type II, deletions and/or rearrangements in Bethesda, MD, and available at http://www3.ncbi.nlm.nih.gov/ the upstream region of CHST618 and recently a missense mu- omim) is an autosomal recessive disorder characterized by tation20 were reported. bilateral progressive stromal clouding and central corneal thin- In our study, mutation screening of CHST6 in five unrelated ning.1,2 MCD accounts for 10% to 75% of the corneal dystro- British families with MCD and with no clinically apparent systemic manifestations, revealed four homozygous and two compound heterozygous mutations in CHST6, all of the mis- From the Departments of 1Molecular Genetics and 4Pathology, sense type. All the mutations involve the substitution of amino Institute of Ophthalmology, London, United Kingdom; the 2Depart- acids highly conserved across related carbohydrate sulfotrans- ment of Ophthalmology, Tanta University Hospitals, Tanta, Egypt; and ferases and/or represent the nonconservative substitution of 3Moorfields Eye Hospital, London, United Kingdom. nonpolar for polar residues and are thought to result in loss of Supported by a grant from Tanta University, Tanta, Egypt. CHST6 gene function. Submitted for publication June 14, 2001; revised September 7, 2001; accepted October 2, 2001. Commercial relationships policy: N MATERIALS AND METHODS The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked “advertise- Clinical Diagnosis ment” in accordance with 18 U.S.C. §1734 solely to indicate this fact. Corresponding author: Mohamed F. El-Ashry, Department of Mo- The study had the approval of Moorfields Eye Hospital Ethics Commit- lecular Genetics, Institute of Ophthalmology, 11-43 Bath Street, Lon- tee and conformed to the tenets of the Declaration of Helsinki. In- don EC1V 9EL, UK; [email protected]. formed consent was obtained from all participants for clinical and Investigative Ophthalmology & Visual Science, February 2002, Vol. 43, No. 2 Copyright © Association for Research in Vision and Ophthalmology 377 Downloaded from iovs.arvojournals.org on 09/25/2021 378 El-Ashry et al. IOVS, February 2002, Vol. 43, No. 2 TABLE 1. Mutations Identified within the CHST6 Gene in MCD-Affected Families Type of Nucleotide Amino Acid Type of Amino Type of Family Nucleotide Change Change Change Acid Substitution Mutation A 1012T3C Homozygous F107S Polar3nonpolar Nonconservative B [783C3Tϩ1291T3G] Heterozygous P31S Nonpolar3polar Non-conservative Heterozygous L200R Non-polar3acidic Non-conservative C [783C3Tϩ1291T3G] Heterozygous P31S Non-polar3polar Non-conservative Heterozygous L200R Non-polar3acidic Non-conservative D 1309C3T Homozygous A206V Non-polar3non-polar Conservative E 906C3T Homozygous P72S Non-polar3polar Non-conservative molecular genetic study. Autosomal recessive MCD in our patients of tively. Similarly, DrdI, with recognition site 5Ј. GAC- white origin was diagnosed on the basis of pedigree structure and the NNNNˇNNGTC. 3Ј, was used to confirm the homozygous C1309T following clinical features: bilateral symmetrical superficial stromal mutation in family D. And finally, BanII, with recognition site 5Ј...G cloudiness studded by small, irregular, rounded, gray-white anterior (A/G) GC (T/C)ˇC...3Ј, was used to confirm the homozygous G905T stromal patches. The diagnosis was confirmed by histopathologic ex- change in family E. amination of corneal buttons from all patients after keratoplasty. The PCR products digested by HinfI, BstN I, and BanII restriction enzymes were analyzed by 6% nondenaturing polyacrylamide gel elec- Mutation Detection trophoresis (Protogel; National Diagnostics, Atlanta, GA) and were Genomic DNA was extracted from 10-mL blood samples obtained, visualized by staining with ethidium bromide. Products digested by according to standard protocols, from all subjects involved in the ApaI and Drd I were analyzed on 3% agarose gels (Bio-Rad, Herts, UK). study. The coding region of CHST6 was amplified by polymerase chain reaction (PCR). Each PCR was performed in a 50-␮L reaction mixture ␮ Assay of Sulfated KS in Serum containing genomic DNA (200 ng), primers (0.4 M each), MgCl2 (1.5–2 mM), deoxynucleoside triphosphates (dNTPs; 0.2 mM), 1ϫ PCR Inhibition ELISA for KS detection using the monoclonal antibody 5-D-4 buffer (containing 10 mM Tris-HCl [pH 8.3], 50 mM KCl, and 0.1% (ICN Biochemicals Ltd., Basingstoke, UK) was performed to assess the gelatin) and Taq polymerase (0.5 U; Bioline, UK). Amplification reac- presence of KS in serum obtained from the probands of MCD-affected tions were performed under the following conditions: 3 minutes of families participating in the study. The method was performed as denaturation at 94°C followed by 35 cycles of denaturation at 94°C for 21,22 1 minute, annealing at 60 to 68°C for 1 minute, extension at 72°C for described previously, except that an antibody (Aggrecan; Sigma Ј 1 minute, and a further extension step at 72°C for 5 minutes. Chemical Co., Poole, UK) was used to coat the plates and 2, 2 -azino- For amplification of the CHST6 coding region the following primer di-[3-ethylbenzthiazoline sulfonate 6] (ABTS; Roche Molecular Bio- pairs were used: for the 5Ј-coding region, CK71h-intrn (5Ј-GCCCCTA- chemicals, Lews, UK) was used as the substrate. The plates were read ACCGCTGCGCTCTC-3Ј) and CK71h-R1180 (5Ј-GGCTTGCACACGGC- at 410 nm with a reference wavelength of 490 nm on a flow plate CTCGCT-3Ј) designed by Akama et al.18 For the middle coding region, reader (ICN Biochemicals Ltd.). The ELISA was sensitive to KS concen- two pairs of primers were designed: CK71M-F1 (5Ј-GACATGGACGT- trations of 10 to 10,000 ng/mL. GTTTGATGC-3Ј) and CK71M-R1 (5Ј-GCACGATGCCGTTGTCAC-3Ј); CK71M-F2 (5Ј-GCTCAACCTACGCATCGTG-3Ј) and CK71M-R2 (5Ј-ATC- CGTGGGTGATGTTATGG-3Ј); and for the 3Ј-coding region the follow- ing primer pair was designed: CK71L-F (5Ј-GAGCCGCTGGCAGAAATC- 3Ј) and CK71L-R (5Ј-TGCACCATGCACTCTCCTC-3Ј). A mismatch primer pair was also designed, sulfohin-F (5Ј-CTGTGCGACATGGAC- GAGT-3Ј) and sulfohin-R (5Ј-CACCACGTGGCTGTAGGAG-3Ј) to con- firm one of the homozygous mutations (in family A, F107S) which does not alter any known restriction enzyme site.
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