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Other entities represented in this entry:
SNOMEDCT: 418054005; ORPHA: 98969; DO: 2565;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 16q23.1 | Macular corneal dystrophy | 217800 | Autosomal recessive | 3 | CHST6 | 605294 |
A number sign (#) is used with this entry because macular corneal dystrophy (MCD) is caused by homozygous or compound heterozygous mutation in the CHST6 gene (605294) on chromosome 16q23.
Macular corneal dystrophy (MCD) is an autosomal recessive disorder in which progressive punctate opacities in the cornea result in bilateral loss of vision, eventually necessitating corneal transplantation. MCD is classified into 2 subtypes, type I and type II, defined by the respective absence and presence of sulfated keratan sulfate in the patient serum, although both types have clinically indistinguishable phenotypes (summary by Akama et al., 2000).
Differentiation from the granular (121900) and lattice (122200) types of corneal dystrophy was discussed by Jones and Zimmerman (1961). Onset of MCD occurs in the first decade, usually between ages 5 and 9. The disorder is progressive. Minute, gray, punctate opacities develop. Corneal sensitivity is usually reduced. Painful attacks with photophobia, foreign body sensations, and recurrent erosions occur in most patients.
Acid mucopolysaccharides are demonstrable in corneal fibroblasts. Klintworth and Vogel (1964) suggested that this is a localized mucopolysaccharidosis. In later studies, Klintworth and Smith (1977) concluded that synthesis of corneal keratan sulfate and other glycosaminoglycans may be abnormal. Corneal keratan sulfate proteoglycan is normally synthesized through a glycoprotein intermediate (Hart and Lennarz, 1978). Hassell et al. (1980) concluded that in macular corneal dystrophy there may be a defect in glycoprotein processing. Thonar et al. (1986) suggested that the defect may not be limited to the cornea. They measured levels of sulfated keratan sulfate in serum, using a monoclonal antibody in an enzyme-linked immunosorbent assay. Sulfated keratan sulfate was detected in the serum of 16 patients with macular corneal dystrophy but was present at normal levels in 66 patients with other corneal diseases. The monoclonal antibody they used recognized a sulfated carbohydrate epitope present in both corneal and skeletal keratan sulfate. Since most serum keratan sulfate is derived from cartilage, the defect in keratan sulfate synthesis in macular corneal dystrophy may not be restricted to corneal cells. Subtle cartilaginous abnormalities should be sought in these patients. Deficient sulfotransferase might be responsible (Nakazawa et al., 1984).
Yang et al. (1987) and Edward et al. (1988) concluded on the basis of immunohistochemical studies that there are subgroups of macular corneal dystrophy. Yang et al. (1988) divided macular corneal dystrophy into 2 types on the basis of immunohistochemical studies and serum analysis for keratan sulfate: MCD type I, in which there is a virtual absence of sulfated keratan sulfate (KS) in the serum and cornea, as determined by KS-specific antibodies; and MCD type II, in which the normal sulfated KS-antibody response is present in cornea and serum.
Jonasson et al. (1996) studied macular corneal dystrophy in Iceland, where it accounts for almost one-third of all corneal grafts performed there. As reviewed by Jonasson et al. (1996), measurement of the serum level of antigenic keratan sulfate (aKS) with a sensitive enzyme-linked immunosorbent assay (ELISA) and an immunohistochemical evaluation of corneal tissue shows that most cases of MCD can be subdivided into 2 types: in MCD type I, antigenic keratan sulfate is absent from both serum and corneal tissue; in MCD type II, the serum aKS level is normal and the corneal accumulations react with the anti-KS antibody. The total amount of aKS in cornea is negligible when compared with the large quantity present in cartilaginous tissues; therefore it contributes little to the pool of aKS present in blood. This suggested that although MCD type I has clinical consequences for only the cornea and vision, it involves a systemic abnormality in the metabolism of all KS-containing proteoglycans in the body. In the corneal stroma, lumican (600616), a KS-containing proteoglycan, interacts with collagen fibrils and helps maintain their crucial size and ordered structure as well as corneal transparency. Lumican also affects corneal transparency by influencing corneal hydration. The cornea contains approximately 78% water and its most important binding component is KS. In MCD type I, the unsulfated keratan chains on lumican are less soluble than normal. With time, they precipitate, causing disorganization of the collagen network, thinning of the corneal stroma, and loss of transparency. By serum analyses, Jonasson et al. (1996) found that of 27 patients with MCD, 22 had type I and 5 had type II. The corneas from patients without detectable KS in the serum lacked immunohistochemical reactivity to the anti-KS antibody. Every MCD cornea examined from individuals with normal serum KS levels showed KS reactivity. All 53 unaffected sibs and parents carrying the recessive gene had normal serum KS levels. Thus, both types of macular corneal dystrophy occurred in Iceland. Members of affected sibships had only one of these types, not both. Nine patients with MCD type I and 4 persons with MCD type II belonged to a large pedigree in which individuals have been traced as far back as the beginning of the 16th century. The linking of patients with 2 types in an inbred pedigree suggested that both types may be manifestations of the same abnormal gene rather than independent entities. Jonasson et al. (1996) showed that serum KS levels are not helpful in detecting heterozygous MCD carriers.
Hasegawa et al. (2000) determined GlnNac6ST activity in normal corneas and corneas with keratoconus (148300) or macular corneal dystrophy by measuring the transfer of 35SO4 from (35S)3-prime phosphoadenosine 5-prime-phosphosulfate into the Gal residue of partially desulfated keratan sulfate and the nonreducing terminal GlcNAc residue of GlcNAc-beta-1/3Gal-beta-1/4GlcNAc (oligo A), respectively. GlcNAc6ST activity in the extracts from MCD-affected corneas, which was measured by using oligo A as an acceptor, was much lower than in those corneas with keratoconus and in normal control corneas. The authors concluded that the decrease in GlcNAc6ST activity in the cornea with MCD might result in the occurrence of low- or nonsulfated KS and thereby cause corneal opacity.
Vance et al. (1996) analyzed for linkage 16 American and Icelandic families, of which 11 were type I and 5 type II. A significant maximum lod score of 7.82 with a maximum recombination fraction of 0.06 was found with the 16q22 locus D16S518 for MCD type I. In addition, a peak lod score of 2.50 at a recombination fraction of 0.00 was obtained for the MCD type II families by use of the identical markers. These findings raised the possibility that these 2 phenotypically distinct forms of MCD are due to mutation at the same genetic locus. Vance et al. (1996) commented that these findings may support the suggestion that some corneal dystrophies are not independent entities but are phenotypic variations in the expression of the same gene. This appears to be the case for lattice corneal dystrophy type I (122200) and granular corneal dystrophy (121900).
The transmission pattern of macular corneal dystrophy in the families reported by Akama et al. (2000) and El-Ashry et al. (2002) was consistent with autosomal recessive inheritance.
Akama et al. (2000) identified a novel carbohydrate sulfotransferase gene (CHST6; 605294) encoding an enzyme designated corneal N-acetylglucosamine-6-sulfotransferase (c-GlnNAc6ST), within the critical region of type I macular corneal dystrophy. In MCD type I, they identified 7 mutations that were predicted to lead to inactivation of the enzyme (see, e.g., 605294.0001-605294.0002); in MCD type II, they found large deletions and/or replacements caused by homologous recombination in the upstream region of the CHST6 gene (605294.0003-605294.0004). In situ hybridization analysis did not detect CHST6 transcripts in corneal epithelium in an MCD type II patient, suggesting that the mutations found in type II lead to loss of cornea-specific expression of CHST6.
El-Ashry et al. (2002) identified 6 novel missense mutations (4 homozygous and 2 heterozygous) in the CHST6 gene in 5 unrelated families with type I MCD. These mutations were thought to result in loss of corneal sulfotransferase function, which would account for the MCD phenotype in the families.
In 31 MCD patients from 26 families from southern India, Sultana et al. (2005) identified 26 different mutations in the CHST6 gene, including 14 novel mutations.
By sequencing the CHST6 gene in 7 patients from 6 unrelated Korean MCD patients, Park et al. (2015) identified compound heterozygous mutations in all 7. Three of the mutations were novel; one of these was found at a very low frequency in the ExAC database, but none were found in the 1000 Genomes Project, dbSNP, or TIARA databases. The most frequent mutation (c.613C-T; R205W) was found in 4 of the families and had not previously been found in other populations.
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