CHST6 – Macular Corneal Dystrophy

Macular corneal dystrophy (MCD) is a rare autosomal recessive corneal stromal dystrophy characterized by progressive loss of transparency, diffuse stromal clouding, recurrent erosions, corneal thinning, and severely reduced visual acuity (HP:0007957, HP:0007663). Histologically, MCD shows glycosaminoglycan deposits in keratocytes and endothelial cells that stain positively with alcian blue, colloidal iron, and periodic acid–Schiff (PMID:24311932). CHST6 encodes corneal N-acetylglucosamine-6-O-sulfotransferase, which catalyzes keratan sulfate 6-O sulfation; loss of function leads to intracellular vacuolation and extracellular matrix disruption.

Inheritance is autosomal recessive. Aggregated analysis of 408 MCD cases demonstrated 165+ distinct CHST6 variants, including missense, nonsense, frameshift indels, and upstream deletions, indicative of loss-of-function alleles (PMID:30716718). One recurrent coding change, c.613C>T (p.Arg205Trp), was homozygous in a Korean patient with classic MCD histopathology (PMID:24311932).

Segregation studies in an Icelandic cohort revealed homozygous C1075T and compound heterozygous 10-bp insertion (c.707_708insATGCTGTGCG) segregating with disease in two siblings, their mother, and maternal aunt (4 affected relatives) (PMID:11139648). Recurrent alleles such as c.599T>G (p.Leu200Arg) have been identified across Japanese, British, and Czech populations, suggesting mutational hotspots (PMID:11818380).

Functional assays including ELISA and immunohistochemistry demonstrate absent or reduced sulfated keratan sulfate in serum and corneal tissue of MCD type I patients, confirming enzymatic inactivity of mutant CHST6 proteins (PMID:11818380). Electron microscopy reveals keratocyte and endothelial vacuoles filled with electron-dense fibrillogranular material, providing ultrastructural concordance (PMID:24311932).

In vitro expression of CHST6 frameshift alleles induces endoplasmic reticulum stress (GRP78, CHOP upregulation), increased keratocyte apoptosis, decreased migration, and senescence, elucidating a pathogenic mechanism linking loss of sulfotransferase activity to corneal opacity (PMID:29221207). Patient-derived iPSC models retain compound heterozygous CHST6 mutations and can differentiate into corneal lineages for disease modeling (PMID:31669782).

The extensive allelic heterogeneity, consistent autosomal recessive segregation, and robust functional concordance across numerous cohorts over >20 years establish a definitive gene–disease relationship. Genetic testing for CHST6 variants supports precise molecular diagnosis, informs prognosis, enables carrier screening, and guides family counseling in macular corneal dystrophy.

References

• Korean journal of ophthalmology : KJO | 2013 | A case of Korean patient with macular corneal dystrophy associated with novel mutation in the CHST6 gene. PMID:24311932
• Molecular vision | 2000 | Mutations in corneal carbohydrate sulfotransferase 6 gene (CHST6) cause macular corneal dystrophy in Iceland. PMID:11139648
• Investigative ophthalmology & visual science | 2002 | Identification of novel mutations in the carbohydrate sulfotransferase gene (CHST6) causing macular corneal dystrophy. PMID:11818380
• Oncotarget | 2017 | CHST6 mutation screening and endoplasmatic reticulum stress in macular corneal dystrophy. PMID:29221207
• Aging | 2019 | A comprehensive evaluation of 181 reported CHST6 variants in patients with macular corneal dystrophy. PMID:30716718

Evidence Based Scoring (AI generated)