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CHST6
carbohydrate sulfotransferase 6
CHST6 is located on the long (q) arm of chromosome 16, at band 16q23.1. Arm ratio per GRCh38 - banding schematic.
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Overview
CHST6 encodes carbohydrate sulphotransferase 6, an enzyme that catalyses the transfer of sulphate groups to keratan sulphate, a type of glycosaminoglycan found predominantly in the cornea. This sulphation process is critical for proper corneal organisation and transparency. Pathogenic variants in CHST6 disrupt the enzyme's catalytic activity, leading to abnormal accumulation of unsulphated keratan in corneal tissue. The resulting structural changes cause progressive corneal clouding and vision impairment, a condition known as macular corneal dystrophy. Understanding CHST6 function helps explain how biochemical modifications at the molecular level directly influence tissue structure and visual function.
What the gene does
The CHST6 enzyme belongs to the sulphotransferase family and specifically acts on keratan sulphate chains within the corneal extracellular matrix. These enzymes transfer a sulphate group from the donor molecule 3'-phosphoadenosine-5'-phosphosulphate (PAPS) to galactose residues on keratan chains. This sulphation is essential for proper spacing and organisation of collagen fibrils in the corneal stroma, the thick middle layer of the cornea that provides structural support. When keratan sulphate is appropriately sulphated, it maintains the precise spacing between collagen fibres that allows light to pass through without scattering. The enzyme displays tissue-specific expression, with particularly high activity in corneal keratocytes, the specialised fibroblast cells that maintain the corneal matrix. Loss of CHST6 function results in accumulation of undersulphated or non-sulphated keratan, which disrupts the regular collagen arrangement and causes the cornea to become opaque over time.
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Chromosome location
CHST6 is located on the long arm of chromosome 16 at position 23.1, designated as 16q23.1. This chromosomal region contains several genes involved in various metabolic and structural processes. The precise genomic structure of CHST6, including exon count and transcript variants, has been mapped through genomic sequencing efforts, though detailed annotation may vary across reference databases.
Protein structure
Domain architecture has not been experimentally characterised in detail for this protein. As a member of the sulphotransferase family, the CHST6 protein is expected to contain catalytic regions that bind both the PAPS sulphate donor and the keratan sulphate acceptor substrate, but specific structural domains have not been formally annotated in protein databases.
Key variants
Variants in CHST6 range from missense changes that alter single amino acids to nonsense variants that introduce premature stop codons, as well as small insertions or deletions that disrupt the reading frame. The majority of pathogenic variants reduce or eliminate enzyme activity, though different changes may affect catalytic efficiency to varying degrees. Macular corneal dystrophy can result from homozygous variants (two copies of the same change) or compound heterozygous variants (two different changes, one inherited from each parent). The specific variants found in affected individuals can influence the age of onset and severity of corneal clouding, though genotype-phenotype correlations remain an area of ongoing research.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.158C>T | p.Ser53Leu | Pathogenic | ★★☆☆ | Macular corneal dystrophy |
c.172C>T | p.Gln58Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Macular corneal dystrophy |
c.1A>T | p.Met1Leu | Pathogenic/Likely pathogenic | ★★☆☆ | Macular corneal dystrophy |
c.304T>G | p.Cys102Gly | Pathogenic | ★★☆☆ | Macular corneal dystrophy |
c.379C>T | p.Arg127Cys | Pathogenic | ★★☆☆ | Macular corneal dystrophy |
c.418C>T | p.Arg140Ter | Pathogenic | ★★☆☆ | Macular corneal dystrophy |
c.599T>G | p.Leu200Arg | Pathogenic | ★★☆☆ | Macular corneal dystrophy |
c.632G>A | p.Arg211Gln | Pathogenic | ★★☆☆ | Macular corneal dystrophy |
c.805del | p.Arg269fs | Pathogenic/Likely pathogenic | ★★☆☆ | Macular corneal dystrophy |
c.847_848delinsTG | p.Glu283Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Macular corneal dystrophy |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in CHST6 cause macular corneal dystrophy, a progressive inherited eye condition characterised by clouding of the cornea. This dystrophy typically presents in the first or second decade of life with visual symptoms including reduced clarity, glare sensitivity, and gradual vision loss. The condition follows an autosomal recessive inheritance pattern, meaning affected individuals carry pathogenic variants in both copies of the gene. Corneal clouding results from abnormal deposits of unsulphated keratan in the stromal layer, which can be observed during eye examination. While macular corneal dystrophy is relatively rare in the general population, it represents one of the better-characterised examples of how defects in a single sulphation enzyme can produce significant tissue pathology.
No disease links recorded for this gene in our reference set.
UK clinical status
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does the CHST6 gene do?
CHST6 provides instructions for an enzyme that adds sulphate groups to keratan sulphate molecules in the cornea. This chemical modification is essential for maintaining the regular arrangement of collagen fibres that keeps the cornea clear and allows light to pass through properly.
How are CHST6 variants inherited?
CHST6-related macular corneal dystrophy follows an autosomal recessive pattern. This means an individual must inherit a pathogenic variant from both parents to develop the condition. Carriers with one variant copy typically do not show symptoms.
Can CHST6 variants affect other parts of the body besides the eyes?
Current evidence suggests that CHST6 variants primarily affect the cornea. While keratan sulphate is found in other tissues such as cartilage, CHST6 appears to have a particularly important role in corneal tissue, and the clinical manifestations are confined to progressive corneal clouding and associated vision problems.