TACSTD2 – Gelatinous Drop-Like Corneal Dystrophy

Trop2, encoded by TACSTD2 (HGNC:11530), is essential for maintaining corneal epithelial barrier integrity. Biallelic pathogenic variants in TACSTD2 cause gelatinous drop-like corneal dystrophy, an early-onset, autosomal recessive amyloidosis of the cornea characterized by mulberry-like subepithelial deposits and progressive visual impairment ([PMID:10192395]).

Genetic studies have identified TACSTD2 mutations in over 40 affected individuals from at least 35 unrelated families worldwide, confirming autosomal recessive inheritance and robust segregation of homozygous or compound heterozygous variants with disease ([PMID:10937555]). The recurrent c.352C>T (p.Gln118Ter) founder variant accounts for 82.5% of disease alleles in Japanese cohorts, while diverse nonsense, frameshift, and missense mutations have been reported in Vietnamese, Chinese, Iranian, Colombian, and Mexican populations ([PMID:10192395]; [PMID:10937555]).

The variant spectrum encompasses nonsense (e.g., c.352C>T (p.Gln118Ter)), frameshift (e.g., c.632delA (p.Gln211Ter)), splice, and missense changes such as c.356G>A (p.Cys119Tyr), with phenotypic variability ranging from typical gelatinous masses to band-shaped opacities and kumquat-like forms. No pathogenic TACSTD2 variants were found in one atypical GDLD case with developmental delay, underscoring locus heterogeneity ([PMID:15254496]).

Functional assays demonstrate that truncating and missense TACSTD2 variants abrogate protein trafficking to cell–cell borders, disrupting tight junction stability and epithelial barrier function. Protein truncation testing effectively detects pathogenic alleles ([PMID:10937555]), while CHO cell transfection studies reveal mislocalization of Cys108Arg and other mutants ([PMID:15295654]). A frameshift p.Lys267SerfsTer4 mutant fails to facilitate claudin-1/7 membrane targeting, confirming loss of function as the pathogenic mechanism ([PMID:31666974]).

Although rare outside Japan (incidence ~1/300,000), GDLD can recur after corneal transplantation, highlighting the need for genetic confirmation. Phenotypic variability suggests modifier factors influence clinical presentation. No evidence refutes the TACSTD2 association; one report excluded M1S1 in a developmental delay case, consistent with alternative etiologies ([PMID:15254496]).

In summary, definitive evidence from genetic linkage, segregation in diverse cohorts, and concordant functional studies establishes TACSTD2 as the causative gene for autosomal recessive gelatinous drop-like corneal dystrophy. Genetic testing for TACSTD2 variants enables accurate diagnosis and informs prognosis and management.

References

• Nature genetics • 1999 • Identification of the gene responsible for gelatinous drop-like corneal dystrophy. PMID:10192395
• Investigative ophthalmology & visual science • 2000 • Rapid detection of M1S1 mutations by the protein truncation test. PMID:10937555
• Japanese journal of ophthalmology • 2004 • Mutations in the membrane component, chromosome 1, surface marker 1 (M1S1) gene in gelatinous drop-like corneal dystrophy. PMID:15295654
• Human genome variation • 2019 • A novel mutation in gelatinous drop-like corneal dystrophy and functional analysis. PMID:31666974

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