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VSX1 – Posterior Polymorphous Corneal Dystrophy

Posterior polymorphous corneal dystrophy (PPCD) was initially linked to heterozygous VSX1 missense variants in four probands, including c.740C>G (p.Pro247Arg) and c.479G>A (p.Gly160Asp), with segregation of mild PPCD in two affected relatives carrying p.Gly160Asp (PMID:11978762). However, linkage analysis in 52 members of two Czech families excluded VSX1 as the PPCD locus (PMID:16303937), and candidate screening of 12 additional PPCD probands failed to identify any pathogenic VSX1 changes (PMID:15725882).

Functional assays demonstrate that several VSX1 missense variants alter transcriptional activity in vitro, but a mouse model carrying p.Pro247Arg shows no corneal phenotype, despite altered electroretinographic responses (PMID:30535423). Taken together, genetic and functional data dispute a primary pathogenic role for VSX1 in PPCD. VSX1 sequencing alone is not recommended for molecular diagnosis of PPCD.

References

  • Human molecular genetics • 2002 • VSX1: a gene for posterior polymorphous dystrophy and keratoconus. PMID:11978762
  • Investigative ophthalmology & visual science • 2005 • Posterior polymorphous corneal dystrophy in Czech families maps to chromosome 20 and excludes the VSX1 gene. PMID:16303937
  • Cornea • 2005 • Candidate gene screening for posterior polymorphous dystrophy. PMID:15725882
  • Investigative ophthalmology & visual science • 2018 • Investigating the Pathogenicity of VSX1 Missense Mutations and Their Association With Corneal Disease. PMID:30535423

Evidence Based Scoring (AI generated)

Gene–Disease Association

Disputed

Initial reports in 4 probands with segregation of p.Gly160Asp in 2 relatives ([PMID:11978762]) but linkage in 52 members excluded VSX1 ([PMID:16303937]) and no pathogenic changes found in 12 probands ([PMID:15725882]).

Genetic Evidence

Limited

Evidence limited to four heterozygous missense variants in small case series without replication and major locus exclusions.

Functional Evidence

Limited

In vitro transcriptional alterations observed, but mouse p.Pro247Arg model shows no corneal phenotype ([PMID:30535423]).