FOXC1 – Aniridia

FOXC1 variants have been identified in a small number of patients with congenital aniridia, an autosomal dominant pan-ocular disorder characterized by complete or partial iris hypoplasia ([HP:0000526]). Three unrelated probands harboring heterozygous FOXC1 missense mutations—c.454T>G (p.Trp152Gly) in a newborn with aniridia and developmental glaucoma ([PMID:19279310]), and c.302T>C (p.Leu101Pro) and c.235C>A (p.Pro79Thr) in PAX6-negative aniridia cases ([PMID:27124303])—support a gene–disease link. No multigenerational segregation has been reported and all variants occurred de novo or in singleton cases, yielding limited genetic evidence.

Functional assays of FOXC1 missense alleles demonstrate consistent loss-of-function: the W152G protein fails to be phosphorylated, localize to the nucleus, bind DNA, or transactivate reporters and forms non-aggresome aggregates more severe than L130F ([PMID:19279310]). Additional forkhead domain mutations decrease DNA binding and transactivation across multiple residues ([PMID:11179011]). These data establish a haploinsufficient mechanism but, given the small number of affected individuals and lack of segregation, the overall clinical validity remains limited. Key take-home: FOXC1 sequencing should be considered in PAX6-negative aniridia for accurate diagnosis and counseling.

References

• Investigative ophthalmology & visual science • 2009 • Severe molecular defects of a novel FOXC1 W152G mutation result in aniridia. PMID:19279310
• PloS one • 2016 • Genetic Analysis of 'PAX6-Negative' Individuals with Aniridia or Gillespie Syndrome. PMID:27124303
• American journal of human genetics • 2001 • Analyses of the effects that disease-causing missense mutations have on the structure and function of the winged-helix protein FOXC1. PMID:11179011

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