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Missense mutations in the most ancient residues of the PAX6 paired domain underlie a spectrum of human congenital eye malformations

Lookup NU author(s): Michael Clarke


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Mutations of the human PAX6gene underlie aniridia (congenital absence of the iris), a rare dominant malformation of the eye, The spectrum of PAX6 mutations in aniridia patients is highly biased, with 92% of all reported mutations leading to premature truncation of the protein (nonsense, splicing, insertions and deletions) and just 2% leading to substitution of one amino acid by another (missense). The extraordinary conservation of the PAX6 protein at the amino acid level amongst vertebrates predicts that pathological missense mutations should in fact be common even though they are hardly ever seen in aniridia patients. This indicates that there is a heavy ascertainment bias in the selection of patients for PAX6 mutation analysis and that the 'missing' PAX6 missense mutations frequently may underlie phenotypes distinct from textbook aniridia. Here we present four novel PAX6 missense mutations, two in association with atypical phenotypes: ectopia pupillae (displaced pupils) and congenital nystagmus (searching gaze), and two in association with more recognizable aniridia phenotypes. Strikingly, all four mutations are located within the PAX6 paired domain and affect amino acids which are highly conserved in all known paired domain proteins. Our results support the hypothesis that the under-representation of missense mutations is caused by ascertainment bias and suggest that a substantial burden of PAX6-related disease remains to be uncovered.

Publication metadata

Author(s): Clarke M; Hanson I; Churchill A; Love J; Axton R; Moore T; Meire F; van Heyningen V

Publication type: Article

Publication status: Published

Journal: Human Molecular Genetics

Year: 1999

Volume: 8

Issue: 2

Pages: 165-172

Print publication date: 01/02/1999

ISSN (print): 0964-6906

ISSN (electronic): 1460-2083

Publisher: Oxford University Press


DOI: 10.1093/hmg/8.2.165


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Funder referenceFunder name
Wellcome Trust
MC_U127527199Medical Research Council