Journal Article

Missense Mutations in the Most Ancient Residues of the PAX6 Paired Domain Underlie a Spectrum of Human Congenital Eye Malformations

Isabel Hanson, Amanda Churchill, James Love, Richard Axton, Tony Moore, Michael Clarke, Francoise Meire and Veronica van Heyningen

in Human Molecular Genetics

Volume 8, issue 2, pages 165-172
Published in print February 1999 | ISSN: 0964-6906
Published online February 1999 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/8.2.165
Missense Mutations in the Most Ancient Residues of the PAX6 Paired Domain Underlie a Spectrum of Human Congenital Eye Malformations

Show Summary Details

Preview

Mutations of the human PAX6 gene 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.

Journal Article.  6225 words.  Illustrated.

Subjects: Genetics and Genomics

Full text: subscription required

How to subscribe Recommend to my Librarian

Users without a subscription are not able to see the full content. Please, subscribe or login to access all content.