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Recurrent heterozygous PAX6 missense variants cause severe bilateral microphthalmia via predictable effects on

Kathleen A Williamson1, H Nikki Hall1, Liusaidh J Owen1

  • 1MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.

Genetics in Medicine : Official Journal of the American College of Medical Genetics
|November 9, 2019
PubMed
Abstract

Insights

PAX6 missense variants, not just haploinsufficiency, can cause severe eye malformations like microphthalmia by altering gene interactions. These findings reveal new mechanisms for PAX6-related developmental eye diseases.

Area of Science:

  • Genetics
  • Developmental Biology
  • Ophthalmology

Background:

  • Classical aniridia is primarily linked to PAX6 haploinsufficiency.
  • PAX6 missense variants can exhibit hypomorphic activity or mimic haploinsufficiency.
  • The precise mechanisms by which PAX6 missense variants cause ocular phenotypes are not fully understood.

Purpose of the Study:

  • To investigate the role of PAX6 missense variants in causing microphthalmia, anophthalmia, and coloboma (MAC).
  • To explore the hypothesis that PAX6 missense variants alter genomic interaction affinity and/or specificity, leading to previously undescribed diseases.
  • To analyze the impact of specific PAX6 missense variants on ocular phenotypes and molecular interactions.

Main Methods:

  • Screened PAX6 in 372 individuals with MAC from a specialized eye malformation cohort.
  • Reviewed data from the Deciphering Developmental Disorders study.
  • Performed cluster analysis of PAX6-associated ocular phenotypes and molecular modeling of 86 PAX6 missense variants.

Main Results:

  • Identified eight PAX6 missense variants in 17 individuals (15 families) with MAC, representing 4% of the cohort.
  • Seven variants affected the paired domain and one affected the homeodomain.
  • Specific variants (p.Ser54Arg, p.Asn124Lys) were exclusively linked to severe bilateral microphthalmia, with predicted alterations in DNA binding but not ablation.

Conclusions:

  • Altered affinity and specificity of PAX6-binding genome-wide offer a plausible mechanism for the severe effects of these missense variants.
  • PAX6 missense variants can cause significant ocular malformations through mechanisms beyond simple haploinsufficiency.
  • No strong evidence for novel PAX6-associated extraocular disease was found.
Keywords:
PAX6microphthalmiamissense variantpaired domainprotein destabilization

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