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Recurrent heterozygous PAX6 missense variants cause severe bilateral microphthalmia via predictable effects on DNA-protein interaction.

ABSTRACT: PURPOSE:Most classical aniridia is caused by PAX6 haploinsufficiency. PAX6 missense variants can be hypomorphic or mimic haploinsufficiency. We hypothesized that missense variants also cause previously undescribed disease by altering the affinity and/or specificity of PAX6 genomic interactions. METHODS:We screened PAX6 in 372 individuals with bilateral microphthalmia, anophthalmia, or coloboma (MAC) from the Medical Research Council Human Genetics Unit eye malformation cohort (HGUeye) and reviewed data from the Deciphering Developmental Disorders study. We performed cluster analysis on PAX6-associated ocular phenotypes by variant type and molecular modeling of the structural impact of 86 different PAX6 causative missense variants. RESULTS:Eight different PAX6 missense variants were identified in 17 individuals (15 families) with MAC, accounting for 4% (15/372) of our cohort. Seven altered the paired domain (p.[Arg26Gln]x1, p.[Gly36Val]x1, p.[Arg38Trp]x2, p.[Arg38Gln]x1, p.[Gly51Arg]x2, p.[Ser54Arg]x2, p.[Asn124Lys]x5) and one the homeodomain (p.[Asn260Tyr]x1). p.Ser54Arg and p.Asn124Lys were exclusively associated with severe bilateral microphthalmia. MAC-associated variants were predicted to alter but not ablate DNA interaction, consistent with the electrophoretic mobility shifts observed using mutant paired domains with well-characterized PAX6-binding sites. We found no strong evidence for novel PAX6-associated extraocular disease. CONCLUSION:Altering the affinity and specificity of PAX6-binding genome-wide provides a plausible mechanism for the worse-than-null effects of MAC-associated missense variants.

SUBMITTER: Williamson KA

PROVIDER: S-EPMC7056646 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Recurrent heterozygous PAX6 missense variants cause severe bilateral microphthalmia via predictable effects on DNA-protein interaction.

Williamson Kathleen A KA Hall H Nikki HN Owen Liusaidh J LJ Livesey Benjamin J BJ Hanson Isabel M IM Adams G G W GGW Bodek Simon S Calvas Patrick P Castle Bruce B Clarke Michael M Deng Alexander T AT Edery Patrick P Fisher Richard R Gillessen-Kaesbach Gabriele G Heon Elise E Hurst Jane J Josifova Dragana D Lorenz Birgit B McKee Shane S Meire Francoise F Moore Anthony T AT Parker Michael M Reiff Charlotte M CM Self Jay J Tobias Edward S ES Verheij Joke B G M JBGM Willems Marjolaine M Williams Denise D van Heyningen Veronica V Marsh Joseph A JA FitzPatrick David R DR

Genetics in medicine : official journal of the American College of Medical Genetics 20191108 3

<h4>Purpose</h4>Most classical aniridia is caused by PAX6 haploinsufficiency. PAX6 missense variants can be hypomorphic or mimic haploinsufficiency. We hypothesized that missense variants also cause previously undescribed disease by altering the affinity and/or specificity of PAX6 genomic interactions.<h4>Methods</h4>We screened PAX6 in 372 individuals with bilateral microphthalmia, anophthalmia, or coloboma (MAC) from the Medical Research Council Human Genetics Unit eye malformation cohort (HGU ...[more]

PMID: 31700164

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Project description:PURPOSE: To investigate the genetic basis of recessively-inherited congenital, non syndromic, bilateral, total sclerocornea in two consanguineous pedigrees, one from the Punjab province of Pakistan and the other from the Tlaxcala province of Mexico. METHODS: Ophthalmic examinations were conducted on each family member to confirm their diagnosis and magnetic resonance imaging (MRI) or ultrasonography of the eyes was performed on some family members. Genomic DNA was analyzed by homozygosity mapping using the Affymetrix 6.0 SNP array and linkage was confirmed with polymorphic microsatellite markers. Candidate genes were sequenced. RESULTS: A diagnosis of autosomal recessive sclerocornea was established for 7 members of the Pakistani and 8 members of the Mexican pedigrees. In the Pakistani family we established linkage to a region on chromosome 1p that contained Forkhead Box E3 (FOXE3), a strong candidate gene since FOXE3 mutations had previously been associated with various anterior segment abnormalities. Sequencing FOXE3 identified the previously reported nonsense mutation, c.720C>A, p.C240X, in the Pakistani pedigree and a novel missense mutation which disrupts an evolutionarily conserved residue in the forkhead domain, c.292T>C, p.Y98H, in the Mexican pedigree. Individuals with heterozygous mutations had no ocular abnormalities. MRI or ultrasonography confirmed that the patients with sclerocornea were also aphakic, had microphthalmia and some had optic disc coloboma. CONCLUSIONS: This is the fourth report detailing homozygous FOXE3 mutations causing anterior segment abnormalities in human patients. Previous papers have emphasized aphakia and microphthalmia as the primary phenotype, but we find that the initial diagnosis - and perhaps the only one possible in a rural setting - is one of non-syndromic, bilateral, total sclerocornea. Dominantly inherited anterior segment defects have also been noted in association with heterozygous FOXE3 mutations. However the absence of any abnormalities in the FOXE3 heterozygotes described suggests that genetic background and environmental factors plays a role in the penetrance of the mutant allele.

Dataset Information

Recurrent heterozygous PAX6 missense variants cause severe bilateral microphthalmia via predictable effects on DNA-protein interaction.

Publications

Recurrent heterozygous PAX6 missense variants cause severe bilateral microphthalmia via predictable effects on DNA-protein interaction.

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