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Genet Med. 2020 Mar;22(3):598-609. doi: 10.1038/s41436-019-0685-9. Epub 2019 Nov 8.

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

Author information

1
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
2
Moorfields Eye Hospital, London, UK.
3
Department of Clinical Genetics, St Michael's Hospital, Southwell Street, Bristol, UK.
4
CHU Toulouse, Service de Génétique Médicale, Hôpital Purpan, Toulouse, France.
5
Peninsula Clinical Genetics, Royal Devon and Exeter Hospitals (Heavitree), Exeter, UK.
6
Newcastle Eye Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Royal Victoria Infirmary, Newcastle Upon Tyne, UK.
7
Clinical Genetics, Guys and St Thomas NHS Trust, Great Maze Pond, London, UK.
8
Hospices Civils de Lyon, Genetic Department and National HHT Reference Center, Femme-Mère-Enfants Hospital, Bron, France.
9
Teeside Genetics Unit, The James Cook University Hospital, Middlesbrough, UK.
10
Institute of Human Genetics, University of Lübeck, Lübeck, Germany.
11
Department of Ophthalmology and Vision Sciences, Hospital for Sick Children, Toronto, ON, Canada.
12
Department of Clinical Genetics, Great Ormond Street Hospital for Children, London, UK.
13
Department of Ophthalmology, Justus-Liebig-University Giessen, Giessen, Germany.
14
Northern Ireland Regional Genetics Service (NIRGS), Belfast City Hospital, Belfast, UK.
15
Department of Ophthalmology, Hôpital Universitaire des Enfants Reine Fabiola, Brussels, Belgium.
16
Department of Clinical Genetics, Sheffield Children's NHS Foundation Trust, Sheffield, UK.
17
Department of Ophthalmology, University of Freiburg, Freiburg, Germany.
18
University Hospital Southampton, Southampton, UK.
19
Clinical and Experimental Sciences, University of Southampton, Southampton, UK.
20
Academic Medical Genetics and Pathology, University of Glasgow, Queen Elizabeth University Hospital, Glasgow, UK.
21
Department of Genetics, University of Groningen, University Medical Center, Groningen, The Netherlands.
22
Medical Genetics, CHRU de Montpellier, Montpellier, France.
23
Clinical Genetics Unit, Birmingham Women's Hospital, Birmingham, UK.
24
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK. david.fitzpatrick@ed.ac.uk.

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.

KEYWORDS:

PAX6; microphthalmia; missense variant; paired domain; protein destabilization

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