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

Lookup NU author(s): Michael Clarke



This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0).


© 2019, The Author(s).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.

Publication metadata

Author(s): Williamson KA, Hall HN, Owen LJ, Livesey BJ, Hanson IM, Adams GGW, Bodek S, Calvas P, Castle B, Clarke M, Deng AT, Edery P, Fisher R, Gillessen-Kaesbach G, Heon E, Hurst J, Josifova D, Lorenz B, McKee S, Meire F, Moore AT, Parker M, Reiff CM, Self J, Tobias ES, Verheij JBGM, Willems M, Williams D, van Heyningen V, Marsh JA, FitzPatrick DR

Publication type: Article

Publication status: Published

Journal: Genetics in Medicine

Year: 2020

Volume: 22

Pages: 598–609

Print publication date: 01/03/2020

Online publication date: 08/11/2019

Acceptance date: 15/10/2019

Date deposited: 25/11/2019

ISSN (print): 1098-3600

ISSN (electronic): 1530-0366

Publisher: Nature Publishing Group


DOI: 10.1038/s41436-019-0685-9

PubMed id: 31700164


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Funder referenceFunder name
Lister Institute Research Prize Fellow
MRC University Unit Award