Journal Article

ATOH7 mutations cause autosomal recessive persistent hyperplasia of the primary vitreous

Lev Prasov, Tehmina Masud, Shagufta Khaliq, S. Qasim Mehdi, Aiysha Abid, Edward R. Oliver, Eduardo D. Silva, Amy Lewanda, Michael C. Brodsky, Mark Borchert, Daniel Kelberman, Jane C. Sowden, Mehul T. Dattani and Tom Glaser

in Human Molecular Genetics

Volume 21, issue 16, pages 3681-3694
Published in print August 2012 | ISSN: 0964-6906
Published online May 2012 | e-ISSN: 1460-2083 | DOI:
ATOH7 mutations cause autosomal recessive persistent hyperplasia of the primary vitreous

Show Summary Details


The vertebrate basic helix–loop–helix (bHLH) transcription factor ATOH7 (Math5) is specifically expressed in the embryonic neural retina and is required for the genesis of retinal ganglion cells (RGCs) and optic nerves. In Atoh7 mutant mice, the absence of trophic factors secreted by RGCs prevents the development of the intrinsic retinal vasculature and the regression of fetal blood vessels, causing persistent hyperplasia of the primary vitreous (PHPV). We therefore screened patients with hereditary PHPV, as well as bilateral optic nerve aplasia (ONA) or hypoplasia (ONH), for mutations in ATOH7. We identified a homozygous ATOH7 mutation (N46H) in a large family with an autosomal recessive PHPV disease trait linked to 10q21, and a heterozygous variant (R65G, p.Arg65Gly) in one of five sporadic ONA patients. High-density single-nucleotide polymorphism analysis also revealed a CNTN4 duplication and an OTX2 deletion in the ONA cohort. Functional analysis of ATOH7 bHLH domain substitutions, by electrophoretic mobility shift and luciferase cotransfection assays, revealed that the N46H variant cannot bind DNA or activate transcription, consistent with structural modeling. The N46H variant also failed to rescue RGC development in mouse Atoh7−/− retinal explants. The R65G variant retains all of these activities, similar to wild-type human ATOH7. Our results strongly suggest that autosomal recessive persistent hyperplastic primary vitreous is caused by N46H and is etiologically related to nonsyndromic congenital retinal nonattachment. The R65G allele, however, cannot explain the ONA phenotype. Our study firmly establishes ATOH7 as a retinal disease gene and provides a functional basis to analyze new coding variants.

Journal Article.  9077 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.