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, Thomas M Glaser

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article numberdds197
Pages (from-to)3681-3694
Number of pages14
JournalHuman Molecular Genetics
Volume21
Issue number16
DOIs
StatePublished - Aug 2012
Externally publishedYes

Fingerprint

Optic Nerve
Hyperplasia
Retinal Ganglion Cells
Mutation
Helix-Loop-Helix Motifs
Basic Helix-Loop-Helix Transcription Factors
Retinal Diseases
Luciferases
Fetal Blood
Single Nucleotide Polymorphism
Blood Vessels
Vertebrates
Retina
Alleles
Phenotype
DNA
Genes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Prasov, L., Masud, T., Khaliq, S., Mehdi, S. Q., Abid, A., Oliver, E. R., ... Glaser, T. M. (2012). ATOH7 mutations cause autosomal recessive persistent hyperplasia of the primary vitreous. Human Molecular Genetics, 21(16), 3681-3694. [dds197]. https://doi.org/10.1093/hmg/dds197

ATOH7 mutations cause autosomal recessive persistent hyperplasia of the primary vitreous. / Prasov, Lev; Masud, Tehmina; Khaliq, Shagufta; Mehdi, S. Qasim; Abid, Aiysha; Oliver, Edward R.; Silva, Eduardo D.; Lewanda, Amy; Brodsky, Michael C.; Borchert, Mark; Kelberman, Daniel; Sowden, Jane C.; Dattani, Mehul T.; Glaser, Thomas M.

In: Human Molecular Genetics, Vol. 21, No. 16, dds197, 08.2012, p. 3681-3694.

Research output: Contribution to journalArticle

Prasov, L, Masud, T, Khaliq, S, Mehdi, SQ, Abid, A, Oliver, ER, Silva, ED, Lewanda, A, Brodsky, MC, Borchert, M, Kelberman, D, Sowden, JC, Dattani, MT & Glaser, TM 2012, 'ATOH7 mutations cause autosomal recessive persistent hyperplasia of the primary vitreous', Human Molecular Genetics, vol. 21, no. 16, dds197, pp. 3681-3694. https://doi.org/10.1093/hmg/dds197
Prasov L, Masud T, Khaliq S, Mehdi SQ, Abid A, Oliver ER et al. ATOH7 mutations cause autosomal recessive persistent hyperplasia of the primary vitreous. Human Molecular Genetics. 2012 Aug;21(16):3681-3694. dds197. https://doi.org/10.1093/hmg/dds197
Prasov, Lev ; Masud, Tehmina ; Khaliq, Shagufta ; Mehdi, S. Qasim ; Abid, Aiysha ; Oliver, Edward R. ; Silva, Eduardo D. ; Lewanda, Amy ; Brodsky, Michael C. ; Borchert, Mark ; Kelberman, Daniel ; Sowden, Jane C. ; Dattani, Mehul T. ; Glaser, Thomas M. / ATOH7 mutations cause autosomal recessive persistent hyperplasia of the primary vitreous. In: Human Molecular Genetics. 2012 ; Vol. 21, No. 16. pp. 3681-3694.
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AU - Silva, Eduardo D.

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