ATOH7 mutations cause autosomal recessive persistent hyperplasia of the primary vitreous.
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.
Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
Lev
L
Prasov
Tehmina
T
Masud
Shagufta
S
Khaliq
S Qasim
SQ
Mehdi
Aiysha
A
Abid
Edward R
ER
Oliver
Eduardo D
ED
Silva
Amy
A
Lewanda
Michael C
MC
Brodsky
Mark
M
Borchert
Daniel
D
Kelberman
Jane C
JC
Sowden
Mehul T
MT
Dattani
Tom
T
Glaser
D000818:Animals; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D002879:Chromosomes, Human, Pair 10; D005260:Female; D005808:Genes, Recessive; D018257:Helix-Loop-Helix Motifs / Q000235:genetics; D006801:Humans; D006965:Hyperplasia / Q000235:genetics*; D007223:Infant; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009900:Optic Nerve / Q000002:abnormalities / Q000473:pathology; D009924:Organ Culture Techniques / Q000379:methods; D010375:Pedigree; D012164:Retinal Diseases / Q000235:genetics* / Q000473:pathology; D014822:Vitreous Body / Q000473:pathology*
D051792:Basic Helix-Loop-Helix Proteins; D009419:Nerve Tissue Proteins; C456975:ATOH7 protein, human; C117638:Atoh7 protein, mouse