Atonal homolog 7 (ATOH7) loss-of-function mutations in predominant bilateral optic nerve hypoplasia

Abstract

Optic nerve hypoplasia (ONH) is a congenital optic nerve abnormality caused by underdevelopment of retinal ganglion cells (RGCs). Despite being a rare disease, ONH is the most common optic disc anomaly in ophthalmological practice. So far, mutations in several genes have been identified as causative, however many cases of ONH remain without a molecular explanation. The early transcription factor atonal basic-helix-loop-helix (bHLH) transcription factor 7 (ATOH7) is expressed in retinal progenitor cells and has a crucial role in RGC development. Previous studies have identified several mutations in the ATOH7 locus in cases of eye developmental diseases such as nonsyndromic congenital retinal nonattachment and persistent hyperplasia of the primary vitreous. Here we present two siblings with a phenotype predominated by bilateral ONH, with additional features of foveal hypoplasia and distinct vascular abnormalities, where whole-exome sequencing identified two compound heterozygous missense mutations affecting a conserved amino acid residue within the bHLH domain of ATOH7 (NM_145178.3:c.175G>A; p.(Ala59Thr) and c.176C>T; p.(Ala59Val)). ATOH7 expression constructs with patient single nucleotide variants were cloned for functional characterization. Protein analyses revealed decreased protein amounts and significantly enhanced degradation in the presence of E47, a putative bHLH dimerization partner. Protein interaction assays revealed decreased heterodimerization and DNA-binding of ATOH7 variants, resulting in total loss of transcriptional activation of luciferase reporter gene expression. These findings strongly support pathogenicity of the two ATOH7 mutations, one of which is novel. Additionally, this report highlights the possible impact of altered ATOH7 dimerization on protein stability and function.

TheAtoh7remote enhancer provides transcriptional robustness during retinal ganglion cell development

“…Human nonsyndromic congenital retinal nonattachment (NCRNA) disease is characterized by optic nerve aplasia, with profound secondary retinovascular and other ocular defects ( 26 , 27 ). The clinical phenotype overlaps autosomal recessive persistent hyperplastic primary vitreous (arPHPV) and vitreoretinal dystrophy, which are caused by point mutations in the ATOH7 coding sequence ( 18 , 26 , 28 , 29 ), and findings in Atoh7 mutant mice ( 16 , 17 , 30 ). NCRNA is caused by a 6.5-kb deletion, extending from 19.2 to 25.7 kb upstream of the TSS.…”

Transcriptome analysis of the zebrafishatoh7−/−Mutant,lakritz, highlights Atoh7‐dependent genetic networks with potential implications for human eye diseases

“…3,5,6 Likewise, an increasing number of studies highlight ATOH7 as an emerging candidate for eye diseases in humans. Variations in the ATOH7 locus have been associated with optic nerve hypoplasia (ONH) and aplasia (ONA), [8][9][10][11] further pointing towards the crucial role of atoh7 in RGC genesis and optic nerve development. Remarkably, a number of studies have also emerged, which highlight ATOH7 variants as associated with multiple eye disease traits.…”

Expression of a Barhl1a reporter in subsets of retinal ganglion cells and commissural neurons of the developing zebrafish brain

“…In tetrapods, barhl2 (previously named MBH1 and XBH1) is expressed in both amacrine cells and RGCs of the developing and mature retina 12,13 . Studies have also reported that Barhl2 is both sufficient and essential for determining the subtype specific identity of amacrine cells as well as to promote the maturation and survival of RGCs downstream of Atoh7 (also known as Ath5) -a bHLH transcription factor required for the specification of RGCs in vertebrates [12][13][14][15][16][17][18] .…”