ATOH7 – Persistent Hyperplastic Primary Vitreous

ATOH7 encodes a basic helix–loop–helix transcription factor essential for retinal ganglion cell (RGC) differentiation and optic nerve formation. It is specifically expressed in the embryonic neural retina, where it regulates the development and regression of fetal ocular vasculature. Disruption of ATOH7 function impairs trophic support from RGCs, predisposing to persistent fetal vasculature and related vitreoretinal anomalies.

Persistent hyperplastic primary vitreous (PHPV; MONDO:0019631) follows an autosomal recessive inheritance pattern. A homozygous c.136A>C (p.Asn46His) variant in ATOH7 was identified in a large consanguineous family with multiple affected individuals, segregating with PHPV across affected relatives (PMID:22645276). No additional ATOH7 LoF variants have been reported in unrelated PHPV cohorts to date.

Other coding changes in ATOH7, such as the heterozygous c.193A>G (p.Arg65Gly) allele found in sporadic optic nerve aplasia/hypoplasia, retain DNA-binding and transactivation activity and do not cosegregate with PHPV (PMID:22645276). This emphasizes the specificity of the biallelic p.Asn46His substitution in mediating the PHPV phenotype.

Functional assays demonstrate that the p.Asn46His substitution abrogates DNA binding in electrophoretic mobility shift assays and fails to activate a reporter in luciferase cotransfection experiments. Moreover, this variant cannot rescue RGC development in Atoh7–/– mouse retinal explants (PMID:22645276). These data support a loss-of-function mechanism.

In mice, complete loss of Atoh7 recapitulates the PHPV phenotype, with persistence of the primary vitreous and failure of intrinsic retinal vessel formation due to absence of RGC-derived trophic factors, mirroring the human presentation (PMID:22645276).

Altogether, genetic segregation in a consanguineous pedigree, combined with concordant functional and animal‐model evidence, establishes ATOH7 deficiency as a pathogenic driver of autosomal recessive PHPV. Key take-home: screening for biallelic LoF ATOH7 variants is clinically indicated in families presenting with persistent fetal vasculature.

References

• Human molecular genetics • 2012 • ATOH7 mutations cause autosomal recessive persistent hyperplasia of the primary vitreous. PMID:22645276

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