Biallelic ATOH1 Gene Variant in Siblings With Pontocerebellar Hypoplasia, Developmental Delay, and Hearing Loss

Abstract

Background and ObjectivesTo report on the novel association of biallelic variant in atonal basic helix-loop-helix transcription factor 1 (ATOH1) gene and pontocerebellar hypoplasia (PCH), severe global developmental delay, intellectual disability, and hearing loss in a family with 2 affected siblings.MethodsA detailed clinical assessment and exome sequencing of peripheral blood sample were performed. Segregation analysis with Sanger sequencing and structural modeling of the variant was performed to support the pathogenicity of the variant.ResultsA homozygous missense variant (NM_005172.1:c.481C>G) in the ATOH1 gene was identified in the proband and his affected sister. The segregation analysis subsequently confirmed its segregation with an apparently recessive PCH in this family. ATOH1 encodes for the atonal basic helix-loop-helix (bHLH) transcription factor 1, a core transcription factor in the developing cerebellum, brainstem, and dorsal spinal cord, and in the ear. The identified variant results in the p.(Arg161Gly) amino acid substitution in the evolutionarily conserved DNA-binding bHLH domain of the ATOH1 protein. Biallelic missense variants in this domain were previously reported to result in disordered cerebellar development and hearing loss in animal models. In silico homology modeling revealed that p.Arg161Gly in ATOH1 protein probably disrupts a salt bridge with DNA backbone phosphate and increases the flexibility of the bHLH helix–both of which together affect the binding capability of the bHLH domain to the DNA.DiscussionBased on the sequencing results and evidence from structural modeling of the identified variant, as well as with previous reports of ATOH1 gene disruption, we conclude that ATOH1 may represent a novel candidate gene associated with the phenotype of PCH, global developmental delay, and hearing loss in humans.

Atoh1 drives the heterogeneity of the pontine nuclei neurons and promotes their differentiation

“…S1). These data suggested that partial loss of function of Atoh1 not only leads to delayed development of PN but also leads to PN hypoplasia in mice reminiscent of the malformation of the PN in patients with ATOH1 missense variant ( 22 ). Together, these data reinforced the importance of Atoh1 in PN development and demonstrated that Atoh1 hypomorphic allele could provide a useful mouse model to dissect the functions of Atoh1 during PN development.…”

“…In the hindbrain, Atoh1 -lineage neurons contribute to many key components of the proprioceptive pathway, including the PN ( 9 , 21 ). A recent report implicated a homozygous missense variant in ATOH1 in two human patients with global developmental delay, motor function deficits, pontocerebellar hypoplasia, and hearing loss ( 22 ). It is thus of great interest and clinical relevance to understand how Atoh1 shapes proper PN development.…”

Cerebellar development after preterm birth

“…Decreased proliferation of GCPs in pigs was associated with reduced expression of cell-cycle promoting cyclins and the Atoh1 and Jag1 genes ( Iskusnykh et al, 2018 ). The Atoh1 transcription factor is critical for the expansion of GCPs, and the secreted mitogen jagged canonical notch ligand 1 (Jag1) promotes the proliferation of GCPs in the mouse ( Solecki et al, 2001 ; Flora et al, 2009 ; Klisch et al, 2011 ; Višnjar et al, 2022 ). Interestingly, supplementation of ex vivo cerebellar slices from preterm pigs with recombinant Jag1 protein rescued GCP proliferation, further supporting the role of Jag1 as an essential mediator of the preterm cerebellar hypoplasia phenotype ( Iskusnykh et al, 2018 ).…”