PUBLICATION
Identification and in vivo functional investigation of a HOMER2 nonstop variant causing hearing loss
- Authors
- Vaché, C., Cubedo, N., Mansard, L., Sarniguet, J., Baux, D., Faugère, V., Baudoin, C., Moclyn, M., Touraine, R., Lina-Granade, G., Cossée, M., Bergougnoux, A., Kalatzis, V., Rossel, M., Roux, A.F.
- ID
- ZDB-PUB-230514-31
- Date
- 2023
- Source
- European journal of human genetics : EJHG 31(7): 834-840 (Journal)
- Registered Authors
- Cubedo, Nicolas, Rossel, Mireille
- Keywords
- none
- MeSH Terms
-
- Animals
- Codon, Terminator
- Deafness*/genetics
- Hearing Loss*/genetics
- Hearing Loss, Sensorineural*/genetics
- Mutation
- Pedigree
- Zebrafish/genetics
- PubMed
- 37173411 Full text @ Eur. J. Hum. Genet.
Citation
Vaché, C., Cubedo, N., Mansard, L., Sarniguet, J., Baux, D., Faugère, V., Baudoin, C., Moclyn, M., Touraine, R., Lina-Granade, G., Cossée, M., Bergougnoux, A., Kalatzis, V., Rossel, M., Roux, A.F. (2023) Identification and in vivo functional investigation of a HOMER2 nonstop variant causing hearing loss. European journal of human genetics : EJHG. 31(7):834-840.
Abstract
DFNA68 is a rare subtype of autosomal dominant nonsyndromic hearing impairment caused by heterozygous alterations in the HOMER2 gene. To date, only 5 pathogenic or likely pathogenic coding variants, including two missense substitutions (c.188 C > T and c.587 G > C), a single base pair duplication (c.840dupC) and two short deletions (c.592_597delACCACA and c.832_836delCCTCA) have been described in 5 families. In this study, we report a novel HOMER2 variation, identified by massively parallel sequencing, in a Sicilian family suffering from progressive dominant hearing loss over 3 generations. This novel alteration is a nonstop substitution (c.1064 A > G) that converts the translational termination codon (TAG) of the gene into a tryptophan codon (TGG) and is predicted to extend the HOMER2 protein by 10 amino acids. RNA analyses from the proband suggested that HOMER2 transcripts carrying the nonstop variant escaped the non-stop decay pathway. Finally, in vivo studies using a zebrafish animal model and behavioral tests clearly established the deleterious impact of this novel HOMER2 alteration on hearing function. This study identifies the fourth causal variation responsible for DFNA68 and describes a simple in vivo approach to assess the pathogenicity of candidate HOMER2 variants.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping