Details

Autor(en) / Beteiligte

• Vaché, Christel
• Cubedo, Nicolas
• Mansard, Luke
• Sarniguet, Jérôme
• Baux, David
• Faugère, Valérie
• Baudoin, Corinne
• Moclyn, Melody
• Touraine, Renaud
• Lina-Granade, Geneviève
• Cossée, Mireille
• Bergougnoux, Anne
• Kalatzis, Vasiliki
• Rossel, Mireille
• Roux, Anne-Françoise

Titel

Identification and in vivo functional investigation of a HOMER2 nonstop variant causing hearing loss

Ist Teil von

• European journal of human genetics : EJHG, 2023-07, Vol.31 (7), p.834-840

Ort / Verlag

England: Nature Publishing Group

Erscheinungsjahr

2023

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.