RESUMEN
Hearing loss is a frequent sensory impairment in humans and genetic factors account for an elevated fraction of the cases. We have investigated a large family of five generations, with 15 reported individuals presenting non-syndromic, sensorineural, bilateral and progressive hearing loss, segregating as an autosomal dominant condition. Linkage analysis, using SNP-array and selected microsatellites, identified a region of near 13 cM in chromosome 20 as the best candidate to harbour the causative mutation. After exome sequencing and filtering of variants, only one predicted deleterious variant in the NCOA3 gene (NM_181659, c.2810C > G; p.Ser937Cys) fit in with our linkage data. RT-PCR, immunostaining and in situ hybridization showed expression of ncoa3 in the inner ear of mice and zebrafish. We generated a stable homozygous zebrafish mutant line using the CRISPR/Cas9 system. ncoa3-/- did not display any major morphological abnormalities in the ear, however, anterior macular hair cells showed altered orientation. Surprisingly, chondrocytes forming the ear cartilage showed abnormal behaviour in ncoa3-/-, detaching from their location, invading the ear canal and blocking the cristae. Adult mutants displayed accumulation of denser material wrapping the otoliths of ncoa3-/- and increased bone mineral density. Altered zebrafish swimming behaviour corroborates a potential role of ncoa3 in hearing loss. In conclusion, we identified a potential candidate gene to explain hereditary hearing loss, and our functional analyses suggest subtle and abnormal skeletal behaviour as mechanisms involved in the pathogenesis of progressive sensory function impairment.
Asunto(s)
Sordera/genética , Predisposición Genética a la Enfermedad , Pérdida Auditiva Sensorineural/genética , Coactivador 3 de Receptor Nuclear/genética , Adulto , Animales , Sordera/patología , Modelos Animales de Enfermedad , Oído Interno/metabolismo , Oído Interno/patología , Exoma/genética , Regulación del Desarrollo de la Expresión Génica/genética , Células Ciliadas Auditivas/metabolismo , Células Ciliadas Auditivas/patología , Pérdida Auditiva Sensorineural/patología , Humanos , Masculino , Ratones , Linaje , Secuenciación del Exoma , Pez Cebra/genéticaRESUMEN
Mutations in the CEACAM6 gene were first described as causing autosomal dominant nonsyndromic hearing loss, but two splice-altering variants have been recently described as causing autosomal recessive nonsyndromic hearing loss. We describe the novel and extremely rare loss-of-function variant c.436 C > T/p.(Arg146Ter) in the CEACAM16 gene segregating with post-lingual progressive autosomal recessive hearing loss. This variant is predicted to significantly reduce the size of the wild type protein. Our results give additional support that loss-of-function variants in CEACAM16 cause autosomal recessive hearing loss in humans.
Asunto(s)
Antígenos CD/genética , Moléculas de Adhesión Celular/genética , Sordera/genética , Genes Recesivos , Mutación , Femenino , Proteínas Ligadas a GPI/genética , Humanos , Masculino , LinajeRESUMEN
Hearing impairment is frequently found associated with pigmentary disorders in many syndromes. However, total oculocutaneous albinism (OCA) associated with deafness has been described only once, by Ziprkowski and Adam (Arch Dermatol 89:151-155, 1964) in an inbred family. A syndrome associating deafness and OCA was suggested by the authors, but two separate recessive genes segregating in this inbred group were also proposed later by Fraser (OMIM # 220900). Combined deafness and total OCA were also observed by us in a family originally reported to be nonconsanguineous but in which haplotyping showed evidence of a common ancestry: the proband was affected by both diseases, one of his sisters had only OCA and another sister had only deafness. Both the proband and his deaf sister were found to be homozygotes for the 35delG mutation (GJB2 gene), the most frequent cause of hereditary deafness. Linkage analysis with markers close to the four known OCA loci excluded linkage to OCA1, OCA2, and OCA3, and homozygosity in markers near OCA4 locus was observed. Sequencing of the corresponding gene (MATP) revealed a c.1121delT mutation, which leads to a stop codon at position 397 (L374fsX397). Clearly, the combined occurrence of deafness and albinism in this pedigree was due to mutations in two different genes, showing autosomal recessive inheritance. We speculate that the putative syndrome reported by Ziprkowski and Adam might have resulted from the co-occurrence of autosomal recessive deafness and albinism in the same pedigree, as suggested by Fraser.
Asunto(s)
Albinismo Oculocutáneo/complicaciones , Sordera/complicaciones , Sordera/genética , Genes Recesivos/genética , Adolescente , Albinismo Oculocutáneo/genética , Antígenos de Neoplasias , Audiometría de Tonos Puros , Niño , Preescolar , Conexina 26 , Conexinas , Análisis Mutacional de ADN , Exones/genética , Femenino , Haplotipos , Heterocigoto , Humanos , Masculino , Proteínas de la Membrana/genética , Proteínas de Transporte de Membrana , Datos de Secuencia Molecular , Linaje , SíndromeRESUMEN
Estudo de 6 casos de crianças com dados audiológicos sugestivos de neuropatia auditiva - NA, de diferentes etiologias
