RESUMEN
BACKGROUND: Many X-linked non-syndromic hearing loss (HL) cases are caused by various mutations in the POU domain class 3 transcription factor 4 (POU3F4) gene. This study aimed to identify allelic variants of this gene in two Chinese families displaying X-linked inheritance deafness-2 (DFNX2) and one sporadic case with indefinite inheritance pattern. METHODS: Direct DNA sequencing of the POU3F4 gene was performed in these families and in 100 Chinese individuals with normal hearing. RESULTS: There are characteristic imaging findings in DFNX2 Chinese families with POU3F4 mutations. The temporal bone computed tomography (CT) images of patients with DFNX2 are characterized by a thickened stapes footplate, hypoplasia of the cochlear base, absence of the bony modiolus, and dilated internal acoustic meatus (IAM) as well as by abnormally wide communication between the IAM and the basal turn of the cochlea. We identified three causative mutations in POU3F4 for three probands and their extended families. In family 1468, we observed a novel deletion mutation, c.973delT, which is predicted to result in a p.Trp325Gly amino acid frameshift. In family 2741, the mutation c.927delCTC was identified, which is predicted to result in the deletion of serine at position 310. In both families, the mutations were located in the POU homeodomain and are predicted to truncate the C-terminus of the POU domain. In the third family, a novel de novo transversion mutation (c.669 T > A) was identified in a 5-year-old boy that resulted in a nonsense mutation (p.Tyr223*). The mutation created a new stop codon and is predicted to result in a truncated POU3F4 protein. CONCLUSIONS: Based on characteristic radiological findings and clinical features, POU3F4 gene mutation analysis will increase the success rate of stapes operations and cochlear implantations, and improve molecular diagnosis, genetic counseling, and knowledge of the molecular epidemiology of HL among patients with DFNX2.
Asunto(s)
Pueblo Asiatico/genética , Genes Ligados a X/genética , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Pérdida Auditiva Conductiva/genética , Pérdida Auditiva Sensorineural/genética , Pérdida Auditiva/genética , Mutación/genética , Factores del Dominio POU/genética , Secuencia de Aminoácidos , Oído Interno/metabolismo , Femenino , Humanos , Masculino , Linaje , Hueso Temporal/metabolismoRESUMEN
OBJECTIVE: Based on the clinical manifestations of a hearing loss patient, the POU3F4 gene was tested for diagnosis of etiology. METHODS: A comprehensive physical examination was performed on the proband to exclude abnormalities of other organs, and detailed audiological testing and temporal bone CT scan were also performed. Genomic DNA was extracted using the proband's peripheral blood leukocytes. Polymerase chain reactions (PCR) were performed in the coding sequence of the POU3F4 gene. Direct DNA sequencing was subsequently applied to screen the entire coding region of the POU3F4 gene. RESULTS: The proband had severe sensorineural hearing loss. Temporal CT showed bilateral cochlear incomplete partition, vestibule dysplasia, internal auditory canal fundus expansion, and cochlear interlink with the internal auditory canal fundus. A novel mutation (c.530C > A (p.S177X)) in the POU3F4 gene was found in this patient, creating an new stop codon and was predicted to result in a truncated protein lacking normal POU3F4 transcription factor function. CONCLUSION: Through analysis of the POU3F4 gene and clinical manifestations in the patient, we conclude that a novel mutation may have resulted in a premature stop codon, contributing to the mutation of POU3F4 gene.
