Hereditary hearing loss and deafness genes in Japan.

Hearing loss (HL) is the most common sensory impairment occurring at birth in developed countries. Epidemiological data show that more than one child in 1000 is born with HL, while more than 50% of prelingual HL cases are found to be hereditary. Approximately 70% of hereditary HL is nonsyndromic and subdivided to autosomal dominant (20%), autosomal recessive (75%), X-linked HL (1%), and maternally-inherited HL associated with the mitochondrial DNA mutation. More than 10 deafness genes have been reported to be responsible for nonsyndromic hereditary HL in Japan. Among them, the most prevalent causative genes, GJB2 and the mitochondrial DNA 12SrRNA are introduced. In addition, this study also refers to the specific genes responsible for the unique audiogram, mainly WFS1. Finally, the genes related to the enlargement of vestibular aqueduct of inner ear abnormality, SLC26A4, EYA1 and SIX1 are discussed. The clinical and genetic findings associated with these disorders including the results of a recent study are reviewed.

Novel ATP6V1B1 mutations in distal renal tubular acidosis and hearing loss.

CONCLUSION: Novel ATP6V1B1 mutations were found in a patient with distal renal tubular acidosis (dRTA), hearing loss (HL), and enlargement of the vestibular aqueduct (EVA). The deterioration of HL and vertiginous attacks may be associated with the disruption of the endolymph pH homeostasis. OBJECTIVES: To study the audiovestibular functions and to identify the causative gene. METHODS: This study enrolled a Japanese family, where the proband showed type 1 dRTA, early onset HL, and bilateral EVA. A deterioration of HL occurred several times in both ears. Vertiginous attacks were always associated with a deterioration of HL. Audiovestibular examinations included distortion product otoacoustic emissions (DPOAEs), auditory brainstem responses (ABRs), caloric testing, and vestibular evoked myogenic potentials (VEMPs). Direct sequencing was utilized to screen for ATP6V1B1, SLC26A4, and GJB2 mutations. RESULTS: The findings of DPOAEs and ABRs indicated cochlear HL. The vestibular function was thought to be mildly impaired according to the caloric responses and VEMP findings. Two novel ATP6V1B1 mutations of a heterozygous 15 base-pair deletion (c.756_770del) in exon 7 and a heterozygous 1 base-pair insertion (c.1242_1243insC) in exon 12 were detected in a compound heterozygous state. No mutation was identified in either SLC26A4 or GJB2.

SIX1 mutation associated with enlargement of the vestibular aqueduct in a patient with branchio-oto syndrome.

OBJECTIVES: : The objectives of this study were to identify SIX1 gene mutations in a patient with branchio-oto syndrome (BO) and to clarify the relationship between SIX1 mutation and enlargement of the vestibular aqueduct (EVA). METHODS: : A genetic study and retrospective chart review for a patient in whom EYA1 mutation had already been excluded was conducted. We studied a Japanese patient who had autosomal-dominant mixed hearing loss, a unilateral ear pit and unilateral EVA, and who was previously diagnosed as having BO. We searched for SIX1 and SLC26A4 mutations using polymerase chain reaction and direct gene sequencing. RESULTS: : The patient carried a heterozygous A-->G mutation at nucleotide 386 within exon 1 of SIX1 that resulted in substitution of a cysteine for a tyrosine at codon 129 (Y129C) of the gene product. Y129C is a previously identified SIX1 mutation and was not detected in any of our 164 control chromosomes. No SLC26A4 mutations were identified. CONCLUSION: : Y129C mutation in SIX1 may cause EVA as well as BO.

A mutation in Wolfram syndrome type 1 gene in a Japanese family with autosomal dominant low-frequency sensorineural hearing loss.

CONCLUSION: Our findings suggest that Wolfram syndrome type 1 gene (WFS1) mutation is an important cause of autosomal dominant low-frequency sensorineural hearing loss (LFSNHL) in Japan. OBJECTIVE: DFNA6/14 is caused by a heterozygous mutation of WFS1 and is a common cause of autosomal dominant LFSNHL among populations in both Europe and the US. The purpose of this study was to investigate WFS1 mutations among Japanese patients whose phenotypes were consistent with those of DFNA6/14. MATERIAL AND METHODS: Using audiometry and genetic analysis, we searched for WFS1 mutations in three unrelated Japanese patients with LFSNHL and a familial history of autosomal dominant hearing loss. RESULTS: One patient carried a heterozygous G2700A mutation at codon 844 in exon 8, resulting in substitution of a threonine for an alanine (A844T). Genetic analysis of the available members of the patient's family showed that the A844T mutation segregated with LFSNHL, but was not detected in any of 140 control chromosomes. It thus appears likely that the A844T mutation is causative for hearing loss in this group. Speech audiometry, self-recording audiometry and auditory brainstem responses showed the patient to have cochlear deafness without retrocochlear dysfunction. No mutation was found in the other two patients.

Audiovestibular findings in patients with mitochondrial A1555G mutation.

OBJECTIVE: The aims of this study were to explore the prevalence of the A1555G mutation among a group of Japanese patients and to assess the pathophysiology of the hearing impairment associated with the mutation. STUDY DESIGN: Genetic study and retrospective chart review. METHODS: We screened for the mitochondrial DNA A1555G mutation in 138 unrelated Japanese deaf patients, including 63 sporadic cases and 75 familial cases with different patterns of inheritance. When available, patients carrying the mutation received audiovestibular examinations, including speech audiometry, distortion-product otoacoustic emission (DPOAE) testing, electrocochleography (ECochG), and electronystagmography. RESULTS: One of 63 sporadic cases (1.6%) and 6 of 75 familial cases (8.0%) carried the A1555G mutation. Patients with the mutation and a familial history included two with autosomal recessive inheritance and four with maternal inheritance. In addition, two of six patients (33.3%) presenting with aminoglycoside-induced sensorineural hearing loss (SNHL) were associated with the A1555G mutation. All but one of the patients carrying the mutation showed high-frequency SNHL. Distortion-product levels of DPOAE were reduced to the noise levels, suggesting the A1555G mutation caused cochlear deafness. Cochlear microphonics in ECochG showed elevation of the detection thresholds and corresponding audiometric thresholds. The ECochG data implied that patients with high-frequency SNHL had impairment of the cochlear hair cells that was most severe toward the basal turn. The electronystagmographic findings indicated no apparent vestibular dysfunction. CONCLUSIONS: Screening for the A1555G mutation, even in patients with idiopathic bilateral SNHL, likely would be useful for preventing further development and/or acceleration of the deafness.

Mutation of the EYA1 gene in patients with branchio-oto syndrome.

Branchio-oto-renal (BOR) and branchio-oto (BO) syndromes are autosomal dominant disorders, characterized by the presence of branchial, otic and renal anomalies of varying degrees of severity. We investigated the presence of EYA1 mutation in two unrelated patients with autosomal dominant hereditary deafness and congenital preauricular fistula. Case 1 had a mutation and polymorphisms, while Case 2 had polymorphisms with no mutations. In Case 1 we detected a heterozygous A-->G mutation at nucleotide 625 resulting in a serine to glycine substitution at codon 189 (S189G). The S189G mutation was not detected in 54 controls (108 alleles). Pure-tone audiometry showed bilateral mixed hearing loss of mild to moderate severity in Case 1. Case 2 had suffered from bilateral hearing loss since the age of 5 years and pure-tone audiometry showed bilateral moderate mixed hearing loss. These results suggest that the S189G mutation is a candidate mutation for BOR/BO syndrome.