Abstract
BackgroundPendred syndrome (PS) and nonsyndromic hearing loss associated with enlarged vestibular aqueduct (EVA) are caused by SLC26A4 mutations. The Okinawa Islands are the southwestern-most islands of the Japanese archipelago. And ancestral differences have been reported between people from Okinawa Island and those from the main islands of Japan. To confirm the ethnic variation of the spectrum of SLC26A4 mutations, we investigated the frequencies of SLC26A4 mutations and clinical manifestations of patients with EVA or PS living in the Okinawa Islands.MethodsWe examined 22 patients with EVA or PS from 21 unrelated families in Okinawa Islands. The patient’s clinical history, findings of physical and otoscopic examinations, hearing test, and computed tomography (CT) scan of the temporal bones were recorded. To detect mutations, all 21 exons and the exon–intron junctions of SLC26A4 were sequenced for all subjects. Quantitative reverse-transcription polymerase chain reaction (qRT-PCR) for SLC26A4 and calculations using the comparative CT (2−ΔΔCT) method were used to determine the pathogenicity associated with gene substitutions.ResultsSLC26A4 mutations were identified in 21 of the 22 patients. We found a compound heterozygous mutation for IVS15 + 5G > A/H723R in nine patients (41%), a homozygous substitution of IVS15 + 5G > A in six patients (27%), and homozygous mutation for H723R in five patients (23%). The most prevalent types of SLC26A4 alleles were IVS15 + 5G > A and H723R, which both accounted for 15/22 (68%) of the patients. There were no significant correlations between the types of SLC26A4 mutation and clinical manifestations. Based on qRT-PCR results, expression of SLC26A4 was not identified in patients with the homozygous substitution of IVS15 + 5G > A.ConclusionsThe substitution of IVS15 + 5G > A in SLC26A4 was the most common mutation in uniquely found in patients with PS and EVA in Okinawa Islands. This suggested that the spectrum of SLC26A4 mutation differed from main islands of Japan and other East Asian countries. The substitution of IVS15 + 5G > A leads to a loss of SLC26A expression and results in a phenotype of PS and EVA.
Highlights
Pendred syndrome (PS) and nonsyndromic hearing loss associated with enlarged vestibular aqueduct (EVA) are caused by SLC26A4 mutations
Among the 21 patients with mutations, a compound heterozygous mutation for IVS15 + 5G > A/H723R was identified in nine patients (Figure 3C, D), a homozygous mutation for H723R was identified in five patients (Figure 3E), and a homozygous substitution of IVS15 + 5G > A was identified in six patients (Figure 3F)
Our results indicate that the substitution of IVS15 + 5G > A is a lossof-function mutation caused by a loss of SLC26A4 expression
Summary
Pendred syndrome (PS) and nonsyndromic hearing loss associated with enlarged vestibular aqueduct (EVA) are caused by SLC26A4 mutations. The Okinawa Islands are the southwestern-most islands of the Japanese archipelago. Ancestral differences have been reported between people from Okinawa Island and those from the main islands of Japan. Pendred syndrome (PS) is an autosomal recessive disorder characterized by congenital sensorineural hearing loss and goiter [6]. Enlarged vestibular aqueduct (EVA) is a common inner ear malformation that can be diagnosed radiographically in patients with impaired hearing (Figure 1). In addition to PS, SLC26A4 mutations cause nonsyndromic hearing loss with EVA in the absence of a thyroid phenotype [12,13]
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