Specificity of <i>SLC26A4</i> Mutations in the Pathogenesis of Inner Ear Malformations

Abstract

The traditional hypothesis concerning the pathogenesis of inner ear malformations holds that various types of malformations represent different stages of developmental arrest during embryogenesis. In order to verify this hypothesis, we surveyed mutations in the SLC26A4(PDS) gene, which were documented to cause enlarged vestibular aqueduct (EVA) and Mondini’s dysplasia (incomplete partition of the cochlea), in 35 families with various types of inner ear malformations. In 25 families, the probands showed EVA or Mondini’s dysplasia as the main temporal bone abnormalities, whereas the probands in the remaining 10 families revealed other types of malformations. In total, 7 mutated SLC26A4 alleles, including 6 missense mutations (A372V, A387V, T410M, S448L, T721M, and H723R) and 1 splice site mutation (IVS7-2A→G), were detected. All mutated alleles segregated the malformations of EVA and Mondini’s dysplasia, whereas no mutated alleles were found in the 10 probands with other types of malformations. SLC26A4 mutations were found in 22 of the 25 probands with EVA or Mondini’s dysplasia, indicating that these might be specific to the development of Mondini’s dysplasia and EVA. It is inferred that the pathogenetic mechanisms of the various malformations essentially differ, although their radiological findings appear to follow a continuum of morphological changes.

SLC26A4 mutations are associated with a specific inner ear malformation

“…A recent study with a similar patient population reported that SLC26A4 mutations were not present in patients with cochlear, vestibular and semicircular 482 S. Fitoz et al canal anomalies, other than EVA or Mondini dysplasia [15]. Our study expands the spectrum of inner ear anomalies that are not associated with SLC26A4 mutations and provide a detailed description of Mondini dysplasia observed in patients with mutant SLC26A4 alleles.…”

Mutations in the <i>OTOF</i> Gene in Taiwanese Patients with Auditory Neuropathy

“…Meanwhile, all probands of the 22 families were also subjected to mutation screening of 3 genes commonly associated with idiopathic SNHI, the GJB2 (or Cx26 ) gene (MIM * 121011) [Wu et al, 2008], the SLC26A4 (PDS) gene (MIM * 605646) [Wu et al, 2005a] and the mitochondrial 12S rRNA (MTRNR1) gene (MIM * 561000) [Wu et al, 2007], to exclude the possibility that the underlying pathology of the hearing impairment was due to a different genetic etiology.…”

Spectrum and Frequency of SLC26A4 Mutations Among Czech Patients with Early Hearing Loss with and without Enlarged Vestibular Aqueduct (EVA)

“…This again raises the question of the existence of DFNB4 as an independent disorder, because there is still a high suspicion for this to be only a juvenile (incomplete) form of PS lacking goitre that will manifest post-pubertally. There is only a single published case of a patient of the age of 40 having EVA and 2 mutations in the SLC26A4 gene and no thyroid impairment (Wu et al, 2005). On the other hand there is evidence of thyroid impairment onset at the age of 37 years (Blons et al, 2004).…”