In 3 families with autosomal recessive deafness-4 with enlarged vestibular aqueduct (DFNB4; 600791), Usami et al. (1999) identified a 2168A-G transition in exon 19 of the SLC26A4 gene, causing a his723-to-arg (H723R) substitution. This mutation was found in homozygosity in 1 family and in compound heterozygosity in affected members of the other 2 families, who also carried a 2162C-T transition in exon 19 of the SLC26A4 gene, resulting in a thr721-to-met (T721M; 605646.0012) substitution.
Tekin et al. (2003) identified the H723R mutation in homozygous state in a Turkish patient with classic Pendred syndrome (PDS; 274600). They noted that the mutation had been identified in families from Japan and China in which affected members had sensorineural hearing loss and enlarged vestibular aqueduct without goiter. Tekin et al. (2003) suggested that the detection of the H723R mutation in Turkey reflected the migration of the Turkish people from central Asia more than 1,000 years ago.
In 2 sibs with enlarged vestibular aqueduct and an unrelated patient with Pendred syndrome, Tsukamoto et al. (2003) identified compound heterozygosity for the H723R and T721M mutations in the SLC26A4 gene, and concluded that the 2 conditions are part of a continuous spectrum of disease.
Among 26 Korean patients with DFNB4 with enlarged vestibular aqueduct (EVA), Park et al. (2005) found that the H723R mutation was the most common, accounting for 40% of the mutant alleles.
Among Chinese patients with DFNB4 with EVA, Wang et al. (2007) found that H723R was the second most common mutation, accounting for 9% of mutant alleles.
Using in vitro cellular expression studies, Yoon et al. (2008) demonstrated that the H723R mutant protein was retained in the endoplasmic reticulum, whereas wildtype pendrin reached the plasma membrane. The mutant protein showed significantly decreased Cl-/HCO3- exchange activity, but the defects could be rescued considerably by decreased temperature.
