Efficient molecular genetic diagnosis of enlarged vestibular aqueducts in East Asians.
BACKGROUND
Enlargement of the vestibular aqueduct (EVA) is a commonly detected inner ear anomaly related to hearing loss and often associated with mutations of SLC26A4 encoding pendrin, a transmembrane exchanger of Cl(-), I(-), and HCO(3)(-). Here we describe the phenotypes of 27 Korean EVA subjects and their SLC26A4 genotypes determined by bidirectional nucleotide sequencing.


RESULTS
The detected variants include two novel missense substitutions (p.V138L and p.P542R). We characterized the ability of p.V138L and p.P542R pendrin products to traffic to the plasma membrane in COS-7 cells and to transport Cl(-), I(-), and HCO(3)(-) in Xenopus oocytes. The results indicate that p.P542R is a benign polymorphic variant, whereas p.V138L is a pathogenic mutation. Since this and other studies of East Asian EVA cohorts show that the majority of SLC26A4 mutations affect either or both of two amplicons (exons 7-8 and 19), we developed a hierarchical protocol that integrates direct sequencing with denaturing high-performance liquid chromatography analyses for detection of SLC26A4 mutations in these populations. We validated the cost efficiency of the integrated protocol by a simulated screen of published East Asian EVA cohorts with known SLC26A4 genotypes.


CONCLUSIONS
Our study further defines the spectrum of SLC26A4 mutations among East Asians and demonstrates a rapid and efficient protocol for their detection.
Choi
Byung Yoon
BY
Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University College of Medicine, Seoul, Korea.
Stewart
Andrew K
AK
Nishimura
Katherine K
KK
Cha
Won Jae
WJ
Seong
Moon-Woo
MW
Park
Sung Sup
SS
Kim
Seung Won
SW
Chun
Yang Sook
YS
Chung
Jong Woo
JW
Park
Shi-Nae
SN
Chang
Sun O
SO
Kim
Chong-Sun
CS
Alper
Seth L
SL
Griffith
Andrew J
AJ
Oh
Seung-Ha
SH
D000293:Adolescent; D000328:Adult; D000818:Animals; D019556:COS Cells; D002648:Child; D002675:Child, Preschool; D002522:Chlorocebus aethiops; D002851:Chromatography, High Pressure Liquid; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics; D025202:Molecular Diagnostic Techniques; D020125:Mutation, Missense; D056910:Republic of Korea; D000076988:Sulfate Transporters; D014723:Vestibular Aqueduct / Q000473:pathology*; D015837:Vestibular Diseases / Q000175:diagnosis* / Q000235:genetics
D026901:Membrane Transport Proteins; C085609:SLC26A4 protein, human; D000076988:Sulfate Transporters