A novel mutation of POU3F4 causes congenital profound sensorineural hearing loss in a large Chinese family.
OBJECTIVE
It is known that approximately 5% of congenital profound hearing impaired cases are inherited in X-linked inheritance. This study aimed at identifying its underlying molecular determinant(s) using a large, five-generation Chinese family with multiple familial cases.


METHODS
Model-based linkage analysis and positional cloning.


METHODS
Model-based genetic linkage analyses were performed with the use of microsatellite polymorphisms to determine disease locus. Mutation screening was performed within the family and unrelated population-based controls to establish molecular evidence as to what caused the specific X-linked inheritance pattern in the family.


RESULTS
Clinical investigations of the pedigree demonstrated the extremely high penetrance in the male members but no penetrance in the female members. Linkage analyses mapped the disease to the chromosomal region Xq13.I-Xq23 (maximum X-linkage logarithm of odds score = 3.27). Mutation screening of the candidate genes in the linkage region by direct sequencing revealed a de novo missense substitution (925T>C) in the well-known deaf gene. POU3F4. Direct sequencing on 240 unrelated controls did not detect any mutation.


CONCLUSIONS
Multiple analysis approaches demonstrated that these disorders in the family were caused by a founder mutation in the POU3F4 gene. Our findings provided confirmatory molecular evidence to support that development of congenital profound sensorineural hearing loss in the Chinese population results from a novel mutation in the same gene.
Wang
Qiu-Ju
QJ
Department of Otorhinolaryngology-Head and Neck Surgery, Chinese People's Liberation Army Institute of Otolaryngology, Chinese People's Liberation Army General Hospital, Beijing, China.
Li
Qing-Zhong
QZ
Rao
Shao-Qi
SQ
Zhao
Ya-Li
YL
Yuan
Hu
H
Yang
Wei-Yan
WY
Han
Dong-Yi
DY
Shen
Yan
Y
D000293:Adolescent; D000328:Adult; D002675:Child, Preschool; D002681:China; D002874:Chromosome Mapping; D005260:Female; D008040:Genetic Linkage / Q000235:genetics; D006319:Hearing Loss, Sensorineural / Q000151:congenital* / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020125:Mutation, Missense; D050809:POU Domain Factors / Q000235:genetics*; D019683:Penetrance; D012730:Sex Chromosomes / Q000235:genetics
D050809:POU Domain Factors; C091774:POU3F4 protein, human