A novel mutation in COCH-implications for genotype-phenotype correlations in DFNA9 hearing loss.
OBJECTIVE
To determine the cause of autosomal dominant hearing loss segregating in an American family.


METHODS
Family study.


METHODS
Otologic and audiometric examination was performed on affected family members. Genome wide parametric multipoint linkage mapping using a dominant model was performed with Affymetrix 50K GeneChip data. Direct sequencing was used to confirm the causative mutation.


RESULTS
In American family 467, segregating autosomal dominant nonsyndromic hearing loss, a novel heterozygous missense mutation (c.362T>C; p.F121S) was identified in the COCH gene. This mutation was also associated with vestibular dysfunction typical of other DFNA9 families. However, affected family members also exhibited memory loss and night blindness.


CONCLUSIONS
The novel COCH mutation affects the functionally important limulus factor C, Coch-5b2 and Lgl1 domain where most DFNA9 mutations have been localized. The onset of the hearing loss, in the 2nd or 3rd decade of life, is earlier than in most DFNA9 families. The progression of hearing loss and vestibular dysfunction in the American family is typical of other DFNA9 families with mutations in this domain. Memory loss and night blindness have not been previously reported in DFNA9 families.
Department of Otolaryngology-Head and Neck Surgery, University of Iowa, Iowa City, Iowa, USA.
Michael S
MS
Hildebrand
Luke
L
Gandolfo
A Eliot
AE
Shearer
Jennifer A
JA
Webster
Maren
M
Jensen
William J
WJ
Kimberling
Dietrich
D
Stephan
Patrick L M
PL
Huygen
Richard J H
RJ
Smith
Melanie
M
Bahlo
D001299:Audiometry; D004247:DNA / Q000235:genetics*; D018450:Disease Progression; D016326:Extracellular Matrix Proteins; D005190:Family; D005260:Female; D056726:Genetic Association Studies / Q000379:methods*; D020022:Genetic Predisposition to Disease; D006319:Hearing Loss, Sensorineural / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics*; D014481:United States
C110668:COCH protein, human; D016326:Extracellular Matrix Proteins; D011506:Proteins; D004247:DNA