Monogenic nonsyndromic otosclerosis: audiological and linkage analysis in a large Greek pedigree.
OBJECTIVE
The aim of our study was to characterize the hearing impairment in a large multigenerational Greek family with autosomal dominant nonsyndromic otosclerosis and to perform genetic linkage analysis to known otosclerosis loci and collagen genes. In addition, we looked for mutations in the NOG gene to rule out congenital stapes ankylosis syndrome.


METHODS
Audiological analysis of the affected persons was based on multiple linear regression (MLR) analysis and construction of age-related typical audiograms (ARTA). Genotyping of microsatellite DNA polymorphisms for known otosclerosis (OTSC) loci or collagen genes and linkage analysis using the MLINK computer program were performed. The coding region of the NOG gene was screened for mutations by direct DNA sequencing.


RESULTS
The hearing loss in this family appears in childhood as conductive, but soon becomes mixed. Because the additional sensorineural component is progressive, this finally has lead to a pure sensorineural hearing loss in some family members, as the conductive component is masked. Audiological analysis showed an age-independent conductive component and a progressive frequency-specific sensorineural component. Linkage analysis excluded linkage to the four known otosclerosis loci (OTSC1, OTSC2, OTSC3, and OTSC5), as well as to the COL1A1 and COL1A2 genes. Mutation analysis of the coding region of the NOG gene did not reveal any disease causing mutation.


CONCLUSIONS
This study represents the first description of a detailed audiological analysis in a large pedigree segregating otosclerosis as a monogenic autosomal dominant trait. Exclusion of the four known otosclerosis loci in this family shows that monogenic otosclerosis is a genetically heterogeneous disease involving at least five different genes. A mutation in the NOG gene is not the underlying molecular mechanism of the early onset otosclerosis segregating in this family.
Iliadou
Vassiliki
V
Audiology Unit, Department of Otorhinolaryngology, Aristotle University of Thessaloniki, AHEPA Hospital, GR-54006 Thessaloniki, Greece.
Van Den Bogaert
Kris
K
Eleftheriades
Nikolaos
N
Aperis
George
G
Vanderstraeten
Kathleen
K
Fransen
Erik
E
Thys
Melissa
M
Grigoriadou
Maria
M
Pampanos
Andreas
A
Economides
John
J
Iliades
Theophilos
T
Van Camp
Guy
G
Petersen
Michael B
MB
D000844:Ankylosis / Q000175:diagnosis; D001299:Audiometry; D025063:Chromosome Disorders; D002874:Chromosome Mapping; D003937:Diagnosis, Differential; D005190:Family; D005799:Genes, Dominant; D005838:Genotype; D006115:Greece; D006801:Humans; D010040:Otosclerosis / Q000235:genetics*; D010375:Pedigree; D040641:Quantitative Trait Loci; D013199:Stapes; D013577:Syndrome