title: Detection of rare nonsynonymous variants in TGFB1 in otosclerosis patients.
abstract: Otosclerosis is one of the most common forms of hearing loss in the European population. We have identified a SNP in the TGFB1 (transforming growth factor beta 1) gene that is associated with susceptibility to otosclerosis. The protective allele of this variant, with isoleucine at position 263 of the protein, is more biologically active than the risk allele, which has a threonine in this position. Because recent studies have shown that not only common, but also rare variants can be involved in complex diseases, we performed DNA sequence analysis of the exons and intron-exon boundaries of TGFB1 in 755 otosclerosis patients and 877 control samples. We found 3 different nonsynonymous variants (E29, A29 and I241) in four otosclerosis patients, but no such changes were found in controls. In silico analysis shows that these variations could influence TGF-beta1 function and activity. Taking into account that most rare missense alleles are thought to have a biological effect, the data suggest that multiple rare amino acid changing variants in TGF-beta1 may contribute to susceptibility to otosclerosis.
authors.affiliation: Department of Medical Genetics, University of Antwerp, Universiteitsplein 1, Antwerp, Belgium.
authors.forename: M
authors.initials: M
authors.lastname: Thys
authors.forename: I
authors.initials: I
authors.lastname: Schrauwen
authors.forename: K
authors.initials: K
authors.lastname: Vanderstraeten
authors.forename: N
authors.initials: N
authors.lastname: Dieltjens
authors.forename: E
authors.initials: E
authors.lastname: Fransen
authors.forename: M
authors.initials: M
authors.lastname: Ealy
authors.forename: C W R J
authors.initials: CW
authors.lastname: Cremers
authors.forename: P
authors.initials: P
authors.lastname: van de Heyning
authors.forename: R
authors.initials: R
authors.lastname: Vincent
authors.forename: E
authors.initials: E
authors.lastname: Offeciers
authors.forename: R H
authors.initials: RH
authors.lastname: Smith
authors.forename: G
authors.initials: G
authors.lastname: van Camp
mesh_terms: D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D005060:Europe; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D010040:Otosclerosis / Q000235:genetics*; D053773:Transforming Growth Factor beta1 / Q000235:genetics*
chemical_list: C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1