Detection of Rare Nonsynonymous Variants in TGFB1 in Otosclerosis Patients

Abstract

SummaryOtosclerosis 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-β1 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-β1 may contribute to susceptibility to otosclerosis.

Etiopathogenesis of otosclerosis

“…Later, Thys et al [64] conformed that the I263 protective allelic variant was biologically more active than the T263 risk allele. This group also found three different nonsynonymous variants of TGF-b1 (E29, A29 and I241) in four otosclerosis patients that could influence TGF-b1 function and activity [64]. These data suggest that multiple rare amino acid variants of TGF-b1 may contribute to susceptibility to otosclerosis.…”

“…In these cohorts, the I263 variant was underrepresented in otosclerosis patients and hence was protective against the disease [63]. Later, Thys et al [64] conformed that the I263 protective allelic variant was biologically more active than the T263 risk allele. This group also found three different nonsynonymous variants of TGF-b1 (E29, A29 and I241) in four otosclerosis patients that could influence TGF-b1 function and activity [64].…”

The pathophysiology of otosclerosis: Review of current research

“…In human otosclerotic bone cell cultures, TGF-b1 can modify the phenotypic expression of glycosamynoglycans, fibronectin and collagen of the extracellular matrix (Bodo et al, 1995). In two large independent population studies (Janssens et al, 2005;Thys et al, 2009), TGF-b1 has been associated with otosclerosis. Based on the association with the TGF-b1 family, 13 new candidate genes were selected and further analyzed, relating to the metabolism of the otic capsule, the involvement in the syndromic or non-syndromic forms of stapes fixation, and other hypothesis related to the development of the otosclerosis.…”

“…Clinical otosclerosis is very rare among black (1%), oriental and American Indian populations (Guild, 1944). The Japanese and South American populations have half the incidence of that of Caucasians S (Tato and Tato, 1967;Thys et al, 2009). About 60% of the patients with clinical otosclerosis report a family history of the disease.…”

Identification of Target Proteins Involved in Cochlear Otosclerosis

“…Genetic linkage analyses have revealed several loci to be involved in otosclerosis, with variable phenotypic expression, emphasizing the extreme heterogeneity of the disease, and the probable interplay of genetic and environmental factors. 12, 13 …”