Homozygous Mutations in Fibroblast Growth Factor 3 Are Associated with a New Form of Syndromic Deafness Characterized by Inner Ear Agenesis, Microtia, and Microdontia

Abstract

We identified nine individuals from three unrelated Turkish families with a unique autosomal recessive syndrome characterized by type I microtia, microdontia, and profound congenital deafness associated with a complete absence of inner ear structures (Michel aplasia). We later demonstrated three different homozygous mutations (p.S156P, p.R104X, and p.V206SfsX117) in the fibroblast growth factor 3 (FGF3) gene in affected members of these families, cosegregating with the autosomal recessive transmission as a completely penetrant phenotype. These findings demonstrate the involvement of FGF3 mutations in a human malformation syndrome for the first time and contribute to our understanding of the role this gene plays in embryonic development. Of particular interest is that the development of the inner ear is completely disturbed at a very early stage--or the otic vesicle is not induced at all--in all of the affected individuals who carried two mutant FGF3 alleles.

Functional evolutionary history of the mouse Fgf gene family

“…Both aplasia of lacrimal and salivary glands and lacrimo-auriculo-dento-digital syndrome are caused by mutations in FGF10 (Entesarian et al, 2005(Entesarian et al, , 2007 2006). Michel aplasia is caused by mutations in FGF3 (Tekin et al, 2007). FGF20 is a potential risk factor for Parkinson's disease (van der Walt et al, 2004;Satake et al, 2007).…”

Modulation of Fgf3 dosage in mouse and men mirrors evolution of mammalian dentition

“…Dental casts of one FGF3 null individual with a homozygous c.616delG (p.V206SfsX117) mutation were from Ankara University School of Medicine. This mutation causes a frameshift resulting in a completely altered and most likely nonfunctional protein, and phenotypic data and mutation analysis have been published (16). The control casts were obtained from the University of California San Francisco Craniofacial Clinic collection.…”

“…The FGF family is composed of at least 22 ligand-encoding genes, and its members are involved in development of many organs in addition to teeth (14). Recently, mutations in Fgf3 have been demonstrated to be implicated in human and mouse microdontia (15,16). We therefore set out to evaluate the role of Fgf3 in the morphogenesis of human and mouse dentition, and to compare the effects of changes in Fgf3 gene expression with modifications that occurred during mammalian evolution.…”

LAMM syndrome with middle ear dysplasia associated with compound heterozygosity for FGF3 mutations

“…Recently a new, rare, autosomal recessive deafness syndrome has been described, with labyrinthine aplasia, microtia, and microdontia (LAMM) (OMIM #610706) [Tekin et al, 2007]. A first sporadic case of the syndrome was possibly reported by Hersh et al [1991], but it was only in 2007 that the syndrome was recognized and linked to mutations of the FGF3 gene [Tekin et al, 2007], already known to be involved in inner ear development [Represa et al, 1991;Mansour et al, 1993].…”

“…Recently a new, rare, autosomal recessive deafness syndrome has been described, with labyrinthine aplasia, microtia, and microdontia (LAMM) (OMIM #610706) [Tekin et al, 2007]. A first sporadic case of the syndrome was possibly reported by Hersh et al [1991], but it was only in 2007 that the syndrome was recognized and linked to mutations of the FGF3 gene [Tekin et al, 2007], already known to be involved in inner ear development [Represa et al, 1991;Mansour et al, 1993]. Up to now seven families (five Turkish, one Arabian, and one Somali), all consanguineous and with homoallelic mutations in affected subjects, have been described [Tekin et al, 2007[Tekin et al, , 2008Alsmadi et al, 2009;Ramsebner et al, 2010].…”