Noncoding Mutations of HGF Are Associated with Nonsyndromic Hearing Loss, DFNB39

Abstract

A gene causing autosomal-recessive, nonsyndromic hearing loss, DFNB39, was previously mapped to an 18 Mb interval on chromosome 7q11.22-q21.12. We mapped an additional 40 consanguineous families segregating nonsyndromic hearing loss to the DFNB39 locus and refined the obligate interval to 1.2 Mb. The coding regions of all genes in this interval were sequenced, and no missense, nonsense, or frameshift mutations were found. We sequenced the noncoding sequences of genes, as well as noncoding genes, and found three mutations clustered in intron 4 and exon 5 in the hepatocyte growth factor gene (HGF). Two intron 4 deletions occur in a highly conserved sequence that is part of the 3' untranslated region of a previously undescribed short isoform of HGF. The third mutation is a silent substitution, and we demonstrate that it affects splicing in vitro. HGF is involved in a wide variety of signaling pathways in many different tissues, yet these putative regulatory mutations cause a surprisingly specific phenotype, which is nonsydromic hearing loss. Two mouse models of Hgf dysregulation, one in which an Hgf transgene is ubiquitously overexpressed and the other a conditional knockout that deletes Hgf from a limited number of tissues, including the cochlea, result in deafness. Overexpression of HGF is associated with progressive degeneration of outer hair cells in the cochlea, whereas cochlear deletion of Hgf is associated with more general dysplasia.

A Novel de novo Mutation in CEACAM16 Associated with Postlingual Hearing Impairment

“…The other variants that were also present in the sequencing dataset were communicated for the c.418A>C variant but limited to the DFNA4 region [Zheng et al, 2011]. One of the consequences of broadly screening large subsets of genes, as in the case of clinical and whole exomes, is the generation of large numbers of variants that require interpretation including synonymous variants, which could impact splice sites [Schultz et al, 2009;Wang et al, 2015]. It is common for even healthy individuals to carry private pathogenic mutations complicating the understanding of disease causing mutations [Jang et al, 2015].…”

Conditional Gene Expression in the Mouse Inner Ear Using Cre-loxP

“…By E13.5, reporter expression was found throughout the otic lines are used. The most commonly used line is the depending on the strength of the fluorescent reporter COX ET.AL: Conditional Gene Expression in the Mouse Inner Ear Using Cre-loxP Pirvola et al 2002;Arnold et al 2006;Zelarayan et al 2007;Barrionuevo et al 2008;Jones et al 2008;Rickheit et al 2008;Grimsley-Myers et al 2009;Schultz et al 2009;Wang et al 2009;Yamamoto et al 2009;Deng et al 2010;Freyer and Morrow 2010;Haugas et al 2010;Hurd et al 2010;Hwang et al 2010;Sipe and Lu 2011 (Hebert and McConnell 2000), which has been reported to cause haploinsufficiency phenotypes that include proliferation in other organs (Shen et al 2006;Eagleson et al 2007;Siegenthaler et al 2008). However, no change in proliferation in the inner ear has been reported in several papers where proper controls of Foxg1-Cre mice (without the floxed allele) were used (Yamamoto et al 2009(Yamamoto et al , 2011Hartman et al 2010;Brown and Epstein 2011).…”

Novel Autosomal Recessive Nonsyndromic Hearing Impairment Locus DFNB90 Maps to 7p22.1-p15.3

“…Although already seven ARNSHI loci have been mapped to chromosome 7 for which three genes have been identified, SLC26A5 [1] (MIM 60493), SLC26A4 [2] (MIM 605646) and HGF [3] (MIM 142409), there is no overlap between this new locus and previously reported loci.…”

“…3 ). For these ARNSHI loci, only the genes SLC26A5 for DFNB61 [1] , SLC26A4 for DFNB4 [2] and HGF for DFNB39 [3] have been identified. Additionally, on chromosome 7p lies the autosomal dominant (AD) locus DFNA5, which is centromeric to DFNB90 by 4.4 Mb, and on chromosome 7q is DFNA50 [19] , which lies between DFNB17 and DFNB13.…”