A mutation of MET, encoding hepatocyte growth factor receptor, is associated with human DFNB97 hearing loss.
BACKGROUND
Hearing loss is a heterogeneous neurosensory disorder. Mutations of 56 genes are reported to cause recessively inherited non-syndromic deafness.


OBJECTIVE
We sought to identify the genetic lesion causing hearing loss segregating in a large consanguineous Pakistani family.


RESULTS
Mutations of GJB2 and all other genes reported to underlie recessive deafness were ruled out as the cause of the phenotype in the affected members of the participating family. Homozygosity mapping with a dense array of one million SNP markers allowed us to map the gene for recessively inherited severe hearing loss to chromosome 7q31.2, defining a new deafness locus designated DFNB97 (maximum logarithm of the odds score of 4.8). Whole-exome sequencing revealed a novel missense mutation c.2521T>G (p.F841V) in MET (mesenchymal epithelial transition factor), which encodes the receptor for hepatocyte growth factor. The mutation cosegregated with the hearing loss phenotype in the family and was absent from 800 chromosomes of ethnically matched control individuals as well as from 136 602 chromosomes in public databases of nucleotide variants. Analyses by multiple prediction programmes indicated that p.F841V likely damages MET function.


CONCLUSIONS
We identified a missense mutation of MET, encoding the hepatocyte growth factor receptor, as a likely cause of hearing loss in humans.
School of Biological Sciences, University of the Punjab, Lahore, Pakistan.
Ghulam
G
Mujtaba
Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland, USA Present address, GeneDx, Gaithersburg, Maryland, USA.
Julie M
JM
Schultz
School of Biological Sciences, University of the Punjab, Lahore, Pakistan.
Ayesha
A
Imtiaz
Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland, USA.
Robert J
RJ
Morell
Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland, USA.
Thomas B
TB
Friedman
School of Biological Sciences, University of the Punjab, Lahore, Pakistan.
Sadaf
S
Naz
D000072259:Connexin 26; D017630:Connexins; D003241:Consanguinity; D005260:Female; D034381:Hearing Loss / Q000235:genetics*; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D017434:Protein Structure, Tertiary; D019859:Proto-Oncogene Proteins c-met / Q000737:chemistry / Q000235:genetics*
D017630:Connexins; C000607042:GJB2 protein, human; D000072259:Connexin 26; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met
Genetics; Genome-wide; Linkage; Molecular genetics