Noncoding mutations of HGF are associated with nonsyndromic hearing loss, DFNB39.
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.
Schultz
Julie M
JM
Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Rockville, MD 20850, USA.
Khan
Shaheen N
SN
Ahmed
Zubair M
ZM
Riazuddin
Saima
S
Waryah
Ali M
AM
Chhatre
Dhananjay
D
Starost
Matthew F
MF
Ploplis
Barbara
B
Buckley
Stephanie
S
Velásquez
David
D
Kabra
Madhulika
M
Lee
Kwanghyuk
K
Hassan
Muhammad J
MJ
Ali
Ghazanfar
G
Ansar
Muhammad
M
Ghosh
Manju
M
Wilcox
Edward R
ER
Ahmad
Wasim
W
Merlino
Glenn
G
Leal
Suzanne M
SM
Riazuddin
Sheikh
S
Friedman
Thomas B
TB
Morell
Robert J
RJ
D020413:3' Untranslated Regions / Q000235:genetics; D017398:Alternative Splicing; D000818:Animals; D003051:Cochlea / Q000473:pathology; D003241:Consanguinity; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D034381:Hearing Loss / Q000235:genetics* / Q000473:pathology; D017228:Hepatocyte Growth Factor / Q000235:genetics*; D007194:India; D007438:Introns; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009154:Mutation; D010154:Pakistan; D010375:Pedigree
D020413:3' Untranslated Regions; C066855:HGF protein, human; D017228:Hepatocyte Growth Factor