Schultz Julie M, Khan Shaheen N, Ahmed Zubair M, Riazuddin Saima, Waryah Ali M, Chhatre Dhananjay, Starost Matthew F, Ploplis Barbara, Buckley Stephanie, Velásquez David, Kabra Madhulika, Lee Kwanghyuk, Hassan Muhammad J, Ali Ghazanfar, Ansar Muhammad, Ghosh Manju, Wilcox Edward R, Ahmad Wasim, Merlino Glenn, Leal Suzanne M, Riazuddin Sheikh, Friedman Thomas B, Morell Robert J
Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Rockville, MD 20850, USA.
Am J Hum Genet. 2009 Jul;85(1):25-39. doi: 10.1016/j.ajhg.2009.06.003. Epub 2009 Jul 2.
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.
一个导致常染色体隐性非综合征性听力损失的基因DFNB39，先前被定位到7号染色体7q11.22 - q21.12上一个18 Mb的区间。我们将另外40个分离非综合征性听力损失的近亲家庭定位到DFNB39位点，并将必需区间缩小至1.2 Mb。对该区间内所有基因的编码区进行了测序，未发现错义、无义或移码突变。我们对基因的非编码序列以及非编码基因进行了测序，在肝细胞生长因子基因（HGF）的内含子4和外显子5中发现了三个聚集的突变。两个内含子4缺失发生在一个高度保守的序列中，该序列是HGF一个先前未描述的短异构体3'非翻译区的一部分。第三个突变是一个沉默替代，我们证明它在体外影响剪接。HGF参与许多不同组织中的多种信号通路，但这些推定的调控突变导致了一种惊人的特定表型，即非综合征性听力损失。两种Hgf失调的小鼠模型，一种是Hgf转基因在全身普遍过度表达，另一种是条件性敲除，从包括耳蜗在内的有限数量组织中删除Hgf，均导致耳聋。HGF的过度表达与耳蜗外毛细胞的进行性退化有关，而耳蜗中Hgf的缺失与更普遍的发育异常有关。
