Noncoding Mutations of HGF Are Associated with Nonsyndromic Hearing Loss, DFNB39
Noncoding Mutations of HGF Are Associated with Nonsyndromic Hearing Loss, DFNB39
复制标题
DOI：
10.1016/j.ajhg.2009.06.003
复制
发表时间：
2009-07-10
影响因子：
9.8
通讯作者：
Morell, Robert J.
中科院分区：
文献类型：
--
作者：
Schultz, Julie M.;Khan, Shaheen N.;Morell, Robert J.
一种引起常染色体隐性非综合征性听力损失的基因DFNB39先前被定位到染色体7q11.22-q21.12上的18mb间隔。我们将另外40个分离非综合征性听力损失的近亲家族定位到DFNB39位点，并将该间隔细化为1.2 Mb。对该间隔中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和非编码基因进行了测序，发现肝细胞生长因子基因（HGF）的3个突变聚集在内含子4和外显子5上。两个内含子4缺失发生在一个高度保守的序列中，该序列是先前未描述的HGF短异构体的3'非翻译区的一部分。第三个突变是沉默替代，我们证明它影响体外剪接。HGF参与许多不同组织的多种信号通路，然而这些假定的调节突变导致令人惊讶的特异性表型，即非综合征性听力损失。两种Hgf失调的小鼠模型，一种是Hgf转基因普遍过度表达，另一种是条件敲除，从有限数量的组织（包括耳蜗）中删除Hgf，导致耳聋。HGF的过度表达与耳蜗外毛细胞的进行性变性有关，而耳蜗HGF的缺失则与更普遍的发育不良有关。
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.