Involvement of DFNB59 mutations in autosomal recessive nonsyndromic hearing impairment
Involvement of DFNB59 mutations in autosomal recessive nonsyndromic hearing impairment
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DOI：
10.1002/humu.20510
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发表时间：
2007-07-01
期刊：
影响因子：
3.9
通讯作者：
Kremer, Hannie
中科院分区：
文献类型：
--
作者：
Collin, Rob W. J.;Kalay, Ersan;Kremer, Hannie
在一个近亲土耳其家庭，常染色体隐性遗传性非综合征性听力障碍（ARNSHI）的基因座被定位到染色体2q31.1-2q33.1。在整个家庭的微卫星标记分析确定的关键连锁区间重叠DFNB 27，其致病基因尚未确定，DFNB 59，最近描述的听神经病引起的错义突变DFNB 59基因。352个氨基酸（aa）的DFNB 59基因产物pejvakin存在于毛细胞、支持细胞、螺旋神经节细胞和传入听觉通路的前三个中继中。在DFNB 59基因上发现一个新的纯合无义突变（c.499C > T，p.R167X），与该家系的耳聋分离。发现来自突变等位基因的mRNA在淋巴细胞中不被降解，这表明在受影响的个体中可能存在截短的166个氨基酸的pejvakin蛋白。筛查67例来自其他土耳其常染色体隐性遗传性听力障碍家系的索引患者，发现一个纯合错义突变（c.547C > T; p.R183W），与一个家系中的听力障碍分离。此外，在一组83名荷兰患者中，发现了另外两种在种族匹配的对照中不存在的新突变（c.509_512delCACT，p.S170CfsX35和c.731T > G; p.L244R）。总之，我们的数据表明，DFNB 59中的无义突变也会导致非综合征性听力损失，但DFNB 59中的突变不是土耳其和荷兰人群中非综合征性听力损伤的主要原因。
In a consanguineous Turkish family, a locus for autosomal recessive nonsyndromic hearing impairment (ARNSHI) was mapped to chromosome 2q31.1-2q33.1. Microsatellite marker analysis in the complete family determined the critical linkage interval that overlapped with DFNB27, for which the causative gene has not yet been identified, and DFNB59, a recently described auditory neuropathy caused by missense mutations in the DFNB59 gene. The 352-amino acid (aa) DFNB59 gene product pejvakin is present in hair cells, supporting cells, spiral ganglion cells, and the first three relays of the afferent auditory pathway. A novel homozygous nonsense mutation (c.499C > T, p.R167X) was detected in the DFNB59 gene, segregating with the deafness in the family. The mRNA derived from the mutant allele was found not to be degraded in lymphocytes, indicating that a truncated pejvakin protein of 166 aa may be present in the affected individuals. Screening of 67 index patients from additional consanguineous Turkish families with autosomal recessive hearing impairment revealed a homozygous missense mutation (c.547C > T; p.R183W) that segregates with the hearing impairment in one family. Furthermore, in a panel of 83 Dutch patients, two additional novel mutations (c.509_512delCACT, p.S170CfsX35 and c.731T > G; p.L244R), which were not present in ethnically matched controls, were found heterozygously. Together, our data indicate that also nonsense mutations in DFNB59 cause nonsyndromic hearing loss, but that mutations in DFNB59 are not a major cause of nonsyndromic hearing impairment in the Turkish and Dutch population.