Kalay Ersan, Li Yun, Uzumcu Abdullah, Uyguner Oya, Collin Rob W, Caylan Refik, Ulubil-Emiroglu Melike, Kersten Ferry F J, Hafiz Gunter, van Wijk Erwin, Kayserili Hulya, Rohmann Edyta, Wagenstaller Janine, Hoefsloot Lies H, Strom Tim M, Nürnberg Gudrun, Baserer Nermin, den Hollander Anneke I, Cremers Frans P M, Cremers Cor W R J, Becker Christian, Brunner Han G, Nürnberg Peter, Karaguzel Ahmet, Basaran Seher, Kubisch Christian, Kremer Hannie, Wollnik Bernd
Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Hum Mutat. 2006 Jul;27(7):633-9. doi: 10.1002/humu.20368.
In two large Turkish consanguineous families, a locus for autosomal recessive nonsyndromic hearing loss (ARNSHL) was mapped to chromosome 6p21.3 by genome-wide linkage analysis in an interval overlapping with the loci DFNB53 (COL11A2), DFNB66, and DFNB67. Fine mapping excluded DFNB53 and subsequently homozygous mutations were identified in the lipoma HMGIC fusion partner-like 5 (LHFPL5) gene, also named tetraspan membrane protein of hair cell stereocilia (TMHS) gene, which was recently shown to be mutated in the "hurry scurry" mouse and in two DFNB67-linked families from Pakistan. In one family, we found a homozygous one-base pair deletion, c.649delG (p.Glu216ArgfsX26) and in the other family we identified a homozygous transition c.494C>T (p.Thr165Met). Further screening of index patients from 96 Turkish ARNSHL families and 90 Dutch ARNSHL patients identified one additional Turkish family carrying the c.649delG mutation. Haplotype analysis revealed that the c.649delG mutation was located on a common haplotype in both families. Mutation screening of the LHFPL5 homologs LHFPL3 and LHFPL4 did not reveal any disease causing mutation. Our findings indicate that LHFPL5 is essential for normal function of the human cochlea.
在两个土耳其近亲家庭中，通过全基因组连锁分析，将常染色体隐性非综合征性听力损失（ARNSHL）的一个基因座定位到6号染色体p21.3区域，该区域与DFNB53（COL11A2）、DFNB66和DFNB67基因座重叠。精细定位排除了DFNB53，随后在脂肪瘤HMGIC融合伴侣样5（LHFPL5）基因中鉴定出纯合突变，该基因也被称为毛细胞静纤毛四跨膜蛋白（TMHS）基因，最近在“匆匆忙忙”小鼠以及来自巴基斯坦的两个与DFNB67连锁的家庭中发现该基因发生了突变。在一个家庭中，我们发现了一个纯合的单碱基对缺失，即c.649delG（p.Glu216ArgfsX26），在另一个家庭中，我们鉴定出一个纯合的转换突变c.494C>T（p.Thr165Met）。对96个土耳其ARNSHL家庭的先证者和90名荷兰ARNSHL患者进行进一步筛查，又发现一个携带c.649delG突变的土耳其家庭。单倍型分析表明，c.649delG突变位于两个家庭的一个共同单倍型上。对LHFPL5的同源物LHFPL3和LHFPL4进行突变筛查，未发现任何致病突变。我们的研究结果表明，LHFPL5对人类耳蜗的正常功能至关重要。
