Defect in the gene encoding the EAR/EPTP domain-containing protein TSPEAR causes DFNB98 profound deafness
Defect in the gene encoding the EAR/EPTP domain-containing protein TSPEAR causes DFNB98 profound deafness
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DOI：
10.1093/hmg/dds212
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发表时间：
2012-09-01
影响因子：
3.5
通讯作者：
Petit, Christine
中科院分区：
文献类型：
--
作者：
Delmaghani, Sedigheh;Aghaie, Asadollah;Petit, Christine
我们报告一个伊朗血缘家庭的影响，先天性深感音神经性耳聋分离在一个常染色体隐性遗传模式。听觉测试表明这些患者至少存在耳蜗缺陷。我们定位耳聋，常染色体隐性遗传（DFNB）基因座涉及的连锁分析，染色体21q22.3-qter的4.8 Mb区域。排除DFNB 8/10基因TMPRSS3，位于这个染色体间隔，使我们确定了一个新的耳聋位点，DFNB 98。全外显子组测序使我们能够确定一个纯合移码突变（c.1726GTc.1728delC）的基因TSPbind（血小板反应蛋白型层粘连蛋白G结构域和重复序列）。这种截短突变（p.V576LfsX37）阻碍了用突变基因转染的细胞分泌所编码的蛋白质。选择性剪接的TSPR4转录预测两种蛋白质亚型，522和669个氨基酸的长度，这两种都将受到突变的影响。这些亚型由一个血小板反应蛋白型层粘连蛋白G（TSP）结构域，随后是七个串联组织的癫痫相关重复序列（EAR），可能形成一个螺旋桨结构域。Tspear在多种鼠组织中表达。在耳蜗中只发现较大的Tspear转录本，并且通过免疫荧光在感觉细胞的毛束表面检测到该蛋白。哺乳动物的α蛋白家族包括六个已知的成员。其中四个缺陷，即Lgi 1，Lgi 2，Vlgr 1和TSPR2，会导致听觉功能障碍：癫痫，包括人类的听觉功能;动物的听源性癫痫发作;和/或人类和小鼠的听力障碍。这些观察结果表明，含EAR的蛋白质对听觉系统的发育和功能是必不可少的。
We report a consanguineous Iranian family affected by congenital profound sensorineural deafness segregating in an autosomal recessive mode. Auditory tests implicated at least a cochlear defect in these patients. We mapped the deafness, autosomal recessive (DFNB) locus involved by linkage analysis to a 4.8 Mb region at chromosome 21q22.3-qter. Exclusion of the DFNB8/10 gene TMPRSS3, located in this chromosomal interval, led us to identify a new deafness locus, DFNB98. Whole exome sequencing allowed us to identify a homozygous frame-shifting mutation (c.1726GTc.1728delC) in the gene TSPEAR (thrombospondin-type laminin G domain and EAR repeats). This truncating mutation (p.V576LfsX37) impeded the secretion of the encoded protein by cells transfected with the mutated gene. Alternative splicing of TSPEAR transcripts predict two protein isoforms, 522 and 669 amino acids in length, both of which would be affected by the mutation. These isoforms are composed of a thrombospondin-type laminin G (TSP) domain followed by seven tandemly organized epilepsy-associated repeats (EARs), probably forming a -propeller domain. Tspear is expressed in a variety of murine tissues. Only the larger Tspear transcript was found in the cochlea, and the protein was detected by immunofluorescence at the surface of the hair bundles of sensory cells. The mammalian EAR protein family includes six known members. Defects in four of them, i.e. Lgi1, Lgi2, Vlgr1 and, we show here, TSPEAR, cause disorders with auditory features: epilepsy, which can include auditory features in humans; audiogenic seizures in animals; and/or hearing impairments in humans and mice. These observations demonstrate that EAR-containing proteins are essential for the development and function of the auditory system.