Loss-of-Function Mutations of ILDR1 Cause Autosomal-Recessive Hearing Impairment DFNB42
Loss-of-Function Mutations of ILDR1 Cause Autosomal-Recessive Hearing Impairment DFNB42
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DOI：
10.1016/j.ajhg.2010.12.011
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发表时间：
2011-02-11
影响因子：
9.8
通讯作者：
Kubisch, Christian
中科院分区：
文献类型：
--
作者：
Borck, Guntram;Rehman, Atteeq Ur;Kubisch, Christian
通过在一个巴基斯坦血缘家庭中进行纯合性定位，我们发现非综合征性听力损失与先前报道的DFNB 42基因座内染色体3q13.31-q21.1上的7.6 Mb区域存在连锁。随后的候选基因测序确定了ILDR 1中的纯合无义突变（c.1135G>T [p.Glu379X]）是听力障碍的原因。通过分析在该位点具有纯合性的其他血缘家庭，我们在来自巴基斯坦和伊朗的另外10个家庭的受影响个体中检测到ILDR 1突变。鉴定的ILDR 1变体包括错义、无义、移码和剪接位点突变以及最初定义DFNB 42基因座的家族中的起始密码子突变。ILDR 1编码进化上保守的含有免疫球蛋白样结构域的受体1，一种功能未知的推定跨膜受体。原位杂交检测Ildr 1，小鼠直系同源物，在前庭和耳蜗的毛细胞和支持细胞的发展早期的表达。在斑马鱼中，包含毛细胞和支持细胞的神经感觉器官的表达是保守的，其中ildr 1的直系同源物在发育中的耳和侧线的神经乳突中显著表达。这些数据确定了ILDR 1的功能丧失突变，ILDR 1是一种具有保守表达模式的基因，指向脊椎动物听力中的保守功能，作为潜在的非综合征性语前感音神经性听力障碍。
By using homozygosity mapping in a consanguineous Pakistani family, we detected linkage of nonsyndromic hearing loss to a 7.6 Mb region on chromosome 3q13.31-q21.1 within the previously reported DFNB42 locus. Subsequent candidate gene sequencing identified a homozygous nonsense mutation (c.1135G>T [p.Glu379X]) in ILDR1 as the cause of hearing impairment. By analyzing additional consanguineous families with homozygosity at this locus, we detected ILDR1 mutations in the affected individuals of 10 more families from Pakistan and Iran. The identified ILDR1 variants include missense, nonsense, frameshift, and splice-site mutations as well as a start codon mutation in the family that originally defined the DFNB42 locus. ILDR1 encodes the evolutionarily conserved immunoglobulin-like domain containing receptor 1, a putative transmembrane receptor of unknown function. In situ hybridization detected expression of Ildr1, the murine ortholog, early in development in the vestibule and in hair cells and supporting cells of the cochlea. Expression in hair cell- and supporting cell-containing neurosensory organs is conserved in the zebrafish, in which the ildr1 ortholog is prominently expressed in the developing ear and neuromasts of the lateral line. These data identify loss-of-function mutations of ILDR1, a gene with a conserved expression pattern pointing to a conserved function in hearing in vertebrates, as underlying nonsyndromic prelingual sensorineural hearing impairment.