Mutations in PTPRQ Are a Cause of Autosomal-Recessive Nonsyndromic Hearing Impairment DFNB84 and Associated with Vestibular Dysfunction
Mutations in PTPRQ Are a Cause of Autosomal-Recessive Nonsyndromic Hearing Impairment DFNB84 and Associated with Vestibular Dysfunction
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DOI：
10.1016/j.ajhg.2010.02.015
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发表时间：
2010-04-09
影响因子：
9.8
通讯作者：
Kremer, Hannie
中科院分区：
文献类型：
--
作者：
Schraders, Margit;Oostrik, Jaap;Kremer, Hannie
我们确定了重叠的纯合子区域内DFNB84基因座在一个非血缘的荷兰家庭和一个血缘的摩洛哥家庭与感音神经性常染色体隐性非综合征性听力障碍（arNSHI）。3.17 Mb的关键区域包含PTPRQ基因，并且在orthotropic基因中具有纯合突变的小鼠模型显示严重的听力损失。我们表明，人类PTPRQ基因没有完全注释，并且在基因的5'端存在额外的可变剪接外显子。不同的PTPRQ同种型编码有不同数量的纤连蛋白3型（FN 3）结构域、跨膜结构域和磷酸酶结构域。家庭成员的PTPRQ基因的序列分析显示，在荷兰家庭的无义突变和摩洛哥家庭的错义突变。错义突变位于FN3结构域之一。无义突变导致仅具有少量FN 3结构域且没有跨膜或磷酸酶结构域的截短蛋白。PTPRQ突变患者的听力损失可能是先天性的，并且在无义突变的家族中是中度至重度的，并且最严重。在两个家庭中都观察到听力损失的进展。听力损失伴随着前庭功能障碍在所有受影响的个体。虽然我们发现PTPRQ在许多组织中表达，但在患者中没有观察到耳聋以外的症状。
We identified overlapping homozygous regions within the DFNB84 locus in a nonconsanguineous Dutch family and a consanguineous Moroccan family with sensorineural autosomal-recessive nonsyndromic hearing impairment (arNSHI). The critical region of 3.17 Mb harbored the PTPRQ gene and mouse models with homozygous mutations in the orthologous gene display severe hearing loss. We show that the human PTPRQ gene was not completely annotated and that additional, alternatively spliced exons are present at the 5' end of the gene. Different PTPRQ isoforms are encoded with a varying number of fibronectin type 3 (FN3) domains, a transmembrane domain, and a phosphatase domain. Sequence analysis of the PTPRQ gene in members of the families revealed a nonsense mutation in the Dutch family and a missense mutation in the Moroccan family. The missense mutation is located in one of the FN3 domains. The nonsense mutation results in a truncated protein with only a small number of FN3 domains and no transmembrane or phosphatase domain. Hearing loss in the patients with PTPRQ mutations is likely to be congenital and moderate to profound and most severe in the family with the nonsense mutation. Progression of the hearing loss was observed in both families. The hearing loss is accompanied by vestibular dysfunction in all affected individuals. Although we show that PTPRQ is expressed in many tissues, no symptoms other than deafness were observed in the patients.