CDH23 mutation and phenotype heterogeneity:: A profile of 107 diverse families with Usher syndrome and nonsyndromic deafness
CDH23 mutation and phenotype heterogeneity:: A profile of 107 diverse families with Usher syndrome and nonsyndromic deafness
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DOI：
10.1086/341558
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发表时间：
2002-08-01
影响因子：
9.8
通讯作者：
Kimberling, WJ
中科院分区：
文献类型：
--
作者：
Astuto, LM;Bork, JM;Kimberling, WJ
Usher综合征I型的特征是先天性听力丧失、色素性视网膜炎（RP）和可变前庭反射消失。Usher综合征ID型，七个Usher综合征I型遗传定位之一，已被映射到与非综合征耳聋定位DFNB 12重叠的染色体间隔。编码具有多个钙粘蛋白样结构域的假定细胞粘附蛋白的基因CDH 23的突变是Usher综合征和DFNB 12非综合征性耳聋的原因。已经鉴定了区分这两种表型的特异性CDH 23突变缺陷。在非综合征性耳聋家族中仅观察到CDH 23的错义突变，而在Usher综合征家族中发现了无义、移码、剪接位点和错义突变。在本研究中，69个先证者与Usher综合征和38个先证者与隐性非综合征性耳聋的面板进行了筛选的突变存在于整个编码区的CDH 23，异源双链，单链构象多态性，直接序列分析。在45个家系中共检测到36种不同的CDH 23突变;其中33种突变是新的，包括18种错义突变、3种无义突变、5种剪接缺陷突变、5种微缺失突变和2种插入突变。共有7个突变是共同的一个以上的家庭。还检测到许多外显子和内含子多态性。非综合征性耳聋患者的眼科检查结果发现了无症状的RP样表现，表明错义突变可能对视网膜有微妙的影响。此外，具有CDH 23突变的患者显示出广泛的听力损失和RP表型，在严重程度、发病年龄、类型和前庭反射消失的存在或不存在方面不同。
Usher syndrome type I is characterized by congenital hearing loss, retinitis pigmentosa (RP), and variable vestibular areflexia. Usher syndrome type ID, one of seven Usher syndrome type I genetic localizations, have been mapped to a chromosomal interval that overlaps with a nonsyndromic-deafness localization, DFNB12. Mutations in CDH23, a gene that encodes a putative cell-adhesion protein with multiple cadherin-like domains, are responsible for both Usher syndrome and DFNB12 nonsyndromic deafness. Specific CDH23 mutational defects have been identified that differentiate these two phenotypes. Only missense mutations of CDH23 have been observed in families with nonsyndromic deafness, whereas nonsense, frameshift, splice-site, and missense mutations have been identified in families with Usher syndrome. In the present study, a panel of 69 probands with Usher syndrome and 38 probands with recessive nonsyndromic deafness were screened for the presence of mutations in the entire coding region of CDH23, by heteroduplex, single-strand conformation polymorphism, and direct sequence analyses. A total of 36 different CDH23 mutations were detected in 45 families; 33 of these mutations were novel, including 18 missense, 3 nonsense, 5 splicing defects, 5 microdeletions, and 2 insertions. A total of seven mutations were common to more than one family. Numerous exonic and intronic polymorphisms also were detected. Results of ophthalmologic examinations of the patients with nonsyndromic deafness have found asymptomatic RP-like manifestations, indicating that missense mutations may have a subtle effect in the retina. Furthermore, patients with mutations in CDH23 display a wide range of hearing loss and RP phenotypes, differing in severity, age at onset, type, and the presence or absence of vestibular areflexia.