Dreyer Bo, Brox Vigdis, Tranebjaerg Lisbeth, Rosenberg Thomas, Sadeghi Andrè M, Möller Claes, Nilssen Oivind
Department of Medical Genetics, Institute of Clinical Medicine, University of Tromsø, NO-9037 Tromsø, Norway.
Hum Mutat. 2008 Mar;29(3):451. doi: 10.1002/humu.9524.
Usher syndrome type II (USH2) is an autosomal recessive disorder, characterised by moderate to severe high-frequency hearing impairment, normal balance function and progressive visual impairment due to retinitis pigmentosa. Usher syndrome type IIa, the most common subtype, is defined by mutations in the USH2A gene encoding a short and a recently discovered long usherin isoform comprising 21 and 73 exons, respectively. More than 120 different disease-causing mutations have been reported, however, most of the previous reports concern mutations restricted to exons 1-21 of the USH2A gene. To explore the spectrum of USH2A disease-causing mutations among Scandinavian USH2 cases, patients from 118 unrelated families of which 27 previously had been found to carry mutations in exons 1-21 were subjected to extensive DNA sequence analysis of the full size USH2A gene. Altogether, 122 USH2A DNA sequence alterations were identified of which 57 were predicted to be disease-causing, 7 were considered to be of uncertain pathogenicity and 58 were predicted to be benign variants. Of 36 novel pathogenic USH2A mutations 31 were located in exons 22-73, specific to the long isoform. USH2A mutations were identified in 89/118 (75.4%) families. In 79/89 (88.8%) of these families two pathogenic mutations were identified whereas in 10/89 (11.2%) families the second mutation remained unidentified. In 5/118 (4.2%) families the USH phenotype could be explained by mutations in the USH3A gene. The results presented here provide a comprehensive picture of the genetic aetiology of Usher syndrome type IIA in Scandinavia as it is known to date.
II型Usher综合征（USH2）是一种常染色体隐性疾病，其特征为中度至重度高频听力损伤、平衡功能正常以及因色素性视网膜炎导致的进行性视力损伤。IIa型Usher综合征是最常见的亚型，由USH2A基因突变所定义，该基因编码一种短的和最近发现的长的usherin异构体，分别包含21个和73个外显子。已报道了120多种不同的致病突变，然而，之前的大多数报道涉及仅限于USH2A基因第1至21外显子的突变。为了探究斯堪的纳维亚USH2病例中USH2A致病突变的谱，对来自118个无关家庭的患者进行了全长USH2A基因的广泛DNA序列分析，其中27个家庭之前已被发现携带第1至21外显子的突变。总共鉴定出122个USH2A DNA序列改变，其中57个被预测为致病的，7个被认为致病可能性不确定，58个被预测为良性变异。在36个新的致病USH2A突变中，31个位于第22至73外显子，这是长异构体特有的。在89/118（75.4%）的家庭中鉴定出USH2A突变。在这些家庭中的79/89（88.8%）中鉴定出两个致病突变，而在10/89（11.2%）的家庭中第二个突变仍未被鉴定。在5/118（4.2%）的家庭中，USH表型可由USH3A基因的突变来解释。此处呈现的结果提供了迄今为止所知的斯堪的纳维亚IIA型Usher综合征遗传病因的全面情况。
