Lalwani A K, Attaie A, Randolph F T, Deshmukh D, Wang C, Mhatre A, Wilcox E
Epstein Laboratories, Department of Otolaryngology-Head and Neck Surgery, University of California San Francisco, 94143-0526, USA.
Am J Med Genet. 1998 Dec 4;80(4):406-9.
Waardenburg syndrome (WS) is an autosomal-dominant neural crest cell disorder phenotypically characterized by hearing impairment and disturbance of pigmentation. A presence of dystopia canthorum is indicative of WS type 1, caused by loss of function mutation in the PAX3 gene. In contrast, type 2 WS (WS2) is characterized by normally placed medial canthi and is genetically heterogeneous; mutations in MITF (microphthalmia associated transcription factor) associated with WS2 have been identified in some but not all affected families. Here, we report on a three-generation Indian family with a point mutation in the MITF gene causing WS2. This mutation, initially reported in a Northern European family, creates a stop codon in exon 7 and is predicted to result in a truncated protein lacking the HLH-Zip or Zip structure necessary for normal interaction with its target DNA motif. Comparison of the phenotype between the two families demonstrates a significant difference in pigmentary disturbance of the eye. This family, with the first documented case of two unrelated WS2 families harboring identical mutations, provides additional evidence for the importance of genetic background on the clinical phenotype.
瓦登伯革氏综合征（WS）是一种常染色体显性神经嵴细胞疾病，其表型特征为听力障碍和色素沉着紊乱。内眦异位的存在提示为1型WS，由PAX3基因功能丧失性突变引起。相比之下，2型WS（WS2）的特征是内眦位置正常且具有遗传异质性；在部分但并非所有受影响家族中已鉴定出与WS2相关的小眼相关转录因子（MITF）突变。在此，我们报告一个印度三代家族，其MITF基因存在点突变导致WS2。该突变最初在一个北欧家族中报道，在第7外显子中产生一个终止密码子，预计会导致一种截短的蛋白质，该蛋白质缺乏与其靶DNA基序正常相互作用所需的HLH-Zip或Zip结构。两个家族之间的表型比较显示眼部色素沉着紊乱存在显著差异。这个家族是首个记录在案的两个不相关WS2家族携带相同突变的案例，为遗传背景对临床表型的重要性提供了额外证据。
