Waardenburg综合征Ⅱ型患者MITF基因突变分析

Mutation screening of MITF gene in patients with Waardenburg syndrome type 2

Waardenburg综合征(WS)是临床上常见的常染色体显性遗传性耳聋综合征,MITF基因突变与部分Waardenburg综合征Ⅱ型(WS2)病例的发病有关。MITF属于碱性螺旋-环-螺旋亮氨酸拉链转录因子家族,能调节酪氨酸酶基因,参与黑色素细胞的分化。文章报道了1个携带MITF基因点突变的3代Waardenburg综合征Ⅱ型中国家系。先证者表现为先天性重度感音神经性聋、虹膜异色、面部雀斑;其他家系成员除一名仅表现为先天性耳聋外,均表现为颜面、上肢雀斑和/或早白发。患者可检测到c.639delA杂合突变,该突变在MITF基因第7外显子上产生了终止密码子(p.I220X),突变产生的截短的MITF蛋白没有DNA结合活性。该突变是WS2病例中第3个位于MITF第7外显子的突变,尚未见报道。该突变与已报道的位于第7外显子其他两个突变仅相差1个碱基,氨基酸改变十分相似,但在表型上有显著差别,提示遗传背景对WS临床表型有重要影响。

Warrgenburg syndrome type 2 （WS2） is the most common autosomal dominantly-inherited syndrome with hearing loss. MITF （microphthalmia associated transcription factor）is a basic-helix-loop-helix-luecine zipper （bHLHZip） factor which regulates expression of tyrosinase, and is involved in melanocyte differentiation. Mutations in MITF associated with WS2 have been identified in some but not all affected families. Here, we report a three-generation Chinese family with a point mutation in the MITF gene causing WS2. The proband exhibits congenital severe sensorineural hearing loss, heterochromia iridis and facial freckles. One of family members manifests sensorineural deafness, and the other patients show premature greying or/and fre, c kles. This mutation, heterozygous deletion c.639delA, creates a stop codon in exon 7 and is predicted to result in a truncated protein lacking normal interaction with its target DNA motif. This mutation is a novel mutation and the third case identified in exon 7 of MITF in WS2. Though there is only one base pair distance between this novel mutation and the other two documented cases and similar amino acids change, significant difference is seen in clinical phenotype, which suggests genetic background may play an important role.