目的对一个常染色体显性遗传的Van der Hoeve综合征家系进行详尽的临床表型分析及可能的致病基因COL1A1突变检测,探讨该家系基因型及表型的关系。方法对收集到的Van der Hoeve综合征家系进行病史及血液样本采集,并对家庭主要成员进行COL1A1基因全部外显子DNA序列分析,利用Gene Tool软件及分子生物学网站的信息分析检测数据。结果该家系先证者及其母亲COL1A1基因第40号外显子有两个碱基的缺失(c.2910_2911delAG),导致COL1A1编码的蛋白质的翻译合成在第980位氨基酸提前终止。先证者父亲无此突变。结论该家系先证者及其母亲确定为由c.2910_2911delAG突变导致的Van der Hoeve综合征。与COL1A1基因突变数据库比对,该突变位点未曾报道过。
Non-syndromic low-frequency sensorineural hearing loss （LFSNHL） is an unusual type of hearing loss in which frequencies ≤2000 Hz predominantly are affected. To date, different mutations in two genes, DIAPHI and WFSI, have been found to be associated with LFSNHL. Here, we report a five-generation Chinese family with postlingual and progressive LFSNHL. We mapped the disease locus to a 2.5 Mb region on chromosome 4p16 between markers SNP_A-2167174 and D4S431, overlapping with the DFNA6/14/38 locus. Sequencing of candidate gene revealed a heterozygous c.2086C〉T substitution in exon 8 of WFS1, leading to p.H696Y substitution at the C-terminus of Wolframin （WFS 1）. In addition, we performed mutational screening of WFS1 in 37 sporadic patients, 7--50 years of age, with LFSNHL. We detected a heterozygous c.2108G〉A substitution in exon 8 of WFSI, leading to p.R703H substitution in a patient. The H696 and R703 in WFS1 are highly conserved across species, including human, orangutan, rat, mouse, and frog （Xenopus）, Sequence analysis demonstrated the absence of c.2086C〉T or c.210gG〉A substitutions in the WFS1 genes among 200 unrelated control subjects of Chinese background, supporting the hypothesis that they represent causative mutations, and not rare polymorphisms. Our data provide additional molecular and clinical information for establishing a better genotype-phenotype correlation for LFSNHL.
Yi SunJing ChengYanping LuJianzhong LiYu LuZhanguo JinPu DaiRongguang WangHuijun Yuan
