Mutations in the WFS1 gene have been reported in Wolfram syndrome (WFS), a rare and autosomal recessive disorder defined <span style="font-family:Verdana;">by early onset of diabetes mellitus and progr...Mutations in the WFS1 gene have been reported in Wolfram syndrome (WFS), a rare and autosomal recessive disorder defined <span style="font-family:Verdana;">by early onset of diabetes mellitus and progressive optic and hearing impairment. Only few data are available concerning the association between clinical and molecular aspects of the WFS. We present a consanguineous family with a patient presenting an early onset of WFS and severe manifestations. Sequencing of </span><i><span style="font-family:Verdana;">WFS1</span></i><span style="font-family:Verdana;"> gene was performed for all the family members to search for responsible mutation and bioinformatics tools </span><span style="font-family:Verdana;">were </span><span style="font-family:;" "=""><span style="font-family:Verdana;">conducted to predict its effect on structure and function of the protein. We have detected a novel frameshift mutation in the proband at homozygous state and at the heterozygous state in the parents who have no WFS manifestations. In silico analysis predicted the pathogenicity of the mutation and could lead to a complete loss of its function. Thus, 3D modeling showed that the mutation abolishes the interaction of the CaM binding region to the N-terminal of WFS1 and then impairs the W</span><span style="font-family:Verdana;">FS1-CaM complex formation. Genotype-phenotype correlation study show</span><span style="font-family:Verdana;">s that the novel mutation predisposes to early onset of diabetes and severe symptoms observed in the proband. We also report the effect of the frameshift mutation on the CaM-WFS1 impaired binding, and we discuss its possible consequence in pancreatic </span><i><span style="font-family:Verdana;">β</span></i><span style="font-family:Verdana;">-cells dysfunction and its role in the early onset of diabetes. In conclusion, the combination of impaired functions of WFS1 including unproper interaction of the CaM, Ca</span><sup><span style="font-family:Verdana;">2+</span></sup><span style="font-family:Verdana;"> uptake, mitochondrial dysfunction, and apoptosis under the ER stress could be involved in the severe phenotype and early onset of WFS of our patient.</span></span>展开更多
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 WFS...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.展开更多
文摘Mutations in the WFS1 gene have been reported in Wolfram syndrome (WFS), a rare and autosomal recessive disorder defined <span style="font-family:Verdana;">by early onset of diabetes mellitus and progressive optic and hearing impairment. Only few data are available concerning the association between clinical and molecular aspects of the WFS. We present a consanguineous family with a patient presenting an early onset of WFS and severe manifestations. Sequencing of </span><i><span style="font-family:Verdana;">WFS1</span></i><span style="font-family:Verdana;"> gene was performed for all the family members to search for responsible mutation and bioinformatics tools </span><span style="font-family:Verdana;">were </span><span style="font-family:;" "=""><span style="font-family:Verdana;">conducted to predict its effect on structure and function of the protein. We have detected a novel frameshift mutation in the proband at homozygous state and at the heterozygous state in the parents who have no WFS manifestations. In silico analysis predicted the pathogenicity of the mutation and could lead to a complete loss of its function. Thus, 3D modeling showed that the mutation abolishes the interaction of the CaM binding region to the N-terminal of WFS1 and then impairs the W</span><span style="font-family:Verdana;">FS1-CaM complex formation. Genotype-phenotype correlation study show</span><span style="font-family:Verdana;">s that the novel mutation predisposes to early onset of diabetes and severe symptoms observed in the proband. We also report the effect of the frameshift mutation on the CaM-WFS1 impaired binding, and we discuss its possible consequence in pancreatic </span><i><span style="font-family:Verdana;">β</span></i><span style="font-family:Verdana;">-cells dysfunction and its role in the early onset of diabetes. In conclusion, the combination of impaired functions of WFS1 including unproper interaction of the CaM, Ca</span><sup><span style="font-family:Verdana;">2+</span></sup><span style="font-family:Verdana;"> uptake, mitochondrial dysfunction, and apoptosis under the ER stress could be involved in the severe phenotype and early onset of WFS of our patient.</span></span>
基金supported by the National High Technology Research and Development Program of China(863 Program) to Huijun Yuan(No.2007AA02E466)Key Project of National Natural Science Foundation of China to Huijun Yuan (No.81030017)and to Pu Dai(No.30872862)
文摘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.
文摘目的:报道1例首诊为脑炎的不完全型Wolfram综合征(Wolfram syndrome,WS)病例。方法:对1例因头痛、言语困难伴记忆力下降5个月的患者应用目标区域捕获高通量测序进行全外显子测序。收集其临床资料并结合基因测序结果进行文献复习。结果:患者41岁,男性,因头痛、言语困难伴记忆力下降5个月入院,既往糖尿病、偏头痛、高度近视、耳聋病史。5个月前突发言语困难,不能交流,颅脑MRI检查提示左侧颞叶、岛叶、顶叶DWI高信号,疑诊为脑炎,遗传代谢病不能排除,完善传染病、自身免疫性脑炎、乳酸、风湿、甲状腺功能等检查,全外显子测序提示WFS1基因外显子8中有1个突变,c.975C>A,经SIFT软件预测该突变为Affect protein function,经Polyphen-2软件预测该突变为Probably damaging。美国医学遗传学与基因组学学会(ACMG)证据显示该位点临床意义未明。对其姑姑、妹妹、舅舅及姨妈进行的家系验证发现其舅舅及姨妈与患者突变位点一致。患者影像学未见明显视神经、脑干及小脑萎缩,与多数文献报道不同。结论:临床表现为脑炎样发作的WS较少见,对于有多系统累及的患者,除考虑免疫、代谢、肿瘤等相关病因外,相对罕见的遗传性疾病也应纳入鉴别诊断。
