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
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>
