BACKGROUND Wolfram syndrome is a rare autosomal recessive genetic disorder characterized by early-onset diabetes and progressive neurodegeneration,most notably sensorineural hearing loss and optic atrophy.Because its ...BACKGROUND Wolfram syndrome is a rare autosomal recessive genetic disorder characterized by early-onset diabetes and progressive neurodegeneration,most notably sensorineural hearing loss and optic atrophy.Because its initial manifestations are usually similar to those of type 1 diabetes,the diagnosis may be delayed until other manifestations appear.Pathogenic variations of the WFS1 gene can disrupt endoplasmic reticulum function and cellular homeostasis,but the complete mutation spectrum of WFS1 has not been fully determined.Early identification of monogenic diabetes caused by Wolfram syndrome is of vital importance,as it enables the provision of targeted multidisciplinary care and genetic counseling for affected families.CASE SUMMARY A 2-year-old Han Chinese girl was admitted with a 1-month history of polydipsia,polyuria,and polyphagia,and was diagnosed with diabetic ketoacidosis and impaired insulin secretion.Sensorineural hearing loss was also detected.Wholeexome sequencing identified a previously unreported heterozygous mutation,WFS1 c.986T>C(p.Phe329Ser),in the patient and her father,confirming the diagnosis of Wolfram syndrome.Bioinformatic analysis supported the likely pathogenicity of this mutation.In silico pathogenicity predictors(REVEL,SIFT,Poly-Phen-2,MutationTaster,and GERP+)supported a deleterious effect on wolframin structure and function.The patient was initially treated with intravenous insulin and fluid resuscitation,then transitioned to a basal–bolus insulin regimen.Glycemic control was subsequently maintained with continuous subcutaneous insulin infusion and intermittent subcutaneous injections.At the 1-and 6-month follow-ups,blood glucose remained well controlled(hemoglobin A1c:5.89%and 6.58%,respectively),with no evidence of organ dysfunction or further complications.CONCLUSION This case identifies WFS1 c.986T>C(p.Phe329Ser)as a novel pathogenic variant causing Wolfram syndrome.It highlights the importance of early genetic testing in pediatric patients with atypical diabetes presentations to enable timely diagnosis,individualized therapy,and comprehensive family support.展开更多
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
基金Supported by Beijing Holistic Integrative Medicine Association Clinical Research Funding Program,No.ZHKY-2024-2209.
文摘BACKGROUND Wolfram syndrome is a rare autosomal recessive genetic disorder characterized by early-onset diabetes and progressive neurodegeneration,most notably sensorineural hearing loss and optic atrophy.Because its initial manifestations are usually similar to those of type 1 diabetes,the diagnosis may be delayed until other manifestations appear.Pathogenic variations of the WFS1 gene can disrupt endoplasmic reticulum function and cellular homeostasis,but the complete mutation spectrum of WFS1 has not been fully determined.Early identification of monogenic diabetes caused by Wolfram syndrome is of vital importance,as it enables the provision of targeted multidisciplinary care and genetic counseling for affected families.CASE SUMMARY A 2-year-old Han Chinese girl was admitted with a 1-month history of polydipsia,polyuria,and polyphagia,and was diagnosed with diabetic ketoacidosis and impaired insulin secretion.Sensorineural hearing loss was also detected.Wholeexome sequencing identified a previously unreported heterozygous mutation,WFS1 c.986T>C(p.Phe329Ser),in the patient and her father,confirming the diagnosis of Wolfram syndrome.Bioinformatic analysis supported the likely pathogenicity of this mutation.In silico pathogenicity predictors(REVEL,SIFT,Poly-Phen-2,MutationTaster,and GERP+)supported a deleterious effect on wolframin structure and function.The patient was initially treated with intravenous insulin and fluid resuscitation,then transitioned to a basal–bolus insulin regimen.Glycemic control was subsequently maintained with continuous subcutaneous insulin infusion and intermittent subcutaneous injections.At the 1-and 6-month follow-ups,blood glucose remained well controlled(hemoglobin A1c:5.89%and 6.58%,respectively),with no evidence of organ dysfunction or further complications.CONCLUSION This case identifies WFS1 c.986T>C(p.Phe329Ser)as a novel pathogenic variant causing Wolfram syndrome.It highlights the importance of early genetic testing in pediatric patients with atypical diabetes presentations to enable timely diagnosis,individualized therapy,and comprehensive family support.
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>
