A novel VCP mutation as the cause of atypical IBMPFD in a Chinese family
Introduction: Indusion-body myopathy (IBM) with Paget”s disease of bone (PDB) and fmntotemporal demen tia (FTD).designatred as IBMPFD,is a rare,autosomal dominant disorder (MIM 605382).IBMPFD is caused by mutations in the gene that encode valosin-containing protein (VCP).We investigated a Chinese family in which multiple members were diagnosed with PDB and suffered fnon weakness of the lkinbs.However.no members of this family were diagnosed with FTD.We made a preliminary diagnosis of PDB.but failed to identify an SQSTM1 mutation in any of the patients.We used whole-exome sequencing to identify the path ogenic gene mutation affecting the Chinese male proband.Materials and methods: Altogether.254 subjects,induding one 56-year-old male proband,four afffected,related individuals and additional nine family members from a non-consanguineous Chinese family,and 240 healthy donors were recruited and genomic DNA was etracted.All eight exons and the exon-intron boundaries of the SQSTM1 gene were amplified by polymerase chain reaction (PCR) and directly sequenced in five patients (Ⅱ13,Ⅱ4,Ⅱ5,Ⅱ8.Ⅱ9).Using whole-exome sequencing we identified a novel mutatuon in VCP as the disease causing mutation.We coofrned the result by sequencing a 500-bp region of the promoter and the coding region of VCP in all 254 of the pafticipants using Sanger sequencing.Results: No mutation in the SQSTM1 gene was identified in the five patients examined using direct Sanger sequencing However,through whole-exome sequencing we were abie to identify a novel missense mutation in exon 3 of the VCP gene (p.Gly97Glu) in the Chinese male pxoband.This mutation was confirmed using Sanger sequencing.The proband,four affected individuab and thee unaffected individuals carried this mutation.We were able to conectly diagnose the patients with atypical IBMPFD.Structural analysis of the p.Gly97Glu mutation in the VCP protein showed that the affected amino-acid is Iocated in the interface of the protein.This abnormality may therefore interrfere with protein function.Conctusions: This is the flrst report of a family from China with IBMPFD.A novel VCP mucation was found as the cause of atypical IBMPfD in a Chinese family.Our findings confirm thiat VCP gene mutations can be a pathogenic cause of IBMPFD.
Valosin-containing protein Mutation Atypical INMPFD
Jie-Mei Gu Yun-Qiu Hu Miao Li Wen-Zhen Fu Zhen-Lin Zhang Yao-Hua Ke Hua Yue Yu-Juan Liu Zeng Zhang Hao Zhang Wei-Wei Hu Chun Wang Jin-Wei He
Metabolic Bone Disease and Genetic Research Unit,Department of Osteoporosis and Bone Diseases,Shanghai Jiao Tong University Affiliated Sixth People”s Hospital,Shanghai 200233,China
国内会议
南昌
英文
119-126
2013-06-13（万方平台首次上网日期，不代表论文的发表时间）