title: A novel VCP mutation as the cause of atypical IBMPFD in a Chinese family.
abstract: BACKGROUND
  Inclusion-body myopathy (IBM) with Paget's disease of bone (PDB) and frontotemporal dementia (FTD), designated 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 from weakness of the limbs. 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 pathogenic gene mutation affecting the Chinese male proband.
  
  
  METHODS
  Altogether, 254 subjects, including one 56-year-old male proband, four affected, related individuals and additional nine family members from a non-consanguineous Chinese family, and 240 healthy donors were recruited and genomic DNA was extracted. 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 mutation in VCP as the disease-causing mutation. We confirmed the result by sequencing a 500-bp region of the promoter and the coding region of VCP in all 254 of the participants 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 able to identify a novel missense mutation in exon 3 of the VCP gene (p.Gly97Glu) in the Chinese male proband. This mutation was confirmed using Sanger sequencing. The proband, four affected individuals and three unaffected individuals carried this mutation. We were able to correctly diagnose the patients with atypical IBMPFD. Structural analysis of the p.Gly97Glu mutation in the VCP protein showed that the affected amino-acid is located in the interface of the protein. This abnormality may therefore interfere with protein function.
  
  
  CONCLUSIONS
  This is the first report of a family from China with IBMPFD. A novel VCP mutation was found as the cause of atypical IBMPFD in a Chinese family. Our findings confirm that VCP gene mutations can be a pathogenic cause of IBMPFD.
authors.affiliation: 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.
authors.forename: Jie-Mei
authors.initials: JM
authors.lastname: Gu
authors.forename: Yao-Hua
authors.initials: YH
authors.lastname: Ke
authors.forename: Hua
authors.initials: H
authors.lastname: Yue
authors.forename: Yu-Juan
authors.initials: YJ
authors.lastname: Liu
authors.forename: Zeng
authors.initials: Z
authors.lastname: Zhang
authors.forename: Hao
authors.initials: H
authors.lastname: Zhang
authors.forename: Wei-Wei
authors.initials: WW
authors.lastname: Hu
authors.forename: Chun
authors.initials: C
authors.lastname: Wang
authors.forename: Jin-Wei
authors.initials: JW
authors.lastname: He
authors.forename: Yun-Qiu
authors.initials: YQ
authors.lastname: Hu
authors.forename: Miao
authors.initials: M
authors.lastname: Li
authors.forename: Wen-Zhen
authors.initials: WZ
authors.lastname: Fu
authors.forename: Zhen-Lin
authors.initials: ZL
authors.lastname: Zhang
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D000368:Aged; D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000235:genetics*; D002681:China; D017931:DNA Primers; D005260:Female; D057180:Frontotemporal Dementia / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics*; D018979:Myositis, Inclusion Body / Q000235:genetics*; D010001:Osteitis Deformans / Q000235:genetics*; D010375:Pedigree; D016133:Polymerase Chain Reaction; D000074405:Valosin Containing Protein
chemical_list: D018797:Cell Cycle Proteins; D017931:DNA Primers; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein