title: One family, one gene and three phenotypes: A novel VCP (valosin-containing protein) mutation associated with myopathy with rimmed vacuoles, amyotrophic lateral sclerosis and frontotemporal dementia.
abstract: BACKGROUND
  VCP (valosin-containing protein gene) variants have been associated with peripheral and central neurodegenerative processes, including inclusion body myopathy (IBM), Paget disease of bone (PDB), frontotemporal dementia (FTD), and familial amyotrophic lateral sclerosis (ALS) type 14. The combination of IBM, PDB (IBMPFD1) can presented in one individual. However, the association of IBMPFD1 and ALS in the same family is rare.
  
  
  METHODS
  We reported three individuals from a Brazilian kindred with intrafamilial phenotype variability. Whole exome sequencing (WES) of the proband was performed and revealed a novel VCP variant. VCP Sanger sequencing was performed in the proband and his family members to confirm WES finding and segregation. We performed a systematic review of the literature regarding the genotypic-phenotypic VCP correlations.
  
  
  RESULTS
  Each individual presented with either myopathy with rimmed vacuoles, ALS, or FTD. There was no PDB. WES of the proband identified the heterozygous variant c.271A>T (p.Asn91Tyr) in the exon 3 of VCP. Sanger sequencing confirmed the segregation of this variant in an autosomal-dominant pattern.
  
  
  CONCLUSIONS
  This study expands the genotypic spectrum of the missense mutations of the VCP gene with a novel p.Asn91Tyr variant found in a Brazilian family presenting with the unusual intrafamiliar association of myopathy with rimmed vacuoles, ALS and FTD.
authors.affiliation: Division of General Neurology and Ataxias, Department of Neurology and Neurosurgery, Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil.
authors.forename: Agessandro
authors.initials: A
authors.lastname: Abrahao
authors.affiliation: Departamento de Neurologia, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil.
authors.forename: Osório
authors.initials: O
authors.lastname: Abath Neto
authors.affiliation: Departamento de Neurologia, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil; Mendelics Genomic Analysis, São Paulo, SP, Brazil.
authors.forename: Fernando
authors.initials: F
authors.lastname: Kok
authors.affiliation: Departamento de Neurologia, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil.
authors.forename: Edmar
authors.initials: E
authors.lastname: Zanoteli
authors.affiliation: Mendelics Genomic Analysis, São Paulo, SP, Brazil.
authors.forename: Bibiana
authors.initials: B
authors.lastname: Santos
authors.affiliation: Division of General Neurology and Ataxias, Department of Neurology and Neurosurgery, Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil.
authors.forename: Wladimir Bocca Vieira de Rezende
authors.initials: WB
authors.lastname: Pinto
authors.affiliation: Division of General Neurology and Ataxias, Department of Neurology and Neurosurgery, Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil.
authors.forename: Orlando Graziani Povoas
authors.initials: OG
authors.lastname: Barsottini
authors.affiliation: Division of Neuromuscular Diseases, Department of Neurology and Neurosurgery, Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil.
authors.forename: Acary Souza Bulle
authors.initials: AS
authors.lastname: Oliveira
authors.affiliation: Division of General Neurology and Ataxias, Department of Neurology and Neurosurgery, Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil. Electronic address: jlpedroso.neuro@gmail.com.
authors.forename: José Luiz
authors.initials: JL
authors.lastname: Pedroso
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics*; D004252:DNA Mutational Analysis; D005192:Family Health; D057180:Frontotemporal Dementia / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009135:Muscular Diseases / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D000074405:Valosin Containing Protein
chemical_list: D018797:Cell Cycle Proteins; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein
keywords: Amyotrophic lateral sclerosis; Frontotemporal dementia; Inclusion body myopathy; VCP; Valosin-containing protein