A Novel Mutation (D395A) in Valosin-Containing Protein Gene Is Associated With Early Onset Frontotemporal Dementia in an Italian Family

Abstract

Inclusion body myopathy (IBM) with Paget's disease of bone (PDB) and/or frontotemporal dementia (FTD) (IBMPFD) was recently identified as rare autosomal dominant disorder due to mutations in VCP gene. However, VCP mutations have also been documented in patients with amyotrophic lateral sclerosis (ALS), Charcot-Marie-Tooth type 2 (CMT2) disease, and hereditary spastic paraplegia (HSP), underlining the heterogeneity of the phenotypes due to VCP mutations. In this study, we reported a novel missense heterozygous variant c.1184A > C (p.D395A) in exon 10 of VCP gene identified in three patients (two sisters and one brother) belonging to an Italian family. The patients underwent a detailed clinical evaluation including medical history, neurological examination, and neuropsychological assessment. Brain's morphologic and functional analysis was also performed. The whole picture was consistent with the criteria of behavioral variant frontotemporal dementia (bvFTD) without IBM and PBD. Our report confirms the high degree of heterogeneity of VCP disease. A VCP analysis should be considered for the genetic screening of familial bvFTD with an early onset also in absence of IBM or PDB signs.

Keywords: D395A; Paget’s disease of bone; VCP gene; Valosin-Containing Protein; body myopathy; bvFTD; frontotemporal dementia; novel mutation.

FIGURE 1

Imaging data of the proband. (A) MRI data: diffuse cortical atrophy prominent in frontal and temporal regions was present. (B) SPECT data: a hypoperfusion was observed in frontal and temporal convolutions of the left hemisphere and upper frontal circumvolution of the right hemisphere. Abbreviations: MRI, magnetic resonance imaging; SPECT, single-photon emission computed tomography.

FIGURE 2

Pedigree of the family. Individuals affected by FTD carrying the D395A mutation are indicated with black diamonds (male) or circle (females). The arrow indicates the proband. Age at onset (AO) or at death (AD) is indicated.

FIGURE 3

Chromatogram of the control (A) and the proband (B) showing the heterozygous VCP mutation: a c.1184A > C nucleotide substitution in exon 10 at codon 395. Vertical arrows indicate the mutation site.

FIGURE 4

Conservation analysis of the mutation site and protein structure modeling of VCP. (A) Alignment of VCP sequences from different species. Mutated residue is boxed. (B) The 3D protein structure modeling wild type and mutation type of VCP protein. The D395A mutation changes the residue side chain at the positions 395 of VCP protein.