تحلیل اگزونی ژن VCP در بیماری پارکینسون

Mutations in the valosin-containing protein gene (VCP) have been identified in neurological disorders (inclusion body myopathy—early Paget's disease of the bone—frontotemporal dementia and amyotrophic lateral sclerosis) and are thought to play a role in the clearance of abnormally folded proteins. Parkinsonism has been noted in kindreds with VCP mutations. Based on this, we hypothesized that mutations in VCP may also contribute to idiopathic Parkinson's disease (PD). We screened the coding region of the VCP gene in a large cohort of 768 late-onset PD cases (average age at onset, 70 years), both sporadic and with positive family history. We identified a number of rare single nucleotide changes, including a variant previously described to be pathogenic, but no clear disease-causing variants. We conclude that mutations in VCP are not a common cause for idiopathic PD.

A member of the AAA+ ATPase family, valosin-containing protein (VCP) is a highly conserved, ubiquitously expressed protein that is known to be involved in a wide variety of key cellular processes. In proteinopathies, VCP is thought to play a central role in the ubiquitin-proteasome and autophagy degradation pathways (Ju and Weihl, 2010). A number of observations support the involvement of VCP in the pathogenesis of neurodegeneration and suggest a dominant-negative effect for VCP mutations that lead to mislocalization and impaired removal of TAR DNA-binding protein 43 (TDP-43) (Shaw, 2010). First, mutations in the valosin-containing protein gene (VCP) cause a multisystem degenerative disorder affecting muscle, brain and bone tissues known as inclusion body myopathy—early Paget's disease of the bone—frontotemporal dementia (IBMPFD; Watts et al., 2004). TDP-43 pathology has been observed in IBMPFD cases (Neumann et al., 2007; Weihl et al., 2008) and VCP-mutant mouse models of the condition (Custer et al., 2010; Ju et al., 2009). Pathological TDP-43 inclusions are also found in Perry syndrome, a rare autosomal dominant disorder with features of Parkinsonism (Wider et al., 2009). Second, we recently extended the phenotype spectrum of VCP mutations to include motor neuron degeneration in the form of familial amyotrophic lateral sclerosis with TDP-43-positive inclusions (Johnson et al., 2011). The observation of concomitant Parkinsonism symptoms in some members of IBMPFD families (Johnson et al., 2011) led us to hypothesize that mutations in VCP may also contribute to idiopathic Parkinson's disease (PD). To test this, we performed mutational screening of VCP in a large cohort of PD cases.