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Novel Variants in the VCP Gene Causing Multisystem Proteinopathy 1

Rod Carlo Agram Columbres1,2, Yue Chin2, Sanjana Pratti2

  • 1Division of Genetics and Genomic Medicine, Department of Pediatrics, University of California, Irvine, CA 92697, USA.

Genes
|March 29, 2023
PubMed

Insights

Mutations in the Valosin-containing protein (VCP) gene cause multisystem proteinopathy 1 (MSP1), a rare progressive disease. This study identifies novel VCP variants linked to MSP1 symptoms, urging earlier diagnosis and management.

Area of Science:

  • Genetics
  • Neurology
  • Molecular Biology

Background:

  • Valosin-containing protein (VCP) gene mutations are linked to multisystem proteinopathy 1 (MSP1), a rare autosomal dominant disorder.
  • MSP1 encompasses a spectrum of conditions including inclusion body myopathy (IBM), Paget's disease of bone (PDB), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS).
  • Clinical heterogeneity and novel genetic variants contribute to diagnostic challenges in MSP1.

Purpose of the Study:

  • To report clinical and genetic findings in five patients with novel VCP gene variants.
  • To expand the understanding of the VCP gene's role in MSP1 pathogenesis.
  • To emphasize the importance of considering MSP1 in the differential diagnosis of related neurological and bone disorders.

Main Methods:

  • Clinical evaluation of five patients presenting with MSP1-related symptoms.
  • Genetic analysis to identify mutations in the VCP gene.
  • Correlation of identified VCP variants with clinical manifestations.

Main Results:

  • Identification of three novel heterozygous pathogenic VCP variants: c.1106T>C (p.I369T), c.478G>A (p.A160T), and c.760A>T (p.I254F).
  • Association of these novel variants with cardinal MSP1 manifestations, including myopathy, PDB, and FTD.
  • Demonstration of significant clinical heterogeneity among patients with VCP variants.

Conclusions:

  • The VCP gene harbors a spectrum of heterozygous pathogenic variants associated with MSP1.
  • High clinical heterogeneity underscores the complexity of MSP1 diagnosis.
  • Increased awareness and early consideration of MSP1 are crucial for timely diagnosis and improved management of affected individuals.
Keywords:
ALSIBMPFDMSP1VCPmultisystem proteinopathy-1valosin-containing protein

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