Novel Variants in the VCP Gene Causing Multisystem Proteinopathy 1

Rod Carlo Agram Columbres; Yue Chin; Sanjana Pratti; Colin Quinn; Luis F Gonzalez-Cuyar; Michael Weiss; Fabiola Quintero-Rivera; Virginia Kimonis

doi:10.3390/genes14030676

Novel Variants in the VCP Gene Causing Multisystem Proteinopathy 1

Genes (Basel). 2023 Mar 8;14(3):676. doi: 10.3390/genes14030676.

Authors

Rod Carlo Agram Columbres^{1

2}, Yue Chin², Sanjana Pratti², Colin Quinn³, Luis F Gonzalez-Cuyar⁴, Michael Weiss⁵, Fabiola Quintero-Rivera^{1

6}, Virginia Kimonis^{1

7

8}

Affiliations

¹ Division of Genetics and Genomic Medicine, Department of Pediatrics, University of California, Irvine, CA 92697, USA.
² College of Osteopathic Medicine, William Carey University, Hattiesburg, MS 39401, USA.
³ Department of Neurology, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁴ Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98104, USA.
⁵ Department of Neurology, University of Washington, Seattle, WA 98195, USA.
⁶ Department of Pathology and Laboratory Medicine, University of California, Irvine, CA 92697, USA.
⁷ Department of Neurology, University of California, Irvine, CA 92697, USA.
⁸ Department of Pathology, University of California, Irvine, CA 92697, USA.

Abstract

Valosin-containing protein (VCP) gene mutations have been associated with a rare autosomal dominant, adult-onset progressive disease known as multisystem proteinopathy 1 (MSP1), or inclusion body myopathy (IBM), Paget's disease of bone (PDB), frontotemporal dementia (FTD), (IBMPFD), and amyotrophic lateral sclerosis (ALS). We report the clinical and genetic analysis findings in five patients, three from the same family, with novel VCP gene variants: NM_007126.5 c.1106T>C (p.I369T), c.478G>A (p.A160T), and c.760A>T (p.I254F), associated with cardinal MSP1 manifestations including myopathy, PDB, and FTD. Our report adds to the spectrum of heterozygous pathogenic variants found in the VCP gene and the high degree of clinical heterogeneity. This case series prompts increased awareness and early consideration of MSP1 in the differential diagnosis of myopathies and/or PDB, dementia, or ALS to improve the diagnosis and early management of clinical symptoms.

Keywords: ALS; IBMPFD; MSP1; VCP; multisystem proteinopathy-1; valosin-containing protein.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Amyotrophic Lateral Sclerosis* / genetics
Cell Cycle Proteins / genetics
Frontotemporal Dementia* / genetics
Frontotemporal Dementia* / pathology
Humans
Merozoite Surface Protein 1
Muscular Dystrophies, Limb-Girdle
Myositis, Inclusion Body* / genetics
Myositis, Inclusion Body* / pathology
Osteitis Deformans* / genetics
Osteitis Deformans* / pathology
Valosin Containing Protein / genetics

Substances

Valosin Containing Protein
Cell Cycle Proteins
Merozoite Surface Protein 1
VCP protein, human

Supplementary concepts

Inclusion Body Myopathy With Early-Onset Paget Disease And Frontotemporal Dementia

Grants and funding

This research was funded by the University of California, Irvine, and the Inclusion Body Myopathy Research Fund.