TY - JOUR
T1 - Multisystem Proteinopathy Due to VCP Mutations
T2 - A Review of Clinical Heterogeneity and Genetic Diagnosis
AU - Pfeffer, Gerald
AU - Lee, Grace
AU - Pontifex, Carly S.
AU - Fanganiello, Roberto D.
AU - Peck, Allison
AU - Weihl, Conrad C.
AU - Kimonis, Virginia
N1 - Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2022/6
Y1 - 2022/6
N2 - In this work, we review clinical features and genetic diagnosis of diseases caused by mutations in the gene encoding valosin-containing protein (VCP/p97), the functionally diverse AAA-ATPase. VCP is crucial to a multitude of cellular functions including protein quality control, stress granule formation and clearance, and genomic integrity functions, among others. Pathogenic mutations in VCP cause multisystem proteinopathy (VCP-MSP), an autosomal dominant, adult-onset disorder causing dysfunction in several tissue types. It can result in complex neurodegenerative conditions including inclusion body myopathy, frontotemporal dementia, amyotrophic lateral sclerosis, or combinations of these. There is also an association with other neurodegenerative phenotypes such as Alzheimer-type dementia and Parkinsonism. Non-neurological presentations include Paget disease of bone and may also include cardiac dysfunction. We provide a detailed discussion of genotype-phenotype correlations, recommendations for genetic diagnosis, and genetic counselling implications of VCP-MSP.
AB - In this work, we review clinical features and genetic diagnosis of diseases caused by mutations in the gene encoding valosin-containing protein (VCP/p97), the functionally diverse AAA-ATPase. VCP is crucial to a multitude of cellular functions including protein quality control, stress granule formation and clearance, and genomic integrity functions, among others. Pathogenic mutations in VCP cause multisystem proteinopathy (VCP-MSP), an autosomal dominant, adult-onset disorder causing dysfunction in several tissue types. It can result in complex neurodegenerative conditions including inclusion body myopathy, frontotemporal dementia, amyotrophic lateral sclerosis, or combinations of these. There is also an association with other neurodegenerative phenotypes such as Alzheimer-type dementia and Parkinsonism. Non-neurological presentations include Paget disease of bone and may also include cardiac dysfunction. We provide a detailed discussion of genotype-phenotype correlations, recommendations for genetic diagnosis, and genetic counselling implications of VCP-MSP.
KW - VCP
KW - amyotrophic lateral sclerosis
KW - dementia
KW - genetics
KW - genotype-phenotype correlation
KW - multisystem proteinopathy
KW - myopathy
UR - http://www.scopus.com/inward/record.url?scp=85131379967&partnerID=8YFLogxK
U2 - 10.3390/genes13060963
DO - 10.3390/genes13060963
M3 - Review article
C2 - 35741724
AN - SCOPUS:85131379967
SN - 2073-4425
VL - 13
JO - Genes
JF - Genes
IS - 6
M1 - 963
ER -