This report describes inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 1 (IBMPFD1), which is the major subtype of inclusion body myopathy with Paget disease of bone and frontotemporal dementia; IBMPFD1 exhibits autosomal dominant inheritance. The term multisystem proteinopathy is also used to describe this disease. The human gene implicated in IBMPFD1 is VCP, which encodes valosin-containing protein, a multifunctional member of the AAA+ (ATPase associated with various activities) protein family, which is required for the export of endoplasmic reticulum to the cytosol. There is one high-scoring fly ortholog, TER94, for which RNAi targeting constructs, alleles caused by insertional mutagenesis, and classical amorphic alleles have been generated. VCP is also associated with the diseases frontotemporal dementia and/or amyotrophic lateral sclerosis 6 (MIM:613954, FBhh0000021), and Charcot-Marie-Tooth disease type, axonal, type 2Y (MIM:616687). Some medical researchers now describe FTDALS6 and IBMPFD1 as a single disease, multisystem proteinopathy 1 (MSP-1), with a continuum of symptoms.
Multiple UAS constructs of the human Hsap\VCP gene have been introduced into flies, including wild-type and genes carrying mutational lesions. Heterologous rescue (functional complementation) has been demonstrated for the larval muscle phenotype.
Variants implicated in IBMPFD1 and/or FTDALS6 have been assessed using transgenic constructs of the human gene and analogous mutations in the fly gene; see the 'Disease-Implicated Variants' table below.
Amorphic and most loss-of-function alleles of Dmel\TER94 are lethal, typically during the larval stage; disruption of sarcoplasmic lysosomal tubular network is observed in muscles of mutant larvae. Targeted knockdown via RNAi results in neuroanatomy defective and learning defective phenotypes. Cardiomyopathy is observed at elevated rates among IBMPFD1 patients; this aspect of the disease has also been investigated in Drosophila. Physical and genetic interactions of Dmel\TER94 have been described; see below and in the TER94 gene report.
[updated Jul. 2021 by FlyBase; FBrf0222196]
Inclusion body myopathy associated with Paget disease of bone (PDB) and/or frontotemporal dementia (IBMPFD) is characterized by adult-onset proximal and distal muscle weakness (clinically resembling a limb-girdle muscular dystrophy syndrome), early-onset PDB, and premature frontotemporal dementia (FTD). Muscle weakness progresses to involve other limb and respiratory muscles. Cardiac failure and cardiomyopathy have been observed in later stages. PDB involves focal areas of increased bone turnover that typically lead to spine and/or hip pain and localized enlargement and deformity of the long bones; pathologic fractures occur on occasion. Early stages of FTD are characterized by dysnomia, dyscalculia, comprehension deficits, paraphasic errors, and relative preservation of memory, and later stages by inability to speak, auditory comprehension deficits for even one-step commands, alexia, and agraphia. Mean age at diagnosis for muscle disease and PDB is 42 years; for FTD, 55 years. [from GeneReviews, Inclusion Body Myopathy with Paget Disease of Bone and/or Frontotemporal Dementia, pubmed:20301649 2016.06.03]
IBMPFD is a autosomal dominant disorder linked to multiple genes, characterized by incomplete penetrance of 3 main features: disabling muscle weakness (in 90%), osteolytic bone lesions consistent with Paget disease (in 51%), and frontotemporal dementia (in 32%). Muscle weakness is an isolated symptom in about 30% of patients and the presenting symptom in greater than half of patients, suggesting that IBMPFD may commonly be seen in a neuromuscular clinic without its other syndromic features (review by Weihl et al., 2009, pubmed:19380227). [From MIM:167320, 2016.06.03]
[INCLUSION BODY MYOPATHY WITH EARLY-ONSET PAGET DISEASE WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA 1; IBMPFD1](https://omim.org/entry/167320)
[VALOSIN-CONTAINING PROTEIN; VCP](https://omim.org/entry/601023)
Inclusion body myopathy associated with Paget disease of bone (PDB) and/or frontotemporal dementia (IBMPFD) is characterized by adult-onset proximal and distal muscle weakness (clinically resembling a limb-girdle muscular dystrophy syndrome), early-onset PDB, and premature frontotemporal dementia (FTD). Muscle weakness progresses to involve other limb and respiratory muscles. Cardiac failure and cardiomyopathy have been observed in later stages. PDB involves focal areas of increased bone turnover that typically lead to spine and/or hip pain and localized enlargement and deformity of the long bones; pathologic fractures occur on occasion. Early stages of FTD are characterized by dysnomia, dyscalculia, comprehension deficits, paraphasic errors, and relative preservation of memory, and later stages by inability to speak, auditory comprehension deficits for even one-step commands, alexia, and agraphia. Mean age at diagnosis for muscle disease and PDB is 42 years; for FTD, 55 years. [from GeneReviews, Inclusion Body Myopathy with Paget Disease of Bone and/or Frontotemporal Dementia, pubmed:20301649 2015.12.13]
IBMPFD is an autosomal dominant disorder characterized by incomplete penetrance of 3 main features: disabling muscle weakness (in 90%), osteolytic bone lesions consistent with Paget disease (in 51%), and frontotemporal dementia (in 32%). Muscle weakness is an isolated symptom in about 30% of patients and the presenting symptom in greater than half of patients, suggesting that IBMPFD may commonly be seen in a neuromuscular clinic without its other syndromic features (review by Weihl et al., 2009, pubmed:19380227). [From MIM:167320, 2016.06.03]
Inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 1 (IBMPFD1) is caused by heterozygous mutation in the VCP gene. [From MIM:167320, 2016.06.03]
Muscle biopsies show inclusion bodies and/or rimmed vacuoles (39%) or nonspecific changes (Kimonis et al., 2008, pubmed:18260132). [From MIM:167320, 2016.06.03]
The VCP gene encodes valosin-containing protein, a ubiquitously expressed multifunctional protein that is a member of the AAA+ (ATPase associated with various activities) protein family. It has been implicated in multiple cellular functions ranging from organelle biogenesis to ubiquitin-dependent protein degradation (summary by Weihl et al., 2009, pubmed:19380227). [From MIM:601023, 2016.06.03]
One to one: 1 human to 1 Drosophila.
Ortholog of human VCP (1 Drosophila to 1 human).
Dmel\TER94 shares 83% identity and 92% similarity with human VCP.
