This report describes an inclusion body myopathy with or without frontotemporal dementia postulated to be caused by the SVIP gene. SVIP (small VCP interacting protein) encodes an inhibitor of the endoplasmic reticulum-associated degradation (ERAD) pathway. The VCP gene is implicated in inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 1 (see FBhh0000075). There is a single gene in Drosophila orthologous to SVIP, Dmel\Svip; both genes encode small polypeptides, 77-82 amino acids. An amorphic mutation, RNAi-targeting constructs, and regulated expression constructs have been generated for Svip.
The human SVIP gene has not been introduced into flies.
Animals homozygous for an amorphic mutation of Svip show increased rates of pupal lethality, have a reduced adult lifespan, and exhibit a progressive, degenerative phenotype in muscle and motor neurons that is similar to that observed in disease-implicated variants of VCP (TER94 in Drosophila). The diminished lifespan can be fully rescued by muscle-specific expression of UAS-Svip, but not by neuronal expression of UAS-Svip. A variant analogous to one found in a patient has been introduced into the fly gene. Variant(s) implicated in human disease introduced (as analogous mutation in fly gene): S82L in the fly Svip gene (corresponds to S77L in the human SVIP gene); see the 'Disease-Implicated Variants' table below. Although the variant protein can still bind VCP in vitro, it disrupts tubular lysosomes in Drosophila larval muscle in a dominant fashion. Animals carrying either the knockout mutation or the S82L mutation of Svip exhibit resistance to tunicamycin, which is known to exacerbate ER stress.
[updated Mar. 2024 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]
A patient suffering from frontotemporal dementia was determined to have a missense (S77L) mutation in SVIP (FBrf0247840). Since SVIP encodes a very small polypeptide (77 amino acids in human), deleterious variants are likely to be rare.
SVIP encodes an inhibitor of the ERAD (endoplasmic reticulum-associated degradation) pathway; this pathway functions to target misfolded proteins in the endoplasmic reticulum to the proteasome for degradation. [Gene Cards, SVIP; 21.02.07]
One to one: 1 human gene to 1 Drosophila gene.
Moderate-scoring ortholog of human SVIP (1 Drosophila to 1 human). Dmel\CG32039 shares 33% identity and 60% similarity with the human gene. Both proteins are small, 79-82 amino acids.
