This report describes frontotemporal dementia and/or amyotrophic lateral sclerosis 6 (FTDALS6), previously designated amyotrophic lateral sclerosis 14; FTDALS6 exhibits autosomal dominant inheritance. The human gene implicated in this disease 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. The human VCP gene is also associated with the disease inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 1, IBMPFD1 (MIM:167320, FBhh0000075). 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 FTDALS6 and/or IBMPFD1 have been assessed using transgenic constructs of the human gene and analogous mutations in 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. Physical and genetic interactions of Dmel\TER94 have been described; see below and in the TER94 gene report.
When expressed in transgenic flies, the human Hsap\ATXN3 protein has been shown to interact with the Dmel\TER94 protein; ATXN3 is implicated in Machado-Joseph disease, a form of spinocerebellar ataxia (see FBhh0000063). This interaction is dependent upon the identified VCP-binding site in the human ATXN3 protein.
[updated Jul. 2021 by FlyBase; FBrf0222196]
Amyotrophic lateral sclerosis is a neurodegenerative disorder characterized by the death of motor neurons in the brain, brainstem, and spinal cord, resulting in fatal paralysis. ALS usually begins with asymmetric involvement of the muscles in middle adult life. Approximately 10% of ALS cases are familial (Siddique and Deng, 1996, pubmed:8875253). ALS is sometimes referred to as 'Lou Gehrig disease' after the famous American baseball player who was diagnosed with the disorder. [from MIM:105400, 2015.02.11]
[FRONTOTEMPORAL DEMENTIA AND/OR AMYOTROPHIC LATERAL SCLEROSIS 6; FTDALS6](https://omim.org/entry/613954)
[VALOSIN-CONTAINING PROTEIN; VCP](https://omim.org/entry/601023)
Pathogenic variants in VCP, encoding valosin-containing protein, have been reported in an Italian family with autosomal dominant ALS. All affected individuals displayed upper motor neuron and lower motor neuron signs, and electomyogram studies revealed denervation and chronic reinnervation changes. Five individuals followed a rapidly progressive course [Johnson et al. 2010, pubmed:21145000]. [From GeneReviews, Amyotrophic Lateral Sclerosis Overview, pubmed:20301623, 2015.12.16]
ALS14 is caused by heterozygous mutation in the VCP gene. [from MIM:613954, 2015.02.12]
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. (Kanekura et al., 2006, pubmed:16891305)[from MIM:601023, 2015.02.12]
One to one: 1 human to 1 Drosophila (See DIOPT, link below).
Ortholog of human VCP (1 Drosophila to 1 human).
Dmel\TER94 shares 83% identity and 92% similarity with human VCP.
