This report describes amyotrophic lateral sclerosis 14 (ALS14), which is a subtype of amyotrophic lateral sclerosis; ALS14 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. This gene is also associated with the disease inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 1, IBMPFD1 (OMIM:167320, FBhh0000075). 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.
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.
Variant(s) implicated in human disease tested (as transgenic human gene, VCP): the R155H variant form of the human gene has been introduced into flies. Variant(s) implicated in human disease tested (as analogous mutation in fly gene): R152H in the fly TER94 gene (corresponds to R155H in the human VCP gene), R188Q in the fly TER94 gene (corresponds to R191Q in the human VCP gene). These variants are all associated with both ALS14 and IBMPFD1; additional variants have been characterized that are associated only with IBMPFD1 (see FBhh0000075).
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 Dec. 2018 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 OMIM:105400, 2015.02.11]
[AMYOTROPHIC LATERAL SCLEROSIS 14 WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA; ALS14](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]
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 OMIM:601023, 2015.02.12]
Ortholog of human VCP (1 Drosophila to 1 human).
Dmel\TER94 shares 83% identity and 92% similarity with human VCP.