This report describes amyotrophic lateral sclerosis 8 (ALS8), which is a subtype of amyotrophic lateral sclerosis; ALS8 exhibits autosomal dominant inheritance. The human gene implicated in this disease is VAPB, which is a member of the vesicle-associated membrane protein (VAMP)-associated protein (VAP) family. This gene is also associated with the disease spinal muscular atrophy, late-onset, Finkel type (MIM:182980, FBhh0000254). There is a single fly ortholog, Vap33, for which classical amorphic and hypomorphic alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated.
Multiple UAS constructs of the human Hsap\VAPB gene have been introduced into flies, including wild-type VAPB and genes carrying mutational lesions implicated in ALS8 and SMAFK; phenotypes similar to aspects of the human disease are observed. Heterologous rescue (functional complementation) has been demonstrated for one or more Dmel\Vap33 loss-of-function phenotypes.
Variant(s) implicated in human disease tested (as transgenic human gene, VAPB): the P56S variant form of the human gene has been introduced into flies. Variant(s) implicated in human disease tested (as analogous mutation in fly gene): T48I in the fly Vap33 gene (corresponds to T46I in the human VAPB gene); P58S in the fly Vap33 gene (corresponds to V234I in the human VAPB gene); V260I in the fly Vap33 gene (corresponds to V234I in the human VAPB gene). The P56S variant is also associated with spinal muscular atrophy, late-onset, Finkel type (see FBhh0000254).
For loss-of-function mutations in the Dmel\Vap33 gene, observed phenotypes include aspects similar to the human disease, including progressive locomotor defects, neurophysiology and neuroanatomy defects, and shortened lifespan. Physical and genetic interactions of Dmel\Vap33 have been described; see below and in the Vap33 gene report.
[updated Aug. 2019 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]
[AMYOTROPHIC LATERAL SCLEROSIS 8; ALS8](https://omim.org/entry/608627)
[VAMP-ASSOCIATED PROTEIN B AND C; VAPB](https://omim.org/entry/605704)
ALS8 is an autosomal dominant slowly progressive disorder characterized by fasciculations, cramps, and postural tremor (Nishimura, et al., 2004, pubmed:15060112; Nishimura, et al., 2004, pubmed:15372378). [From MIM:608627, 2015.12.16]
ALS8 is caused by heterozygous mutation in the VAPB gene. [from MIM:608627, 2015.02.12]
In vitro functional expression studies in COS-7 and neuronal cells showed that the VABP T46I mutation formed intracellular protein aggregates and ubiquitin aggregates, ultimately resulting in cell death. (Chen, et al., 2010, pubmed:20940299). [from MIM:605704 and MIM:608627, 2015.02.12]
The VAPB gene encodes a protein that is a member of the vesicle-associated membrane protein (VAMP)-associated protein (VAP) family. VAPB plays a role in the unfolded protein response (UPR), a process that suppresses the accumulation of unfolded proteins in the endoplasmic reticulum (Kanekura, et al., 2006, pubmed:16891305). [from MIM:605704, 2015.02.12]
Many to one: 2 human to 1 Drosophila (See DIOPT, link below).
Ortholog of human VAPB and human VAPA (1 Drosophila to 2 human; additional more distantly related gene(s) in both species).
Dmel\Vap-33A shares 37% identity and 54% similarity with human VAPB, and 36% identity and 51% similarity with human VAPA.
