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FB2026_01
,
released March 12, 2026
This report describes spinal muscular atrophy, late onset, Finkel type (SMAFK), a subtype of spinal muscular atrophy; SMAFK 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 amyotrophic lateral sclerosis 8 (MIM:608627, FBhh0000020). 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): P58S in the fly Vap33 gene (corresponds to P56S in the human VAPB gene). The P56S variant is also associated with amyotrophic lateral sclerosis 8 (see FBhh0000020).
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 Jul. 2017 by FlyBase; FBrf0222196]
Spinal muscular atrophy (SMA) is characterized by progressive muscle weakness resulting from degeneration and loss of the anterior horn cells (i.e., lower motor neurons) in the spinal cord and the brain stem nuclei. Onset ranges from before birth to adolescence or young adulthood. Poor weight gain, sleep difficulties, pneumonia, scoliosis, and joint contractures are common complications. [From GeneReviews, Spinal Muscular Atrophy, pubmed:20301526 2016.07.11]
[SPINAL MUSCULAR ATROPHY, LATE-ONSET, FINKEL TYPE; SMAFK](https://omim.org/entry/182980)
[VAMP-ASSOCIATED PROTEIN B AND C; VAPB](https://omim.org/entry/605704)
Spinal muscular atrophy is a genetic disorder that affects the control of muscle movement. It is caused by a loss of specialized nerve cells, called motor neurons, in the spinal cord and the part of the brain that is connected to the spinal cord (the brainstem). The loss of motor neurons leads to weakness and wasting (atrophy) of muscles used for activities such as crawling, walking, sitting up, and controlling head movement. In severe cases of spinal muscular atrophy, the muscles used for breathing and swallowing are affected. There are many types of spinal muscular atrophy distinguished by the pattern of features, severity of muscle weakness, and age when the muscle problems begin. VAPB-associated spinal muscular atrophy is an adult-onset form. [From Genetics Home Reference, spinal muscular atrophy, 2016.04.15]
Spinal muscular atrophy is characterized by degeneration of the anterior horn cells in the spinal cord, leading to symmetric muscle weakness and wasting. [From MIM:182980, 2016.04.12]
The Finkel type of late-onset autosomal dominant spinal muscular atrophy (SMAFK) is caused by heterozygous mutation in the gene encoding vesicle-associated membrane protein-associated protein B (VAPB). [From MIM:182980, 2016.04.12]
In vitro functional expression studies in rat hippocampal neurons and HEK293 cells showed that the P56S mutation disrupted the normal subcellular distribution of the VAPB protein and caused intracellular aggregates. Unlike the wildtype protein, the mutant P56S protein did not colocalize with either the Golgi apparatus or the endoplasmic reticulum (ER) (Nishimura et al., 2004, pubmed:15372378). [from MIM:605704, 2016.04.12]
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). In a large white Brazilian family with atypical ALS (ALS8; MIM:608627), Nishimura et al. (2004, pubmed:15372378) found a heterozygous 166C-T transition in exon 2 of the VAPB gene, leading to a pro56-to-ser (P56S) mutation. Subsequently the authors demonstrated the same mutation in patients from 6 additional kindreds in which the clinical course varied, including some with Finkel type late-onset spinal muscular atrophy and some with typical severe ALS with rapid progression (see MIM:105400). Although it was not possible to link all of these families, haplotype analysis suggested founder effect. [from MIM:605704, 2016.04.12]
Many to one: 2 human to 1 Drosophila.
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.