This report describes a model of autosomal recessive spinocerebellar ataxia 4 (SCAR4), which is a subtype of spinocerebellar ataxia. The human gene implicated in this disease, VPS13D, encodes a ubiquitously expressed protein that plays an important role in mitochondrial size, autophagy, and clearance. There is a single orthologous gene in Drosophila, also designated Vps13D, for which loss-of-function mutations, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated.
The human VPS13D has not been introduced into flies.
Animals that carry transheterozygous combinations of severe loss-of-function alleles of Dmel\Vps13D typically die in the larval stage. Animals homozygous for a hypomorphic allele (lacking the UBA domain) exhibit reduced survival to adulthood; pupal midgut cells have significantly enlarged mitochondria and show mitochondrial clearance defects. Knockdown in neurons, effected by RNAi, results in changes in mitochondrial morphology and impairment in mitochondrial distribution along axons. A small number of physical and genetic interactions of Dmel\Vps13D have been described; see below and in the Vps13D gene report.
[updated Feb. 2019 by FlyBase; FBrf0222196]
Autosomal recessive cerebellar ataxias (ARCA) are a heterogeneous group of rare neurological disorders involving both central and peripheral nervous system, and in some case other systems and organs, and characterized by degeneration or abnormal development of cerebellum and spinal cord, autosomal recessive inheritance and, in most cases, early onset occurring before the age of 20 years (Palau and Espinos, 2006; pubmed:17112370).
The hereditary ataxias are a group of genetic disorders characterized by slowly progressive incoordination of gait and often associated with poor coordination of hands, speech, and eye movements. Frequently, atrophy of the cerebellum occurs. [from Gene Reviews, Hereditary Ataxia Overview; pubmed:20301317; 2017.06.16]
See also Jayadev and Bird, 2013 (pubmed:23538602).
Autosomal recessive spinocerebellar ataxia is a neurologic disorder characterized by onset of progressive gait difficulties, eye movement abnormalities, and dysarthria in the first or second decade of life (summary, Dy et al, 2105; pubmed:26224725). [from MIM:609270; 2020.07.13]
[SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 4; SCAR4](https://omim.org/entry/607317)
[VACUOLAR PROTEIN SORTING 13 HOMOLOG D; VPS13D](https://omim.org/entry/608877)
SCAR4 is an autosomal recessive neurologic disorder characterized by abnormal movements. Most patients have ataxic gait with spasticity and hyperreflexia of the lower limbs resulting in difficulty walking. The age at onset is highly variable: some have onset in early childhood with delayed walking, whereas others have onset of gait difficulties in adulthood. Additional features may include dysarthria, oculomotor abnormalities, distal sensory impairment, dystonia, chorea, hypotonia, pyramidal signs, and cerebellar atrophy on brain imaging. The disorder is slowly progressive. Some patients with onset in childhood may have global developmental delay with mild intellectual disability (summary by Seong et al., 2018; pubmed:29604224). [from MIM:607317; 2019.02.06]
Autosomal recessive spinocerebellar ataxia-4 (SCAR4) is caused by compound heterozygous mutation in the VPS13D gene. [from MIM:607317; 2019.02.06]
VPS13D (vacuolar protein sorting 13D) encodes a protein that functions in promoting mitochondrial clearance by mitochondrial autophagy (mitophagy), also possibly by positively regulating mitochondrial fission. [Gene Cards, VPS13D; 2019.02.06]
The VPS13D gene encodes a ubiquitously expressed protein that plays an important role in mitochondrial size, autophagy, and clearance (summary by Gauthier et al., 2018; pubmed:29518281). [from MIM:608877; 2019.02.06]
One to one: 1 human to 1 Drosophila
High-scoring ortholog of human VPS13D (1 Drosophila to 1 human). Dmel\Vps13D shares 29% identity and 47% similarity with the human gene.
