This report describes dystonia, early-onset, and/or spastic paraplegia (DYTSPG); DYTSPG exhibits autosomal dominant inheritance. The human gene implicated in this disease is ATP5MC3, one of three genes that encode a specific subunit of mitochondrial ATP synthase (complex V). There is a single orthologous gene in Drosophila, ATPsynC, for which multiple genetic reagents have been generated including classical amorphic and hypomorphic alleles, RNAi-targeting constructs, overexpression constructs, and alleles caused by insertional mutagenesis.
A UAS construct of the human Hsap\ATP5MC3 gene has not been introduced into flies, but has not been characterized; a stock is available.
This disease has been investigated in Drosophila using a variant of Dmel\ATPsynC analogous to the human variant associated with the disease; see the 'Disease-Implicated Variants' table below. Using UAS constructs and various GAL4 drivers, over-expression of the wild-type gene does not appear to be deleterious; similarly, neural-specific or muscle-specific expression the disease-associated variant results in no discernible phenotype. High levels of constitutive expression of the disease-associated variant results in lethality. Lower levels of constitutive expression of the variant allows survival to adulthood; progressive locomotor defects are observed; a significant reduction in activity of mitochondrial ATP synthase is detected.
[updated Feb. 2022 by FlyBase; FBrf0222196]
Dystonia describes a neurologic condition characterized by involuntary, sustained muscle contractions affecting one or more sites of the body; 'torsion' refers to the twisting nature of body movements observed in some types of dystonia. Dystonia has been classified as primary (dystonia as the sole or major symptom) or secondary (a symptom of another disorder), and by age of onset, muscle groups affected, and mode of inheritance (Muller and Kupke, 1990, pubmed:2404852; Nemeth, 2002, pubmed:11912106). [from MIM:128100; 15.07.07]
Dystonic movements are typically patterned, twisting, and may be tremulous. Dystonia is often initiated or worsened by voluntary action and associated with overflow muscle activation. Dystonias are classified by several clinical characteristics including age of onset (infancy (birth to 2 years), childhood (3-12 years), adolescence (13-20 years), early adulthood (21-40 years), and late adulthood (over 40 years)), temporal pattern (static or progressive disease course and the variability of symptoms, which may persist, fluctuate diurnally or occur only with specific actions or in paroxysms), by body distribution, which is divided into focal (affecting a single body part), segmental (affecting two or more contiguous muscle groups, multifocal (affecting two or more non-contiguous muscle groups), hemidystonia (affecting an arm and a leg on one side of the body), or generalized (affecting the trunk and two or more other sites), and by coexistence of other movement disorders. (Balint and Bhatia, 2014, PMID:24978640, Gene_reviews, Dystonia Overview, 2015.07.09)
[DYSTONIA, EARLY-ONSET, AND/OR SPASTIC PARAPLEGIA; DYTSPG](https://omim.org/entry/619681)
[ATP SYNTHASE MEMBRANE SUBUNIT C, LOCUS 3; ATP5MC3](https://omim.org/entry/602736)
Early-onset dystonia and/or spastic paraplegia (DYTSPG) is an autosomal dominant movement disorder characterized by phenotypic variability, even within the same family. Some patients have onset of progressive focal and generalized dystonia in the first decade, as young as infancy, whereas others develop progressive spastic paraplegia as adults, suggesting that age affects the phenotype. Some patients have manifestations of both disorders. Although most patients have ambulation difficulties, cognition is not affected (summary by Gilbert et al., 2009; pubmed:19006192). [from MIM:619681; 2022.02.21]
Early-onset dystonia and/or spastic paraplegia (DYTSPG) is caused by heterozygous mutation in the ATP5MC3 gene. [from MIM:619681; 2022.02.21]
ATP5MC1, ATP5MC2, and ATP5MC3 encode a subunit of the proton channel of mitochondrial ATP synthase (mitochondrial complex V). Each of the three genes have distinct mitochondrial import sequences but encode the identical mature protein. [Gene Cards, ATP5MC1, ATP5MC2, ATP5MC3; 2020.08.14]
Many to one: 3 human genes to 1 Drosophila gene.
Moderate-scoring ortholog of human ATP5MC1, ATP5MC, and ATP5MC3 (1 Drosophila to 3 human). Dmel\ATPsynC shares 64-71% identity and 76-83% similarity with the human genes.
