This report describes mitochondrial complex IV deficiency, nuclear type 17 (MC4DN17), which shows autosomal recessive inheritance. The human gene implicated in this disease is COA8 (previously named ADOPT1), a nuclear-encoded gene. There is a single high-ranking ortholog in Drosophila, Dmel\Coa8, for which RNAi targeting constructs and insertion lines have been generated.
The human gene COA8 has not been introduced into flies.
Knockdown of Coa8 does not reduce flies' lifespan, but it does reduce cytochrome c oxidase activity and mitochondrial complex IV activity, as well as general locomotor and climbing activity. Flies lacking Coa8 have lower survival rates after treatment with paraquat, which indicates that Coa8 participates in the response to reactive oxygen species, as is seen in mammals.
[updated Feb. 2021 by FlyBase; FBrf0222196]
Mitochondrial complex IV deficiency (cytochrome c oxidase deficiency) is clinically heterogeneous, ranging from isolated myopathy to severe multisystem disease, with onset from infancy to adulthood. [from MIM:220110; 2016.08.12]
[MITOCHONDRIAL COMPLEX IV DEFICIENCY, NUCLEAR TYPE 17; MC4DN17](https://omim.org/entry/619061)
[CYTOCHROME C OXIDASE ASSEMBLY FACTOR 8; COA8](https://omim.org/entry/616003)
Clinical features include abnormalities of brain magnetic resonance imaging (cavitating leukodystrophy), and neurometabolic failure, including progressive ataxia and spastic tetraparesis. (Brischigliaro et al. 2019 and references therein, FBrf0243568.)
Mitochondrial complex IV deficiency nuclear type 17 (MC4DN17) is an autosomal recessive neurometabolic disorder with somewhat variable clinical manifestations and severity. Most affected individuals present in early childhood with motor and gait difficulties after normal early development. These motor abnormalities progress to spastic tetraparesis, sometimes resulting in loss of ambulation. Many patients also show episodic developmental regression: some have impaired cognition and dysarthria, although others have normal speech and cognition. [from MIM:619061; 2021.02.26]
Loss-of-function mutations in the COA8 gene (alias APOPT1, APOP-1, or C14ORF153) have been identified in seven subjects from six different families presenting a distinctive form of mitochondrial encephalopathy. (Brischigliaro et al. 2019 and references therein, FBrf0243568.)
mitochondrial complex IV deficiency nuclear type 17 (MC4DN17) is caused by homozygous or compound heterozygous mutation in the APOPT1 (COA8) gene. [from MIM:619061; 2021.02.26]
Absence of APOPT1/COA8 does not affect the synthesis of any of the mtDNA-encoded COX subunits. However, their stability is severely compromised, being most probably actively degraded due to impaired incorporation into the nascent complex. (Signes et al. 2019, pubmed:30552096.)
COA8 encodes a 206-amino acid protein targeted and localized within mitochondria in mammals. Recent evidence proved that it is associated with the inner membrane, with the C-terminal region facing the mitochondrial matrix. (Signes et al. 2019, pubmed:30552096; Brischigliaro et al. 2019 and references therein, FBrf0243568.)
One to one: 1 human gene to 1 Drosophila gene.
Single high-ranking ortholog of human gene COA8.
