This report describes combined oxidative phosphorylation deficiency 17 (COXPD17); COXPD17 exhibits autosomal recessive inheritance. The human gene implicated in this disease is ELAC2, a nuclear-encoded gene that is required for mitochondrial tRNA maturation. A paralogous gene, ELAC1, exists in human. There is a single orthologous gene in Drosophila, RNaseZ, for which multiple genetic reagents have been generated, including loss-of-function alleles, RNAi targeting constructs, alleles caused by insertional mutagenesis, overexpression constructs, and a targeted CRISPR knockout construct.
Several constructs of the wild-type human Hsap\ELAC2 gene have been introduced into flies. Expression of the human gene slightly ameliorates the lethal phenotype of a null RNaseZ mutation, but significant functional complementation is not observed.
Animals homozygous for a null mutation of RNaseZ typically die during the second larval instar stage. Constructs of RNaseZ carrying mutations analogous to disease-implicated variants in COXPD17 have been characterized (see the 'Disease-Implicated Variants' table, below). Each transgene was crossed into a RNaseZ null background, in order to provide the sole source of RNaseZ protein. The viability of such RNaseZ mutant flies at eclosion is normal, however, longevity at the adult stage is significantly reduced. Histological analyses of hearts obtained from larvae and young adults revealed phenotypes associated with both hypertrophic and dilated cardiomyopathy. Cellular phenotypes of the affected hearts have been described.
[updated Sep. 2021 by FlyBase; FBrf0222196]
Combined oxidative phosphorylation deficiency is an autosomal recessive multisystem disorder with variable manifestations resulting from a defect in the mitochondrial oxidative phosphorylation (OXPHOS) system. Onset occurs at or soon after birth, and features can include growth retardation, microcephaly, hypertonicity, axial hypotonia, encephalopathy, cardiomyopathy, and liver dysfunction. Death usually occurs in the first weeks or years of life (summary by Smits et al., 2011; pubmed:21119709). [from MIM:609060; 2021.04.17]
[COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 17; COXPD17](https://omim.org/entry/615440)
[ELAC RIBONUCLEASE Z 2; ELAC2](https://omim.org/entry/605367)
Combined oxidative phosphorylation deficiency-17 is an autosomal recessive disorder of mitochondrial dysfunction characterized by onset of severe hypertrophic cardiomyopathy in the first year of life. Other features include hypotonia, poor growth, lactic acidosis, and failure to thrive. The disorder may be fatal in early childhood (summary by Haack et al., 2013; pubmed:23849775). [from MIM:615440; 2021.09.12]
Oxidative phosphorylation deficiency-17 (COXPD17) is caused by homozygous or compound heterozygous mutation in the ELAC2 gene. [from MIM:615440; 2021.09.12]
ELAC2 encodes a zinc phosphodiesterase which displays mitochondrial tRNA 3'-processing endonuclease activity; it is involved in mitochondrial tRNA maturation, by removing a 3'-trailer from precursor tRNA. The ELAC2 protein associates with mitochondrial DNA complexes at the nucleoids to initiate RNA processing and ribosome assembly. [Gene Cards, ELAC2; 2021.09.12]
Many to one: 2 human genes to 1 Drosophila gene.
High-scoring ortholog of human ELAC2; low-scoring ortholog of ELAC1. Dmel\RNaseZ shares 35% identity and 51% similarity with the human ELAC2 gene.
