This report describes combined oxidative phosphorylation deficiency 14 (COXPD14); COXPD14 exhibits autosomal recessive inheritance. The human gene implicated in this disease is FARS2, which encodes mitochondrial phenylalanyl-tRNA synthetase. There is a single orthologous gene in Drosophila, PheRS-m. A small number of genetic reagents have been generated for Dmel\PheRS-m including RNAi-targeting constructs and an amorphic mutation generated by genome editing using the CRISPR/Cas9 system.
Multiple UAS constructs of Hsap\FARS2 have been introduced into flies, including wild-type and variants implicated in disease. Partial heterologous rescue (functional complementation) has been demonstrated. See the 'Disease-Implicated Variants' table below. A variant implicated in COXPD14, FARS2:p.Gly309Ser , has been assessed in the context of rescue of phenotypes of a null mutation of Dmel\PheRS-m. Pan-neuronal expression of the human gene carrying this variant results in partial rescue, allowing survival to the adult stage. Surviving adults exhibit bang sensitivity (a seizure-like phenotype); this phenotype is not observed in the case of rescue with the wild-type human gene.
FARS2 is also implicated in a less severe disease, spastic paraplegia 77; see FBhh0001430. See, also, the human disease model report 'developmental delay and seizure, FARS2-related' (FBhh0001428).
[updated Feb. 2022 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 14; COXPD14](https://omim.org/entry/614946)
[PHENYLALANYL-tRNA SYNTHETASE 2, MITOCHONDRIAL; FARS2](https://omim.org/entry/611592)
COXPD14 is a severe multisystemic autosomal recessive disorder characterized by neonatal onset of global developmental delay, refractory seizures, and lactic acidosis. Biochemical studies show deficiencies of multiple mitochondrial respiratory enzymes (Elo et al., 2012; pubmed:22833457). [from MIM:614946; 2022.01.31]
Combined oxidative phosphorylation deficiency-14 (COXPD14) is caused by homozygous or compound heterozygous mutation in the FARS2 gene. [from MIM:614946; 2022.01.31]
FARS2 encodes mitochondrial phenylalanyl-tRNA synthetase, a protein that transfers phenylalanine to its cognate tRNA in the process of mitochondrial translation. [Gene Cards, FARS2; 2022.01.31]
One to one: 1 human gene to 1 Drosophila gene.
High-scoring ortholog of human FARS2 (1 Drosophila to 1 human).
