This report describes a potential model of mitochondrial complex I deficiency, nuclear type 4 (MC1DN4); MC1DN4 exhibits autosomal recessive inheritance. The human gene implicated in this disease subtype is NDUFV1, a nuclear gene that encodes a subunit of the catalytic flavoprotein component of NADH:ubiquinone oxidoreductase. This enzyme complex, also known as Complex I, is the first in the mitochondrial electron transport chain. There is a single fly ortholog, Dmel\ND-51, for which RNAi-targeting constructs and a P-element insertion line have been generated.
The human gene NDUFV1 has not been introduced into flies.
In an RNAi screen of mitochondrial complex I genes, ubiquitous knockdown of ND-20 at 25 degrees C was found to be larval lethal, which was unlike other genes tested. This suggests that it may provide a model for MC1DN3.
[updated July 2019 by FlyBase; FBrf0222196]
Mitochondrial complex I deficiency causes a wide range of clinical disorders, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, nonspecific encephalopathy, hypertrophic cardiomyopathy, myopathy, and liver disease. [from MIM:252010; 2016.08.12]
[MITOCHONDRIAL COMPLEX I DEFICIENCY, NUCLEAR TYPE 4; MC1DN4](https://omim.org/entry/618225)
[NADH-UBIQUINONE OXIDOREDUCTASE FLAVOPROTEIN 1; NDUFV1](https://omim.org/entry/161015)
Clinical presentation of children with NDUFV1 mutation includes developmental regression, epilepsy, hypotonia, spasticity, dystonia, opthalmoplegia, strabismus and nystagmus. Early onset, diffuse leucoencephalopathy with or without cavitations have been reported among those with NDUFV1 gene mutation. (Wadhwa et al. 2018 and references therein, pubmed:29948731.)
As reported by Schuelke et al. (pubmed:10080174), two brothers presented with repeated vomiting and developed strabismus, progressive muscular hypotonia, myoclonic epilepsy, and psychomotor regression. Cranial CT scans showed brain atrophy, but cranial MRIs were not available to confirm Leigh syndrome. Lactate and pyruvate concentrations in blood and cerebrospinal fluid were elevated. Isolated complex I deficiency was demonstrated in muscle and cultured fibroblasts. [from MIM:618225, 2019.7.17]
Mitochondrial complex I deficiency nuclear type 4 (MC1DN4) is caused by homozygous or compound heterozygous mutation in the NDUFV1 gene (MIM:161015) on chromosome 11q13. (MIM:618225, accessed 2019.7.17.)
Mitochondrial complex I deficiency nuclear type 4 (MC1DN4) is caused by homozygous or compound heterozygous mutation in the NDUFV1 gene (MIM:161015) on chromosome 11q13. [from MIM:618225, 2019.7.17]
NDUFV1 binds the flavin cofactor that oxidizes NADH and is the site of complex I-mediated reactive oxygen species production. Expressing seven mutations indentified from patients in yeast caused loss of complex I expression, suggesting they are detrimental but precluding further study. In two variants complex I was fully assembled but did not contain any flavin, and four mutations led to functionally compromised enzymes. (Adapted from Varghese et al. 2015, pubmed:26345448).
1 to 1: one human gene to one Drosophila gene.
