Alternative titles; symbols
HGNC Approved Gene Symbol: NDUFV1
Cytogenetic location: 11q13.2 Genomic coordinates (GRCh38): 11:67,606,936-67,612,554 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q13.2 | Mitochondrial complex I deficiency, nuclear type 4 | 618225 | Autosomal recessive | 3 |
NADH:ubiquinone oxidoreductase (complex I; EC 1.6.5.3) is an inner mitochondrial membrane-bound multisubunit enzyme complex. Complex I consists of at least 41 subunits, of which 7 are encoded by the mitochondrial genome. See MTND1 (516000) through MTND6 (516006). As one of the complexes of the mitochondrial respiratory chain, complex I functions in the catalysis of the rotenone-sensitive oxidation of NADH and the reduction of ubiquinone. By means of chaotropic agents, complex I can be resolved into 2 hydrophilic fractions, the flavoprotein fraction and the iron-protein fraction, and a hydrophobic fraction. The flavoprotein fraction comprises the 51-, 24-, and 10-kD subunits, all encoded by the nuclear genes NDUFV1, NDUFV2 (600532), and NDUFV3 (602184), respectively. This fraction plays a catalytic role in the oxidation of NADH as it is associated with flavoprotein and NAD binding. The 51-kD and 24-kD subunits are involved in electron transfer (summary by de Coo et al., 1997).
NDUFV1 binds the flavin cofactor that oxidizes NADH and is the site of complex I-mediated reactive oxygen species production (summary by Varghese et al., 2015).
Spencer et al. (1992) studied the '11q13 amplicon,' a DNA unit of approximately 2,000 to 2,500 kb formed by several genes including GST3 (GSTP1; 134660) and oncogenes INT2 (164950), HSTF1 (164980), and PRAD1 (168461). In a cosmid clone containing a full-length GSTP1 gene, Spencer et al. (1992) identified a novel gene which, from sequence data and its high degree of sequence identity to a bovine sequence, they identified as the 51-kD subunit of NADH:ubiquinone oxidoreductase. The 51-kD subunit forms the NADH- and FMN-binding site of complex I, the first enzyme of the mitochondrial electron transport chain. Of note is the fact that subunit VIII of cytochrome c oxidase (123870) maps to approximately the same chromosomal region.
By PCR, Ali et al. (1993) generated human cDNA fragments corresponding to the 51-kD protein and used them to localize the human NDUFV1 gene to 11q13 by isotopic and fluorescence in situ hybridization. The 11q13 region has been implicated in several forms of cancer.
Disturbances of mitochondrial energy metabolism occur with an estimated incidence of 1 in 10,000 live births and are often caused by isolated mitochondrial complex I (NADH:ubiquinone oxidoreductase) deficiency. In 3 of 20 patients with isolated complex I deficiency, Schuelke et al. (1999) detected homozygous or compound heterozygous mutations in the NDUFV1 gene (161015.0001-161015.0003); see MC1DN4 (618225).
In a series of 36 patients with mitochondrial complex I deficiency, Benit et al. (2001) identified 3 patients carrying a total of 6 mutations in the NDUFV1 gene (see, e.g., 161015.0004 and 161015.0005).
Grad and Lemire (2004) generated transgenic strains of C. elegans that expressed disease-causing mutations (see, e.g., 161015.0001 and 161015.0003) in the nuo-1 gene, the C. elegans homolog of the NDUFV1 gene. The transgenic strains demonstrated lactic acidosis and decreased NADH-dependent mitochondrial respiration. They were also hypersensitive to exogenous oxidative stress, suggesting that defense mechanisms against reactive oxygen species were already taxed by an endogenous stress. Lactic acidosis induced by the NDUFV1 mutations could be partially corrected by riboflavin, thiamine, or sodium dichloroacetate (an activator of the pyruvate dehydrogenase complex), resulting in significant increases in animal fitness. Cytochrome c oxidase activity and protein levels were reduced, establishing a connection between complexes I and IV. Grad and Lemire (2004) concluded that complex I mutations exert their pathogenic effects in multiple ways: by impeding the metabolism of NADH, by increasing the production of reactive oxygen species, and by interfering with the function or assembly of other mitochondrial respiratory chain components.
In 2 brothers with complex I deficiency nuclear type 4 (MC1DN4; 618225), Schuelke et al. (1999) identified compound heterozygosity for 2 mutations in the NDUFV1 gene: a 1268C-T transition inherited from the mother, resulting in a thr423-to-met substitution, and a 175C-T transition, resulting in an arg59-to-ter (R59X; 161015.0002) substitution inherited from the father, resulting in a premature stop codon in exon 3 and truncation of 91% of the mature protein. Nonsense-mediated messenger decay was demonstrated by the low abundance (3%) of the father's allelic transcripts in both children, as shown by restriction analysis of radioactive PCR fragments. The phenotype was a severe encephalopathy with death at ages 14 and 17 months, respectively. Neither cranial MRIs nor postmortem reports were available to confirm Leigh syndrome (256000).
In a yeast model system, Varghese et al. (2015) found that expression of the T423M variant resulted in no detectable complex I assembly or activity, consistent with a severe pathogenic effect.
For discussion of the 175C-T transition in the NDUFV1 gene, resulting in an arg59-to-ter (R59X) substitution, that was found in compound heterozygous state in 2 brothers with complex I deficiency (MC1DN4; 618225) by Schuelke et al. (1999), see 161015.0001.
This variant, formerly titled MITOCHONDRIAL COMPLEX I DEFICIENCY, has been reclassified based on the findings of Varghese et al. (2015).
In a girl with isolated complex I deficiency (MC1DN4; 618225), Schuelke et al. (1999) identified a homozygous 1022C-T transition in the NDUFV1 gene, resulting in an ala341-to-val (A341V) substitution. Schuelke et al. (1999) stated that the phenotype of this patient resembled Alexander disease (203450), but a brain biopsy was not available for histologic confirmation.
In a yeast model system, Varghese et al. (2015) found that expression of the A341V variant had no effect on the assembly, flavin content, or catalytic activity of NDUFV1, suggesting that it is not a pathogenic variant. Varghese et al. (2015) noted that A341 is in the ubiquitin-like domain on the external surface of the subunit and is generally conserved only in chordates.
In a patient with mitochondrial complex I deficiency (MC1DN4; 618225) characterized by neurologic abnormalities, Benit et al. (2001) identified compound heterozygosity for 2 mutations in the NDUFV1 gene: a 640G-A transition in exon 5, resulting in a glu214-to-lys (E214K) substitution, and an A-to-C transversion in the donor splice site of intron 8 (161015.0005) and an unstable RNA.
In a yeast model system, Varghese et al. (2015) found that expression of the E214K variant was associated with decreased FMN content and decreased complex I activity, consistent with a moderate pathogenic effect. Expression of this variant was also associated with increased production of reactive oxygen species.
For discussion of the A-to-C transversion in the donor splice site of intron 8 in the NDUFV1 gene that was found in compound heterozygous state in a patient with mitochondrial complex I deficiency (MC1DN4; 618225) by Benit et al. (2001), see 161015.0004.
Ali, S. T., Duncan, A. M. V., Schappert, K., Heng, H. H. Q., Tsui, L. C., Chow, W., Robinson, B. H. Chromosomal localization of the human gene encoding the 51-kDa subunit of mitochondrial complex I (NDUFV1) to 11q13. Genomics 18: 435-439, 1993. [PubMed: 8288251] [Full Text: https://doi.org/10.1006/geno.1993.1493]
Benit, P., Chretien, D., Kadhom, N., de Lonlay-Debeney, P., Cormier-Daire, V., Cabral, A., Peudenier, S., Rustin, P., Munnich, A., Rotig, A. Large-scale deletion and point mutations of the nuclear NDUFV1 and NDUFS1 genes in mitochondrial complex I deficiency. Am. J. Hum. Genet. 68: 1344-1352, 2001. [PubMed: 11349233] [Full Text: https://doi.org/10.1086/320603]
de Coo, R. F. M., Buddiger, P., Smeets, H. J. M., van Oost, B. A. Molecular cloning and characterization of the human mitochondrial NADH:oxidoreductase 10-kDa gene (NDUFV3). Genomics 45: 434-437, 1997. [PubMed: 9344673] [Full Text: https://doi.org/10.1006/geno.1997.4930]
Grad, L. I., Lemire, B. D. Mitochondrial complex I mutations in Caenorhabditis elegans produce cytochrome c oxidase deficiency, oxidative stress and vitamin-responsive lactic acidosis. Hum. Molec. Genet. 13: 303-314, 2004. [PubMed: 14662656] [Full Text: https://doi.org/10.1093/hmg/ddh027]
Schuelke, M., Smeitink, J., Mariman, E., Loeffen, J., Plecko, B., Trijbels, F., Stockler-Ipsiroglu, S., van den Heuvel, L. Mutant NDUFV1 subunit of mitochondrial complex I causes leukodystrophy and myoclonic epilepsy. (Letter) Nature Genet. 21: 260-261, 1999. [PubMed: 10080174] [Full Text: https://doi.org/10.1038/6772]
Spencer, S. R., Taylor, J. B., Cowell, I. G., Xia, C.-L., Pemble, S. E., Ketterer, B. The human mitochondrial NADH: ubiquinone oxidoreductase 51-kDa subunit maps adjacent to the glutathione S-transferase Pi-1 gene on chromosome 11q13. Genomics 14: 1116-1118, 1992. [PubMed: 1478657] [Full Text: https://doi.org/10.1016/s0888-7543(05)80144-2]
Varghese, F., Atcheson, E., Bridges, H. R., Hirst, J. Characterization of clinically identified mutations in NDUFV1, the flavin-binding subunit of respiratory complex I, using a yeast model system. Hum. Molec. Genet. 24: 6350-6360, 2015. [PubMed: 26345448] [Full Text: https://doi.org/10.1093/hmg/ddv344]