Alternative titles; symbols
HGNC Approved Gene Symbol: NDUFS7
Cytogenetic location: 19p13.3 Genomic coordinates (GRCh38): 19:1,383,907-1,395,584 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19p13.3 | Mitochondrial complex I deficiency, nuclear type 3 | 618224 | Autosomal recessive | 3 |
The human NDUFS7 protein is one of the most conserved subunits of mitochondrial respiratory chain complex I and plays a central role in the interaction with the electron acceptor ubiquinone and in the proton-translocating mechanism (summary by Visch et al., 2004).
The mitochondrial respiratory chain consists of several large complexes whose subunits may be encoded by either the mitochondrial or nuclear genomes. Complex I (nicotinamide adenine dinucleotide (NADH):ubiquinone oxidoreductase) is composed of over 40 subunits. Hyslop et al. (1996) used PCR to clone the 20-kD, or PSST, subunit of complex I from liver RNA. The sequence of the mature protein has 93% homology to that of the bovine protein. Northern blot analysis revealed an mRNA of approximately 700 bp that was expressed in all tissues tested.
Hyslop et al. (1996) used radioactive in situ hybridization to map the NDUFS7 gene to chromosome 19p13.
Smeitink and van den Heuvel (1999) reviewed the available molecular data regarding the human nuclear-encoded complex I subunits and tabulated nuclear gene mutations in patients with isolated complex I deficiency. They described sibs with complex I deficiency nuclear type 3 (MC1DN3; 618224) and Leigh syndrome (see 256000) with a V122M mutation in the NDUFS7 gene (601825.0001).
In a girl, born to consanguineous Tunisian parents, with severe complex I defect and Leigh syndrome, Lebon et al. (2007) identified homozygosity for a missense mutation in the NDUFS7 gene (R145H; 601825.0002). The parents were heterozygous carriers for the mutation, which was not detected in over 100 healthy controls of Tunisian origin.
In 2 brothers, born of consanguineous Turkish parents, with complex I deficiency and Leigh syndrome, Lebon et al. (2007) identified a homozygous splice site mutation in the NDUFS7 gene (601825.0003).
In a study of 1,751 knockout alleles created by the International Mouse Phenotyping Consortium (IMPC), Dickinson et al. (2016) found that knockout of the mouse homolog of human NDUFS7 is homozygous-lethal (defined as absence of homozygous mice after screening of at least 28 pups before weaning).
Smeitink and van den Heuvel (1999) described a val122-to-met substitution in the NDUFS7 gene as the causative mutation in 2 male sibs with complex I deficiency nuclear type 3 (MC1DN3; 618224) and features of Leigh syndrome (see 256000) confirmed postmortem. One sib presented with feeding problems, dysarthria, and ataxia at age 26 months; the other presented with vomiting at age 11 months. The course was progressive, especially after infection. Lactic acid concentration was normal in blood, urine, and cerebrospinal fluid (slight increase in cerebrospinal fluid). Magnetic resonance imaging showed symmetrical hypodensities in both sibs, who died at 3.5 years and 5 years, respectively.
Visch et al. (2004) presented evidence suggesting that the V122M mutation causes a defect in calcium homeostasis. Skin fibroblasts from patients with the V122M mutation had impaired agonist-induced mitochondrial calcium uptake and, consequently, impaired stimulation of mitochondrial ATP production. The defects were corrected after treatment with a benzothiazepine that inhibited the mitochondrial sodium-calcium exchange pump, which releases calcium from the mitochondria. Visch et al. (2004) postulated that reduced ATP production may also result in a defect in energy-dependent calcium extrusion from the cytoplasm, leading to an increase in calcium levels that may be toxic to the cell.
Lebon et al. (2007) reported a patient, born to consanguineous Tunisian parents, with severe complex I defect nuclear type 3 (MC1DN3; 618224) and Leigh syndrome (see 256000). The patient was homozygous for a G-to-A substitution at nucleotide 434 of the NDUFS7 gene, resulting in an arginine-to-histidine change at codon 145 (R145H) in a highly conserved region of the protein. The parents were heterozygous carriers for this mutation. The mutation was not detected in over 100 healthy controls of Tunisian origin.
In 2 brothers, born of consanguineous Turkish parents, with complex I deficiency nuclear type 3 (MC1DN3; 618224) and Leigh syndrome (see 256000) resulting in death in infancy, Lebon et al. (2007) identified a homozygous C-to-G transversion in intron 1 of the NDUFS7 gene (17-1167C-G), resulting in the creation of a splice site and the generation of a 122-bp cryptic exon. The mutation was predicted to result in a shortened mutant protein of 41 instead of 213 amino acids. Patient fibroblasts showed a marked decrease of fully assembled complex I.
Dickinson, M. E., Flenniken, A. M., Ji, X., Teboul, L., Wong, M. D., White, J. K., Meehan, T. F., Weninger, W. J., Westerberg, H., Adissu, H., Baker, C. N., Bower, L., and 73 others. High-throughput discovery of novel developmental phenotypes. Nature 537: 508-514, 2016. Note: Erratum: Nature 551: 398 only, 2017. [PubMed: 27626380] [Full Text: https://doi.org/10.1038/nature19356]
Hyslop, S. J., Duncan, A. M. V., Pitkanen, S., Robinson, B. H. Assignment of the PSST subunit gene of human mitochondrial complex I to chromosome 19p13. Genomics 37: 375-380, 1996. [PubMed: 8938450] [Full Text: https://doi.org/10.1006/geno.1996.0572]
Lebon, S., Minai, L., Chretien, D., Corcos, J., Serre, V., Kadhom, N., Steffann, J., Pauchard, J.-Y., Munnich, A., Bonnefont, J.-P., Rotig, A. A novel mutation of the NDUFS7 gene leads to activation of a cryptic exon and impaired assembly of mitochondrial complex I in a patient with Leigh syndrome. Molec. Genet. Metab. 92: 104-108, 2007. [PubMed: 17604671] [Full Text: https://doi.org/10.1016/j.ymgme.2007.05.010]
Lebon, S., Rodriguez, D., Bridoux, D., Zerrad, A., Rotig, A., Munnich, A., Legrand, A., Slama, A. A novel mutation in the human complex I NDUFS7 subunit associated with Leigh syndrome. Molec. Genet. Metab. 90: 379-382, 2007. [PubMed: 17275378] [Full Text: https://doi.org/10.1016/j.ymgme.2006.12.007]
Smeitink, J., van den Heuvel, L. Human mitochondrial complex I in health and disease. Am. J. Hum. Genet. 64: 1505-1510, 1999. [PubMed: 10330338] [Full Text: https://doi.org/10.1086/302432]
Visch, H.-J., Rutter, G. A., Koopman, W. J. H., Koenderink, J. B., Verkaart, S., de Groot, T., Varadi, A., Mitchell, K. J., van den Heuvel, L. P., Smeitink, J. A. M., Willems, P. H. G. M. Inhibition of mitochondrial Na(+)-Ca(2+) exchange restores agonist-induced ATP production and Ca(2+) handling in human complex I deficiency. J. Biol. Chem. 279: 40328-40336, 2004. [PubMed: 15269216] [Full Text: https://doi.org/10.1074/jbc.M408068200]