Alternative titles; symbols
HGNC Approved Gene Symbol: NDUFS1
Cytogenetic location: 2q33.3 Genomic coordinates (GRCh38): 2:206,114,817-206,159,444 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q33.3 | Mitochondrial complex I deficiency, nuclear type 5 | 618226 | Autosomal recessive | 3 |
The multisubunit NADH:ubiquinone oxidoreductase (complex I; EC 1.6.5.3) is the first enzyme complex in the electron transport chain of mitochondria. By use of chaotropic agents, complex I can be fragmented into 3 different fractions: a flavoprotein fraction, an iron-sulfur protein (IP) fraction, and a hydrophobic protein (HP) fraction. The IP fraction contains NDUFS1, NDUFS2 (602985), NDUFS3 (603846), NDUFS4 (602694), NDUFS5 (603847), NDUFS6 (603848), and NDUFA5 (601677) (Loeffen et al., 1998). The 75-kD Fe-S protein of the mitochondrial NADH-CoQ reductase is an integral part of the respiratory chain and is one of several Fe-S proteins operating within complex I of the mitochondrial respiratory chain assembly (Ragan, 1987). Functionally, this enzyme is thought to be the first of the Fe-S proteins to accept electrons from an NADH-flavoprotein reductase within the complex.
By screening a human hepatoma cDNA expression library with antibodies against complex I, Chow et al. (1991) isolated a partial cDNA encoding a protein similar to the bovine 75-kD Fe-S protein. The authors used PCR to isolate additional kidney cDNAs corresponding to the entire coding region of the human gene. The predicted human 75-kD Fe-S protein contains 727 amino acids including a 23-amino acid presequence and is 97% identical to the bovine homolog. Various cysteine-rich motifs similar to those found in rubredoxins, in the Reiske Fe-S protein in Neurospora, and in 4Fe-4S ferredoxins are present in the protein sequence. Northern blot analysis revealed that the gene encoding the 75-kD Fe-S protein is expressed as a 2.6-kb mRNA in skin fibroblasts.
Ricci et al. (2004) identified NDUFS1 as a critical caspase substrate in mitochondria. Cells expressing a noncleavable mutant of NDUFS1 sustained mitochondrial transmembrane potential and ATP levels during apoptosis, and reactive oxygen species production in response to apoptotic stimuli was dampened. While cytochrome c release and DNA fragmentation were unaffected by the noncleavable NDUFS1 mutant, mitochondrial morphology of dying cells was maintained and loss of plasma membrane integrity was delayed. Ricci et al. (2004) concluded that caspase cleavage of NDUFS1 is required for several mitochondrial changes associated with apoptosis.
Duncan et al. (1992) showed by isotopic in situ hybridization that the gene encoding the 75-kD Fe-S protein, NDUFS1, is located in the 2q33-q34 region.
In 3 of 36 patients with isolated mitochondrial complex I deficiency (MC1D), Benit et al. (2001) identified 5 different point mutations and 1 large-scale deletion in the NDUFS1 gene (see, e.g., 157655.0001-157655.0003); see MC1DN5, 618226.
Martin et al. (2005) reported a Spanish child with complex I deficiency nuclear type 5 and features of Leigh syndrome (see 256000) caused by a homozygous mutation in the NDUFS1 gene (L231V; 157655.0004). Ferreira et al. (2011) reported 2 sibs, born of consanguineous parents, with complex I deficiency due to a homozygous mutation in the NDUFS1 gene (T595A; 157655.0005).
In 4 patients from 3 families with severe mitochondrial complex I deficiency and very low complex I activity (less than 30% of normal), Hoefs et al. (2010) identified 5 different biallelic mutations in the NDUFS1 gene (see, e.g., 157655.0006-157655.0008). Patient cells also showed decreased amounts of assembled complex I and accumulation of subcomplexes, indicating disturbance in the assembly or stability of complex I. All patients had a severe, progressive disease course resulting in death in childhood due to neurologic disability. Brain MRI performed in 2 patients showed severe and progressive white matter abnormalities. Hoefs et al. (2010) suggested that patients with very low complex I deficiency should be specifically screened for NDUFS1 mutations.
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 NDUFS1 is homozygous-lethal (defined as absence of homozygous mice after screening of at least 28 pups before weaning).
In a patient with mitochondrial complex I deficiency nuclear type 5 (MC1DN5; 618226), Benit et al. (2001) identified compound heterozygosity for 2 mutations in the NDUFS1 gene: a 3-bp deletion (664delCAT), resulting in the in-frame deletion of ile222, and a 755A-G transition, resulting in an asp252-to-gly substitution (D252G; 157655.0002). The proband had unrelated healthy parents and was normal until age 4 months, when he developed psychomotor retardation with hypotonia. At age 7 months, he presented with nystagmus and bilateral optic atrophy. Leukodystrophy, lactic acidosis, and hyperlactatorachia were noted. He died at age 10 months. An older sister with similar findings died at age 7 months, and an older brother developed 2 episodes of ataxia and mild psychomotor retardation at age 2 years.
For discussion of the asp252-to-gly (D252G) mutation in the NDUFS1 gene that was found in compound heterozygous state in a patient with mitochondrial complex I deficiency (MC1DN5; 618226) by Benit et al. (2001), see 157655.0001.
In a child with mitochondrial complex I deficiency (MC1DN5; 618226), Benit et al. (2001) identified a 721C-T transition in the NDUFS1 gene, resulting in an arg241-to-trp (R241W) substitution. The patient was the offspring of healthy unrelated parents and was normal until age 2 months, when he presented with growth retardation, axial hypotonia, hepatomegaly, and persistent hyperlactatemia. Magnetic resonance imaging showed hyperintensity of basal ganglia. The child later developed macrocytic anemia and dystonia. He died suddenly at age 5 months. His older sister presented with growth retardation, macrocytic anemia, and metabolic acidosis at age 3 months and died shortly thereafter in an acute episode of hyperlactatemia.
In a Spanish child with mitochondrial complex I deficiency (MC1DN5; 618226) and features of Leigh syndrome (see 256000), Martin et al. (2005) identified a homozygous 691C-G transversion in the NDUFS1 gene, resulting in a leu231-to-val (L231V) substitution in a highly conserved region near the C terminus of the protein thought to be involved in the ligation of iron-sulfur clusters. The parents were heterozygous for the mutation. The mutation was not identified in 200 control chromosomes.
In 2 sibs, born of consanguineous parents, with complex I deficiency (MC1DN5; 618226), Ferreira et al. (2011) identified a homozygous 1783A-G transition in the NDUFS1 gene, resulting in a thr595-to-ala (T595A) substitution in a highly conserved residue. Each unaffected parent was heterozygous for the mutation, which was not found in 200 control chromosomes. The patients had a neurodegenerative disorder of the white matter beginning around the first year of life. One showed loss of early developmental milestones and the other showed early delayed psychomotor development and irritability. Both had dystonic posturing, difficulty swallowing, and increased lactate in bodily fluids. Although there were episodes of deterioration, there was also some improvement in symptoms with age. Brain MRI showed progressive cavitating leukoencephalopathy with multiple cystic lesions in the white matter. Muscle biopsy of 1 sib showed significantly decreased complex I activity (45% of controls) and a decreased amount of complex I subunits. Reduced fully assembled complex I was seen in mitochondria isolated from fibroblasts from the other sib, but only under stress conditions. Modeling of the mutation in yeast showed that reduced complex I activity was due mainly to decreased accumulation of fully assembled active complex I in the membrane and not to diminished activity of the mutant enzyme.
In a girl with mitochondrial complex I deficiency (MC1DN5; 618226), Hoefs et al. (2010) identified compound heterozygosity for 2 mutations in the NDUFS1 gene: a c.1855G-A transition resulting in an asp619-to-asn (D619N) substitution at a highly conserved residue in the molybdopterin oxidoreductase domain, and a c.1669C-T transition resulting in an arg557-to-ter (R557X; 157655.0007) substitution. Each unaffected parent carried 1 of the mutations, which were not found in 100 controls. She had normal development in the first months of life, but showed crying and regression of motor skills at age 8 months. Brain MRI showed progressive leukodystrophic lesions with rarefaction and atrophy of the corpus callosum. The disease course was progressive, and she developed spasticity, microcephaly, mental retardation, and neuropathy. She died at age 12 years. Patient fibroblasts showed extremely low complex I activity (27% of controls), as well as decreased assembly of complex I and accumulation of subcomplexes.
For discussion of the arg557-to-ter (R557X) mutation in the NDUFS1 gene that was found in compound heterozygous state in a patient with mitochondrial complex I deficiency (MC1DN5; 618226) by Hoefs et al. (2010), see 157655.0006.
In a boy, born of consanguineous parents, with complex I deficiency (MC1DN5; 618226), Hoefs et al. (2010) identified a homozygous c.1222C-T transition in the NDUFS1 gene, resulting in an arg408-to-cys (R408C) substitution at a highly conserved residue in the molybdopterin oxidoreductase domain. In infancy, the patient showed decreased spontaneous movements, abnormal breathing pattern, feeding problems, and hypotonia, resulting in death at age 8 months. One of his brothers had the same mutation and a similar clinical picture, with increased lactate, pyruvate, and alanine in both plasma and CSFS, consistent with mitochondrial dysfunction. Patient fibroblasts showed severely reduced complex I activity (20% of controls). The mutation was not found in 100 controls.
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]
Chow, W., Ragan, I., Robinson, B. H. Determination of the cDNA sequence for the human mitochondrial 75-kDa Fe-S protein of NADH-coenzyme Q reductase. Europ. J. Biochem. 201: 547-550, 1991. [PubMed: 1935949] [Full Text: https://doi.org/10.1111/j.1432-1033.1991.tb16313.x]
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]
Duncan, A. M. V., Chow, W., Robinson, B. H. Localization of the human 75-kDal Fe-S protein of NADH-coenzyme Q reductase gene (NDUFS1) to 2q33-q34. Cytogenet. Cell Genet. 60: 212-213, 1992. [PubMed: 1505218] [Full Text: https://doi.org/10.1159/000133340]
Ferreira, M., Torraco, A., Rizza, T., Fattori, F., Meschini, M. C., Castana, C., Go, N. E., Nargang, F. E., Duarte, M., Piemonte, F., Dionisi-Vici, C., Videira, A., Vilarinho, L., Santorelli, F. M., Carrozzo, R., Bertini, E. Progressive cavitating leukoencephalopathy associated with respiratory chain complex I deficiency and a novel mutation in NDUFS1. Neurogenetics 12: 9-17, 2011. [PubMed: 21203893] [Full Text: https://doi.org/10.1007/s10048-010-0265-2]
Hoefs, S. J. G., Skjeldal, O. H., Rodenburg, R. J., Nedregaard, B., van Kaauwen, E. P. M., Spiekerkotter, U., von Kleist-Retzow, J.-C., Smeitink, J. A. M., Nijtmans, L. G., van den Heuvel, L. P. Novel mutations in the NDUFS1 gene cause low residual activities in human complex I deficiencies. Molec. Genet. Metab. 100: 251-256, 2010. [PubMed: 20382551] [Full Text: https://doi.org/10.1016/j.ymgme.2010.03.015]
Loeffen, J. L. C. M., Triepels, R. H., van den Heuvel, L. P., Schuelke, M., Buskens, C. A. F., Smeets, R. J. P., Trijbels, J. M. F., Smeitink, J. A. M. cDNA of eight nuclear encoded subunits of NADH:ubiquinone oxidoreductase: human complex I cDNA characterization completed. Biochem. Biophys. Res. Commun. 253: 415-422, 1998. [PubMed: 9878551] [Full Text: https://doi.org/10.1006/bbrc.1998.9786]
Martin, M. A., Blazquez, A., Gutierrez-Solana, L. G., Fernandez-Moreira, D., Briones, P., Andreu, A. L., Garesse, R., Campos, Y., Arenas, J. Leigh syndrome associated with mitochondrial complex I deficiency due to a novel mutation in the NDUFS1 gene. Arch. Neurol. 62: 659-661, 2005. [PubMed: 15824269] [Full Text: https://doi.org/10.1001/archneur.62.4.659]
Ragan, C. I. Structure of NADH-ubiquinone reductase (complex I). Curr. Top. Bioenerg. 15: 1-36, 1987.
Ricci, J.-E., Munoz-Pinedo, C., Fitzgerald, P., Bailly-Maitre, B., Perkins, G. A., Yadava, N., Scheffler, I. E., Ellisman, M. H., Green, D. R. Disruption of mitochondrial function during apoptosis is mediated by caspase cleavage of the p75 subunit of complex I of the electron transport chain. Cell 117: 773-786, 2004. [PubMed: 15186778] [Full Text: https://doi.org/10.1016/j.cell.2004.05.008]