Alternative titles; symbols
HGNC Approved Gene Symbol: NDUFS2
Cytogenetic location: 1q23.3 Genomic coordinates (GRCh38): 1:161,197,417-161,214,395 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q23.3 | ?Leber-like hereditary optic neuropathy, autosomal recessive 2 | 620569 | Autosomal recessive | 3 |
| Mitochondrial complex I deficiency, nuclear type 6 | 618228 | Autosomal recessive | 3 |
Mitochondrial complex I (NADH-ubiquinone reductase; EC 1.6.5.3) is the first multimeric complex of the respiratory chain that catalyzes the NADH oxidation with concomitant ubiquinone reduction and proton ejection out of the mitochondria. Mammalian mitochondrial complex I is an assembly of at least 43 different subunits. Seven of the subunits are encoded by the mitochondrial genome; the remainder are the products of nuclear genes. The iron-sulfur protein (IP) fraction of complex I is made up of 7 subunits, including NDUFS2 (summary by Loeffen et al., 1998).
By screening a human lymphocyte cDNA library with a bovine probe, Procaccio et al. (1998) isolated cDNAs for the 49-kD subunit of the mitochondrial respiratory complex I. The predicted mature NDUFS2 protein has 430 amino acids. Independently, Loeffen et al. (1998) isolated cDNAs encoding NDUFS2, NDUFS3 (603846), and NDUFS6 (603848). They reported that the deduced human NDUFS2 protein contains 463 amino acids and that the first 20 amino acids comprise a possible mitochondrial targeting sequence. Human and bovine NDUFS2 share 96% protein sequence identity.
By Northern blot analysis, Loeffen et al. (2001) found that NDUFS2 was ubiquitously expressed, with relatively higher expression in adult and fetal heart, kidney, skeletal muscle, adrenal gland, and liver.
By radioactive in situ hybridization to metaphase spreads, Procaccio et al. (1998) mapped the NDUFS2 gene to chromosome 1. By PCR screening of a mapped YAC library, they narrowed the assignment to chromosome 1q23.
Using short hairpin RNA, Carilla-Latorre et al. (2010) found that knockdown of MIDA (NDUFAF7; 615898) reduced complex I assembly and activity in HEK293T cells. Protein pull-down and immunoprecipitation experiments revealed that both Dictyostelium and human MIDA bound NDUFS2, suggesting a conserved role for MIDA in complex I assembly.
Rhein et al. (2013) found that NDUFAF7 symmetrically dimethylated the guanidino group of arg85 (R85) in NDUFS2. Knockdown of NDUFAF7 progressively shifted the methylation status of R85 from dimethylated to nonmethylated, concomitant with loss of complex I assembly. Rhein et al. (2013) concluded that dimethylation of NDUFS2 is required to stabilize an early intermediate in the assembly of mitochondrial complex I.
Complex I Deficiency, Nuclear Type 6
In affected members of 3 families with isolated complex I deficiency nuclear type 6 (MC1DN6; 618228), Loeffen et al. (2001) identified homozygosity for 3 different missense mutations in the NDUFS2 gene (602985.0001-602985.0003).
Ugalde et al. (2004) used blue native electrophoresis to study how different nuclear mutations affected the integrity of mitochondrial OXPHOS complexes in fibroblasts from 15 complex I-deficient patients. The authors found a decrease in the levels of intact complex I in patients harboring mutations in nuclear-encoded complex I subunits, indicating that complex I assembly and/or stability was compromised. Different patterns of low molecular mass subcomplexes were present in these patients, suggesting that the formation of the peripheral arm may be affected at an early assembly stage. Mutations in complex I genes also affected the stability of other mitochondrial complexes, with a specific decrease of fully-assembled complex III in patients with mutations in NDUFS2 and NDUFS4 (602694). In patients with an isolated complex I deficiency in which no mutations in structural subunits had been found, Ugalde et al. (2004) could discriminate between complex I assembly and catalytic defects based on the presence or absence of correlation between assembly and activity levels.
Leber-like Hereditary Optic Neuropathy, Autosomal Recessive 2
In 3 French sibs with Leber-like hereditary optic neuropathy in whom sequencing of mtDNA and known nuclear genes associated with nonsyndromic optic neuropathy were excluded, Gerber et al. (2017) identified compound heterozygous missense mutations in the NDUFS2 gene (Y53C, 602985.0004 and Y308C, 602985.0005). The mutations, which were identified by linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disease in the family. Analysis of fibroblasts from 2 of the patients demonstrated a trend towards reduced NDUFS2 protein expression and a slight decrease in abundance of complex I. Gerber et al. (2017) generated a yeast model with a Y311C mutation in the Nucm gene, the yeast ortholog of NDUFS2, with a mutation correlating to the human Y308C mutation. The mutant yeast had no detectable complex I expression or enzyme activity. Because there was no direct correlating residue in the yeast Nucm gene to Y53C in the NDUFS2 gene, a yeast model with an H57C mutation in the Nucm gene at a structurally similar region was generated. This mutant yeast demonstrated normal complex I expression and enzyme activity. Gerber et al. (2017) concluded that the combination of functionally severe and mild mutations in the NDUFS2 gene led to the phenotype of isolated optic atrophy as opposed to 2 severe mutations, which would produce a more severe, multisystemic disorder.
Jimenez-Gomez et al. (2023) found that transgenic expression of the yeast NADH dehydrogenase Ndi1 restored the hypoxic ventilatory response and prevented systemic pathologies in mice with mitochondrial complex (MC) I deficiency due to deletion of Ndufs2. Analysis of chemoreceptor glomus cells in carotid body from MCI-deficient mice showed that Ndi1 expression reversed metabolic reprogramming induced by MCI deficiency and rescued their responsiveness to hypoxia. Analysis of mitochondrial signaling of hypoxia revealed that Ndi1 was the predominant mitochondrial NADH dehydrogenase that also responded to hypoxia, and that NADH dehydrogenase activity in glomus cells was mainly mediated by Ndi1 when MCI and Ndi1 were both present. Further analysis demonstrated that Ndi1 expression also restored acute O2 sensing and survival in MCI-deficient adult mice.
In a consanguineous family with 2 children affected with isolated complex I deficiency nuclear type 6 (MC1DN6; 618228), Loeffen et al. (2001) identified a homozygous 683G-A transition in the NDUFS2 gene, resulting in an arg228-to-gln (R228Q) substitution. This arginine is conserved through evolution, and this mutation was not identified in 85 control samples.
In a child with isolated complex I deficiency nuclear type 6 (MC1DN6; 618228) manifesting as neonatal lactic acidosis and hypertrophic cardiomyopathy, Loeffen et al. (2001) identified a 686C-A transversion in the NDUFS2 gene, resulting in a pro229-to-gln (P229Q) substitution. This mutation was not identified in 85 control samples.
In a consanguineous family with 3 children with complex I deficiency nuclear type 6 (MC1DN6; 618228), Loeffen et al. (2001) identified homozygosity for a homozygous 1237T-C transition in the NDUFS2 gene, resulting in a ser413-to-pro (S413P) substitution. This mutation was not identified in 85 control samples.
In 3 French sibs with autosomal recessive Leber-like hereditary optic neuropathy-2 (LHONAR2; 620569), Gerber et al. (2017) identified compound heterozygous mutations in the NDUFS2 gene: a c.158A-G transition (c.158A-G, NM_004550.4), resulting in a tyr53-to-cys (Y53C) substitution, and a c.923A-G transition, resulting in a tyr308-to-cys (Y308C; 602985.0005) substitution. The mutations, which were identified by linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with disease in the family. Each mutation was present in the ExAC database at an allele frequency of 1 in 121,412. Analysis of fibroblasts from 2 of the patients demonstrated a trend towards reduced NDUFS2 protein expression and a slight decrease in abundance of complex I.
For discussion of the c.923A-G transition (c.923A-G, NM_004450.4) in the NDUFS2 gene, resulting in a tyr308-to-cys (Y308C) substitution, that was identified in compound heterozygous state in 3 French sibs with autosomal recessive Leber-like hereditary optic neuropathy-2 (LHONAR2; 620569) by Gerber et al. (2017), see 602985.0004.
Carilla-Latorre, S., Gallardo, M. E., Annesley, S. J., Calvo-Garrido, J., Grana, O., Accari, S. L., Smith, P. K., Valencia, A., Garesse, R., Fisher, P. R., Escalante, R. MidA is a putative methyltransferase that is required for mitochondrial complex I function. J. Cell Sci. 123: 1674-1683, 2010. [PubMed: 20406883] [Full Text: https://doi.org/10.1242/jcs.066076]
Gerber, S., Ding, M. G., Gerard, X., Zwicker, K., Zanlonghi, X., Rio, M., Serre, V., Hanein, S., Munnich, A., Rotig, A., Bianchi, L., Amati-Bonneau, P., Elpeleg, O., Kaplan, J., Brandt, U., Rozet, J. M. Compound heterozygosity for severe and hypomorphic NDUFS2 mutations cause non-syndromic LHON-like optic neuropathy. J. Med. Genet. 54: 346-356, 2017. [PubMed: 28031252] [Full Text: https://doi.org/10.1136/jmedgenet-2016-104212]
Jimenez-Gomez, B., Ortega-Saenz, P., Gao, L., Gonzalez-Rodriguez, P., Garcia-Flores, P., Chandel, N., Lopez-Barneo, J. Transgenic NADH dehydrogenase restores oxygen regulation of breathing in mitochondrial complex I-deficient mice. Nature Commun. 14: 1172, 2023. [PubMed: 36859533] [Full Text: https://doi.org/10.1038/s41467-023-36894-2]
Loeffen, J., Elpeleg, O., Smeitink, J., Smeets, R., Stockler-Ipsiroglu, S., Mandel, H., Sengers, R., Trijbels, F., van den Heuvel, L. Mutations in the complex I NDUFS2 gene of patients with cardiomyopathy and encephalomyopathy. Ann. Neurol. 49: 195-201, 2001. [PubMed: 11220739] [Full Text: https://doi.org/10.1002/1531-8249(20010201)49:2<195::aid-ana39>3.0.co;2-m]
Loeffen, J., van den Heuvel, L., Smeets, R., Triepels, R., Sengers, R., Trijbels, F., Smeitink, J. cDNA sequence and chromosomal localization of the remaining three human nuclear encoded iron sulphur protein (IP) subunits of complex I: the human IP fraction is completed. Biochem. Biophys. Res. Commun. 247: 751-758, 1998. [PubMed: 9647766] [Full Text: https://doi.org/10.1006/bbrc.1998.8882]
Procaccio, V., de Sury, R., Martinez, P., Depetris, D., Rabilloud, T., Soularue, P., Lunardi, J., Issartel, J.-P. Mapping to 1q23 of the human gene (NDUFS2) encoding the 49-kDa subunit of the mitochondrial respiratory complex I and immunodetection of the mature protein in mitochondria. Mammalian Genome 9: 482-484, 1998. [PubMed: 9585441] [Full Text: https://doi.org/10.1007/s003359900803]
Rhein, V. F., Carroll, J., Ding, S., Fearnley, I. M., Walker, J. E. NDUFAF7 methylates arginine 85 in the NDUFS2 subunit of human complex I. J. Biol. Chem. 288: 33016-33026, 2013. [PubMed: 24089531] [Full Text: https://doi.org/10.1074/jbc.M113.518803]
Ugalde, C., Janssen, R. J. R. J., van den Heuvel, L. P., Smeitink, J. A. M., Nijtmans, L. G. J. Differences in assembly or stability of complex I and other mitochondrial OXPHOS complexes in inherited complex I deficiency. Hum. Molec. Genet. 13: 659-667, 2004. [PubMed: 14749350] [Full Text: https://doi.org/10.1093/hmg/ddh071]