Alternative titles; symbols
HGNC Approved Gene Symbol: NDUFA1
Cytogenetic location: Xq24 Genomic coordinates (GRCh38): X:119,871,832-119,876,662 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xq24 | Mitochondrial complex I deficiency, nuclear type 12 | 301020 | X-linked recessive | 3 |
The NDUFA1 gene encodes a subunit of mitochondrial NADH:ubiquinone oxidoreductase, also known as mitochondrial complex I. Complex I is the first of 5 complexes involved in the mitochondrial respiratory chain pathway for the generation of cellular energy (Zhuchenko et al., 1996).
Zhuchenko et al. (1996) cloned the cDNA and a genomic cosmid for a polypeptide of human complex 1, the NADH dehydrogenase ubiquinone subcomplex A protein 1 (NDUFA1). The deduced 70-amino acid polypeptide is 80% identical to the bovine gene MWFE. Like MWFE, the protein lacks a cleavable N-terminal presequence to direct the polypeptide into the mitochondrion, but has the transportation signal sequence within the mature polypeptide. The deduced polypeptide sequence of NDUFA1 was found to have an N-terminal hydrophobic domain, likely to be a transmembrane domain, and a C-terminal hydrophilic domain. Northern blot analysis showed expression in heart and skeletal muscle. Sequence analysis of the promoter region of NDUFA1 showed that it has several potential binding sites for transcription factors associated with cardiac and muscle-specific expression, including MYOD1 (159970), the MEF2 family (600660), and CArG.
Zhuchenko et al. (1996) determined that the NDUFA1 gene contains 3 exons and spans about 5.0 kb of genomic DNA.
By FISH, Zhuchenko et al. (1996) mapped the NDUFA1 gene to chromosome Xq24.
The MWFE polypeptide is 1 of approximately 28 'accessory proteins' identified in mitochondrial complex I, which is composed of 42 unlike subunits. It was considered accessory because it is not one of the 14 polypeptides making up the core complex I; a homologous set of 14 polypeptides can make a fully functional proton-translocating NADH-quinone oxidoreductase in prokaryotes. Au et al. (1999) identified and isolated an MWFE mutant from a collection of respiration-deficient Chinese hamster cell mutants. The mutant had suffered a deletion that would produce a truncated and abnormal MWFE protein. In these mutant cells, complex I activity was reduced severely (less than 10%). Complementation with hamster Ndufa1 cDNA restored the rotenone-sensitive complex I activity of these mutant cells to approximately 100% of the parent cell activity. The findings established that the MWFE polypeptide is absolutely essential for an active complex I in mammals.
In 2 unrelated male patients with mitochondrial complex I deficiency nuclear type 12 (MC1DN12; 301020), Fernandez-Moreira et al. (2007) identified 2 different hemizygous mutations in the NDUFA1 gene (300078.0001 and 300078.0002).
Reclassified Variants
The G32R variant described by Potluri et al. (2009) has been reclassified; see 300078.0003. Potluri et al. (2009) identified a hemizygous mutation in the NDUFA1 gene (G32R; 300078.0003) in 2 first-cousin males, related by the maternal line, with a progressive neurodegenerative disorder and complex I deficiency. Muscle biopsies showed significantly decreased complex I activity (5-10% of normal).
Qi et al. (2004) created a mouse model of severe complex I deficiency by targeted disruption of Ndufa1 mRNA using ribozymes. In vitro complex I activity was reduced by more than 80%, and reactive oxygen species were increased by 21 to 24% in cells from affected mice. The mice showed damage to the optic nerve and retina. Adeno-associated viral delivery of the human SOD2 gene (147460) resulted in suppression of optic nerve degeneration and rescue of retinal ganglion cells. The findings suggested that reactive oxygen species contributed to retinal cell death and optic nerve damage in mice with complex I deficiency, and that expression of SOD2 attenuated the disease process.
In a Spanish male infant with mitochondrial complex I deficiency nuclear type 12 (MC1DN12; 301020), Fernandez-Moreira et al. (2007) identified a hemizygous 22G-C transversion in exon 1 of the NDUFA1 gene, resulting in a gly8-to-arg (G8R) substitution in a highly conserved residue within the N-terminal domain. The mutation may affect import and orientation of the protein within the inner mitochondrial membrane. The patient was conceived via in vitro fertilization with an anonymous donor from a sperm bank. Developmental delay was noted at 4 months, and he later developed axial hypotonia, nystagmus, generalized choreoathetosis, and decreased reflexes. MRI showed bilateral lesions within the brain consistent with Leigh syndrome (see 256000). He developed an abnormal breathing pattern and died at age 14 months. His eldest brother, conceived via a different biologic father, had a similar disease course with death at age 19 months. The unaffected mother was heterozygous for the mutation; 3 maternal uncles reportedly died of an unknown disease. The proband's muscle and fibroblast complex I activities were 20% and 17%, respectively. Further studies showed impaired complex I assembly and stability.
In a Spanish male infant with mitochondrial complex I deficiency nuclear type 12 (MC1DN12; 301020), Fernandez-Moreira et al. (2007) identified a hemizygous 251G-C transversion in the 2 of the NDUFA1 gene, resulting in an arg37-to-ser (R37S) substitution in the hydrophilic domain. The mutation may affect phosphorylation of the protein or its interaction with other subunits. The patient had psychomotor delay from 6 months of age, delayed language, and generalized hypotonia. At 9 years, he developed myoclonic epilepsy but remained clinically stable. Muscle and fibroblast complex I activities were 30% and 70%, respectively. Further studies showed impaired complex I assembly and stability. The patient's unaffected mother was heterozygous for the mutation.
This variant, formerly titled MITOCHONDRIAL COMPLEX I DEFICIENCY, has been reclassified based on a review of the ExAC database by Hamosh (2017).
In 2 first-cousin males, related by the maternal line, with a progressive neurodegenerative disorder and complex I deficiency (301020), Potluri et al. (2009) identified a 111G-C transversion in the NDUFA1 gene, resulting in a gly32-to-arg (G32R) substitution at a highly conserved residue in a hydrophilic domain close to the outer surface of the inner membrane and adjacent to the transmembrane anchor. Expression of the G32R substitution in a hamster cell line caused complex I activity to be reduced by 41% compared to wildtype, and the mutant cells showed poor growth. Patient muscle also showed variants in other mitochondrial-encoded genes, which may have contributed to the phenotype. Both patients had early normal development and then showed progressive loss of motor and cognitive functions around age 4 to 5 years. Other features included seizures, ataxia, and loss of speech. One had retinitis pigmentosa and cerebellar atrophy, and the other had sensorineural hearing loss. Muscle biopsies showed significantly decreased complex I activity (5-10% of normal). Family history revealed a maternal uncle who developed ataxia and mental retardation at age 4 years and committed suicide at age 35 years.
Mayr et al. (2011) identified a heterozygous G32R substitution, resulting from a 94G-C transversion in the NDUFA1 gene, in a girl with a very mild form of complex I deficiency. She presented at age 11 months with recurrent episodes of vomiting and phases of somnolence associated with mildly increased plasma lactate. Development was normal, except for recurrent similar episodes during intercurrent illnesses. At age 5 years, she had normal psychomotor and speech development with no other abnormalities. Laboratory studies during the acute episodes suggested a defect in the mitochondrial respiratory chain. There was decreased complex I staining in muscle only, and muscle cDNA showed predominant expression of the mutant allele (72%); in addition, the patient had higher expression of the paternal AR receptor in muscle, indicating skewed X inactivation. Neither parent had the mutation in blood, suggesting either a de novo event or somatic mosaicism.
Hamosh (2017) found the c.111G-C variant in 475 hemizygotes and 1 homozygote of non-Finnish Europeans in the ExAC database (December 14, 2017), giving an allele frequency of 0.0099.
Au, H. C., Seo, B. B., Matsuno-Yagi, A., Yagi, T., Scheffler, I. E. The NDUFA1 gene product (MWFE protein) is essential for activity of complex I in mammalian mitochondria. Proc. Nat. Acad. Sci. 96: 4354-4359, 1999. [PubMed: 10200266] [Full Text: https://doi.org/10.1073/pnas.96.8.4354]
Fernandez-Moreira, D., Ugalde, C., Smeets, R., Rodenburg, R. J. T., Lopez-Laso, E., Ruiz-Falco, M. L., Briones, P., Martin, M. A., Smeitink, J. A. M., Arenas, J. X-linked NDUFA1 gene mutations associated with mitochondrial encephalomyopathy. Ann. Neurol. 61: 73-83, 2007. [PubMed: 17262856] [Full Text: https://doi.org/10.1002/ana.21036]
Hamosh, A. Personal Communication. Baltimore, Md. 12/14/2017.
Mayr, J. A., Bodamer, O., Haack, T. B., Zimmermann, F. A., Madignier, F., Prokisch, H., Rauscher, C., Koch, J., Sperl, W. Heterozygous mutation in the X chromosomal NDUFA1 gene in a girl with complex I deficiency. Molec. Genet. Metab. 103: 358-361, 2011. [PubMed: 21596602] [Full Text: https://doi.org/10.1016/j.ymgme.2011.04.010]
Potluri, P., Davila, A., Ruiz-Pesini, E., Mishmar, D., O'Hearn, S., Hancock, S., Simon, M., Scheffler, I. E., Wallace, D. C., Procaccio, V. A novel NDUFA1 mutation leads to a progressive mitochondrial complex I-specific neurodegenerative disease. Molec. Genet. Metab. 96: 189-195, 2009. [PubMed: 19185523] [Full Text: https://doi.org/10.1016/j.ymgme.2008.12.004]
Qi, X., Lewin, A. S., Sun, L., Hauswirth, W. W., Guy, J. SOD2 gene transfer protects against optic neuropathy induced by deficiency of complex I. Ann. Neurol. 56: 182-191, 2004. [PubMed: 15293270] [Full Text: https://doi.org/10.1002/ana.20175]
Zhuchenko, O., Wehnert, M., Bailey, J., Sun, Z. S., Lee, C. C. Isolation, mapping, and genomic structure of an X-linked gene for a subunit of human mitochondrial complex I. Genomics 37: 281-288, 1996. [PubMed: 8938439] [Full Text: https://doi.org/10.1006/geno.1996.0561]