Alternative titles; symbols
HGNC Approved Gene Symbol: NDUFA11
Cytogenetic location: 19p13.3 Genomic coordinates (GRCh38): 19:5,891,229-5,903,790 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19p13.3 | Mitochondrial complex I deficiency, nuclear type 14 | 618236 | Autosomal recessive | 3 |
Mitochondrial complex I (NADH:ubiquinone oxidoreductase; EC 1.6.5.3) is assembled from 44 subunits into an L-shaped complex, with a hydrophobic arm embedded in the inner mitochondrial membrane and the other arm protruding into the mitochondrial matrix. Mitochondrial DNA encodes 7 hydrophobic subunits of the complex, and nuclear DNA encodes 7 catalytic core subunits in the protruding arm. The 30 remaining nuclear-encoded subunits, including NDUFA11, are believed to function in assembly, stability, and regulation of the complex (Andrews et al., 2013).
Carroll et al. (2002) cloned bovine Ndufa11, which they called B14.7, and identified human NDUFA11 by database analysis. The bovine and human proteins share 72% amino acid identity. The initiating methionine of the bovine protein is removed, and the deduced 140-amino acid mature protein has an acetylated N-terminal alanine and 4 possible transmembrane spans.
Hartz (2009) mapped the NDUFA11 gene to chromosome 19p13.3 based on an alignment of the NDUFA11 sequence (GenBank AF539081) with the genomic sequence (build 36.1).
Andrews et al. (2013) found that knockdown of NDUFA11 in 143B human osteosarcoma cells reduced the amount of intact mitochondrial complex I, caused accumulation of subcomplexes with molecular masses of 815 and 550 kD, and reduced cellular oxygen consumption.
In affected offspring from 3 consanguineous families of Israeli Bedouin origin with mitochondrial complex I deficiency nuclear type 14 (MC1ND14; 618236), Berger et al. (2008) identified a homozygous mutation in the NDUFA11 gene (612638.0001). The phenotype was severe, resulting in fatal infantile metabolic acidosis or encephalocardiomyopathy.
In affected offspring from 3 consanguineous families of Israeli Bedouin origin with severe mitochondrial complex I deficiency nuclear type 14 (MC1DN14; 618236), Berger et al. (2008) identified a homozygous G-to-A transition in intron 1 of the NDUFA11 gene, resulting in a splice site mutation. The mutation was predicted to abolish the first transmembrane domain and destabilize the enzymatic complex. RT-PCR analysis indicated that the mutation was a leaky mutation, with a 2:1 ratio of wildtype to normal transcript in patient fibroblasts. Three of the affected children presented with a fatal infantile metabolic acidosis. Affected children in 1 family survived beyond infancy but developed severe encephalocardiomyopathy with brain atrophy, no motor development, and hypertrophic cardiomyopathy. Berger et al. (2008) hypothesized a modifier gene effect or differential transcript expression in various tissues to explain the different clinical presentations observed in these families. The parents of each family did not recall any relationship between the families, but haplotype analysis indicated a founder effect.
Andrews, B., Carroll, J., Ding, S., Fearnley, I. M., Walker, J. E. Assembly factors for the membrane arm of human complex I. Proc. Nat. Acad. Sci. 110: 18934-18939, 2013. [PubMed: 24191001] [Full Text: https://doi.org/10.1073/pnas.1319247110]
Berger, I., Hershkovitz, E., Shaag, A., Edvardson, S., Saada, A., Elpeleg, O. Mitochondrial complex I deficiency caused by a deleterious NDUFA11 mutation. Ann. Neurol. 63: 405-408, 2008. [PubMed: 18306244] [Full Text: https://doi.org/10.1002/ana.21332]
Carroll, J., Shannon, R. J., Fearnley, I. M., Walker, J. E., Hirst, J. Definition of the nuclear encoded protein composition of bovine heart mitochondrial complex I: identification of two new subunits. J. Biol. Chem. 277: 50311-50317, 2002. [PubMed: 12381726] [Full Text: https://doi.org/10.1074/jbc.M209166200]
Hartz, P. A. Personal Communication. Baltimore, Md. 2/23/2009.