Alternative titles; symbols
HGNC Approved Gene Symbol: NDUFB3
Cytogenetic location: 2q33.1 Genomic coordinates (GRCh38): 2:201,072,001-201,085,750 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q33.1 | Mitochondrial complex I deficiency, nuclear type 25 | 618246 | Autosomal recessive | 3 |
The multisubunit NADH:ubiquinone oxidoreductase (complex I) is the first enzyme complex in the electron transport chain of mitochondria. See NDUFA2 (602137).
Ton et al. (1997) isolated human heart cDNAs encoding CI-B12 (NDUFB3) and 4 other complex I subunits.
Jensen et al. (2001) determined that the NDUFB3 gene contains 3 exons and spans 13.9 kb of genomic DNA.
By radiation hybrid analysis, Jensen et al. (2001) mapped the NDUFB3 gene to chromosome 2q31.3. They also mapped 4 NDUFB3 pseudogenes. One of the pseudogenes, NDUFB3P4, is positioned in intron 2 of the WARS gene (191050) in the opposite direction.
In a patient with severe mitochondrial complex I deficiency nuclear type 25 (MC1DN25; 603839) (patient 2 in Lamont et al., 2004), Calvo et al. (2012) identified a homozygous mutation in the NDUFB3 gene (W22R; 603839.0001). The pregnancy was complicated by intrauterine growth retardation and premature birth at 31 weeks' gestation; respiratory insufficiency required extensive artificial ventilation in the neonatal period. After discharge home, she showed hypotonia with poor feeding and significant lactic acidosis and died unexpectedly at age 4 months. Skeletal muscle biopsy showed variation in the shape and size of muscle fibers, and atrophic fibers containing nemaline rods. Biochemical analysis showed complex I deficiency with borderline low complex III deficiency, the latter of which may have been an artifact.
In a patient with MC1DN25, Haack et al. (2012) identified compound heterozygosity for 2 mutations in the NDUFB3 gene (W22R; and G70X, 603839.0002). The mutations were identified by exome sequencing. The patient had encephalopathy, myopathy, hypotonia, developmental delay, and lactic acidosis. Complex I activity in patient fibroblasts was 17% of normal and the level of assembled complex I was decreased. Expression of wildtype NDUFB3 rescued the biochemical defect. Of note, complex IV and V were also slightly decreased in patient fibroblasts to 48% and 76% of controls, respectively; these latter defects were not altered by expression of wildtype NDUFB3. The findings established NDUFB3 as a gene responsible for human complex I deficiency.
In a female infant, born of unrelated parents of British and Dutch descent, with severe lethal mitochondrial complex I deficiency nuclear type 25 (MC1DN25; 618246), Calvo et al. (2012) identified a homozygous 64T-C transition in the NDUFB3 gene, resulting in a trp22-to-arg (W22R) substitution in a highly conserved residue. The unaffected mother was a carrier; DNA from the father was not available. Fibroblasts from the patient showed 2 to 15% residual complex I protein levels and activity, depending on the method used, and expression of wildtype NDUFB3 rescued the defect.
In a patient with mitochondrial complex I deficiency nuclear type 25 (MC1DN25; 618246), Haack et al. (2012) identified compound heterozygosity for 2 mutations in the NDUFB3 gene: the previously described W22R mutation (603839.0001) and a 208G-T transversion, resulting in a gly70-to-ter (G70X) substitution. The mutations were identified by exome sequencing. The patient had encephalopathy, myopathy, hypotonia, developmental delay, and lactic acidosis. Complex I activity in patient fibroblasts was 17% of normal and the level of assembled complex I was decreased. Expression of wildtype NDUFB3 rescued the biochemical defect. Of note, complex IV and V were also slightly decreased in patient fibroblasts to 48% and 76% of controls, respectively; these defects were not altered by expression of wildtype NDUFB3. The findings established NDUFB3 as a gene responsible for human complex I deficiency.
Calvo, S. E., Compton, A. G., Hershman, S. G., Lim, S. C., Lieber, D. S., Tucker, E. J., Laskowski, A., Garone, C., Liu, S., Jaffe, D. B., Christodoulou, J., Fletcher, J. M., Bruno, D. L., Goldblatt, J., DiMauro, S., Thorburn, D. R., Mootha, V. K. Molecular diagnosis of infantile mitochondrial disease with targeted next-generation sequencing. Sci. Transl. Med. 4: 118ra10, 2012. Note: Electronic Article. [PubMed: 22277967] [Full Text: https://doi.org/10.1126/scitranslmed.3003310]
Haack, T. B., Haberberger, B., Frisch, E.-M., Wieland, T., Iuso, A., Gorza, M., Strecker, V., Graf, E., Mayr, J. A., Herberg, U., Hennermann, J. B., Klopstock, T., and 16 others. Molecular diagnosis in mitochondrial complex I deficiency using exome sequencing. J. Med. Genet. 49: 277-283, 2012. [PubMed: 22499348] [Full Text: https://doi.org/10.1136/jmedgenet-2012-100846]
Jensen, L. L., Nielsen, M. M., Justesen, J., Hansen, L. L. Assignment of human NADH dehydrogenase (ubiquinone) 1 beta subcomplex 3 (NDUFB3) and of its four pseudogenes to human chromosomes 2q31.3, 1p13.3-p13.1, 9q32-q34.1, 14q22.3-q23.1 and 14q32.2 by radiation hybrid mapping. Cytogenet. Cell Genet. 93: 147-150, 2001. [PubMed: 11474204] [Full Text: https://doi.org/10.1159/000056973]
Lamont, P. J., Thorburn, D. R., Fabian, V., Vajsar, J., Hawkins, C., Saada Reisch, A., Durling, H., Laing, N. G., Nevo, Y. Nemaline rods and complex I deficiency in three infants with hypotonia, motor delay and failure to thrive. Neuropediatrics 35: 302-306, 2004. [PubMed: 15534765] [Full Text: https://doi.org/10.1055/s-2004-821243]
Ton, C., Hwang, D. M., Dempsey, A. A., Liew, C.-C. Identification and primary structure of five human NADH-ubiquinone oxidoreductase subunits. Biochem. Biophys. Res. Commun. 241: 589-594, 1997. [PubMed: 9425316] [Full Text: https://doi.org/10.1006/bbrc.1997.7707]