Structural Nuclear Genes in Mitochondrial Disease

Last update: March 2012

Complex Name OMIM Function Chromosome Inheritance Clinical Phenotype References
I NDUFS1 157655 IP fraction 2q33-q34 AR Leigh Syndrome (17)
I NDUFS2 602985 IP fraction 1q23 AR Encephalopathy, Cardiomyopathy (18)
I NDUFS3 603846 IP fraction 11p11.11 AR Leigh Syndrome (11)
I NDUFS4 602694 IP fraction 5q11.1 AR Leigh Syndrome (23)
I NDUFS6 603848 IP fraction 5pter-p15.33 AR Fatal Infantile Lactic Acidosis (5,12)
I NDUFS7 601825 HP fraction 19p13.3 AR Leigh Syndrome (21)
I NDUFS8 602141 HP fraction 11q13 AR Leigh Syndrome (13,22)
I NDUFB3 603839 HP fraction 2q31.3 AR Fatal Infantile Lactic Acidosis (1)
I NDUFV1 161015 FP fraction 11q13 AR Leigh Syndrome (21)
I NDUFV2 600532 FP fraction 18p11 AR Cardiomyopathy, hypotonia, encephalopathy (14)
I NDUFA1 300078 HP fraction Xq24 X Leigh Syndrome, Progressive neurodegenerative disorder (4, 10)
I NDUFA2 602137 HP fraction 5q31.2 AR Leigh Syndrome (8)
I NDUFA10 603835 HP fraction 2q37.3 AR Leigh Syndrome (2)
I NDUFA11 612638 IP fraction 19p13.3 AR Fatal Infantile Lactic Acidosis Encephalocardiomyopathy (7)
II SDH-A 600857 FP subunit 5p15 AR Leigh Syndrome (24)
II SDH-B 185470 IP subunit 1p36.1-p35 AD Phaeochromocytoma and paraganglioma (16)
II SDH-C 602413 Membrane subunit 1q21 AD Autosomal dominant paraganglioma type 3 (20)
II SDH-D 602690 Membrane subunit 11q23 AD Autosomal dominant paraganglioma type 1, Pheochromocytoma (19)
III UQCRB 191330 electron transfer 8q22 AR Hypoglycemia, Lactic acidosis (15)
III UQCRQ 612080 electron transfer 5q31.1 AR Severe neurological phenotype (6)
IV COX6B1 124089 Cytochrome oxidase activity 19q13.1 AR Encephalomyopathy (9)
V ATP5E 606153 ATPase activity 20q13.3 AR Lactic acidosis, mental retardation, peripheral neuropathy (3)

Abbreviations
FP: Complex I or II flavoprotein fraction; IP: Complex I or II iron-sulfur protein fraction; HP: Complex I hydrophobic protein; AR: Autosomal Recessive; AD: Autosomal Dominant; X: X-linked

References

1. 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. and Mootha, V. K. (2012). "Molecular diagnosis of infantile mitochondrial disease with targeted next-generation sequencing". Science Translational Medicine 4(118):118ra10.

2. Hoefs, S. J., van Spronsen, F. J., Lenssen, E. W., Nijtmans, L. G., Rodenburg, R. J., Smeitink, J. A. and van den Heuvel, L. P. (2011). "NDUFA10 mutations cause complex I deficiency in a patient with Leigh disease". European Journal of Human Genetics 19(3):270-274.

3. Mayr, J. A., Havlickova, V., Zimmermann, F., Magler, I., Kaplanova, V., Jesina, P., Pecinova, A., Nuskova, H., Koch, J., Sperl, W. and Houstek, J. (2010). "Mitochondrial ATP synthase deficiency due to a mutation in the ATP5E? gene for the F1 epsilon subunit". Human Molecular Genetics 19(17):3430-3439.

4. Potluri, P., Davila, A., Ruiz-Pesini, E., Mishmar, D., O'Hearn, S., Hancock, S., Simon, M. C., Scheffler, I., Wallace, D. C. and Procaccio, V. (2009). "A novel NDUFA1 mutation leads to a progressive mitochondrial complex I-specific neurodegenerative disease". Molecular Genetics and Metabolism 96(4):189-195.

5. Spiegel, R., Shaag, A., Mandel, H., Reich, D., Penyakov, M., Hujeirat, Y., Saada, A., Elpeleg, O. and Shalev, S. A. (2009). "Mutated NDUFS6 is the cause of fatal neonatal lactic acidemia in Caucasus Jews". European Journal of Human Genetics 17(9):1200-1203.

6. Barel, O., Shorer, Z., Flusser, H., Ofir, R., Narkis, G., Finer, G., Shalev, H., Nasasra, A., Saada, A. and Birk, O. S. (2008). "Mitochondrial complex III deficiency associated with a homozygous mutation in UQCRQ". American Journal of Human Genetics 82(5):1211-1216.

7. Berger, I., Hershkovitz, E., Shaag, A., Edvardson, S., Saada, A. and Elpeleg, O. (2008). "Mitochondrial complex I deficiency caused by a deleterious NDUFA11 mutation". Annals of Neurology 63(3):405-408.

8. Hoefs, S. J., Dieteren, C. E., Distelmaier, F., Janssen, R. J., Epplen, A., Swarts, H. G., Forkink, M., Rodenburg, R. J., Nijtmans, L. G., Willems, P. H., Smeitink, J. A. and van den Heuvel, L. P. (2008). "NDUFA2 complex I mutation leads to Leigh disease". American Journal of Human Genetics 82(6):1306-1315.

9. Massa, V., Fernandez-Vizarra, E., Alshahwan, S., Bakhsh, E., Goffrini, P., Ferrero, I., Mereghetti, P., D'Adamo, P., Gasparini, P. and Zeviani, M. (2008). "Severe infantile encephalomyopathy caused by a mutation in COX6B1?, a nucleus-encoded subunit of cytochrome c oxidase". American Journal of Human Genetics 82(6):1281-1289.

10. Fernandez-Moreira, D., Ugalde, C., Smeets, R., Rodenburg, R. J., Lopez-Laso, E., Ruiz-Falco, M. L., Briones, P., Martin, M. A., Smeitink, J. A. and Arenas, J. (2007). "X-linked NDUFA1 gene mutations associated with mitochondrial encephalomyopathy". Annals of Neurology 61(1):73-83.

11. Benit, P., Slama, A., Cartault, F., Giurgea, I., Chretien, D., Lebon, S., Marsac, C., Munnich, A., Rotig, A. and Rustin, P. (2004). "Mutant NDUFS3 subunit of mitochondrial complex I causes Leigh syndrome". Journal of Medical Genetics 41(1):14-17.

12. Kirby, D. M., Salemi, R., Sugiana, C., Ohtake, A., Parry, L., Bell, K. M., Kirk, E. P., Boneh, A., Taylor, R. W., Dahl, H. H., Ryan, M. T. and Thorburn, D. R. (2004). "NDUFS6 mutations are a novel cause of lethal neonatal mitochondrial complex I deficiency". The Journal of Clinical Investigation 114(6):837-845.

13. Procaccio, V. and Wallace, D. C. (2004). "Late-onset Leigh syndrome in a patient with mitochondrial complex I NDUFS8 mutations". Neurology 62(10):1899-1901.

14. Benit, P., Beugnot, R., Chretien, D., Giurgea, I., De Lonlay-Debeney, P., Issartel, J. P., Corral-Debrinski, M., Kerscher, S., Rustin, P., Rotig, A. and Munnich, A. (2003). "Mutant NDUFV2 subunit of mitochondrial complex I causes early onset hypertrophic cardiomyopathy and encephalopathy". Human Mutation 21(6):582-586.

15. Haut, S., Brivet, M., Touati, G., Rustin, P., Lebon, S., Garcia-Cazorla, A., Saudubray, J. M., Boutron, A., Legrand, A. and Slama, A. (2003). "A deletion in the human QP-C gene causes a complex III deficiency resulting in hypoglycaemia and lactic acidosis". Human Genetics 113(2):118-122.

16. Astuti, D., Latif, F., Dallol, A., Dahia, P. L., Douglas, F., George, E., Skoldberg, F., Husebye, E. S., Eng, C. and Maher, E. R. (2001). "Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma". American Journal of Human Genetics 69(1):49-54.

17. Benit, P., Chretien, D., Kadhom, N., de Lonlay-Debeney, P., Cormier-Daire, V., Cabral, A., Peudenier, S., Rustin, P., Munnich, A. and Rotig, A. (2001). "Large-scale deletion and point mutations of the nuclear NDUFV1 and NDUFS1 genes in mitochondrial complex I deficiency.". American Journal of Human Genetics 68(6):1344-1352.

18. Loeffen, J., Elpeleg, O., Smeitink, J., Smeets, R., Stockler-Ipsiroglu, S., Mandel, H., Sengers, R., Trijbels, F. and van den Heuvel, L. (2001). "Mutations in the complex I NDUFS2 gene of patients with cardiomyopathy and encephalomyopathy". Annals of Neurology 49(2):195-201.

19. Baysal, B. E., Ferrell, R. E., Willett-Brozick, J. E., Lawrence, E. C., Myssiorek, D., Bosch, A., van der Mey, A., Taschner, P. E., Rubinstein, W. S., Myers, E. N., Richard, C. W., Cornelisse, C. J., Devilee, P. and Devlin, B. (2000). "Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma". Science 287(5454):848-851.

20. Niemann, S. and Muller, U. (2000). "Mutations in SDHC cause autosomal dominant paraganglioma, type 3". Nature Genetics 26(3):268-270.

21. Smeitink, J. and van den Heuvel, L. (1999). "Human mitochondrial complex I in health and disease". American Journal of Human Genetics 64(6):1505-1510.

22. Loeffen, J., Smeitink, J., Triepels, R., Smeets, R., Schuelke, M., Sengers, R., Trijbels, F., Hamel, B., Mullaart, R. and van den Heuvel, L. (1998). "The first nuclear-encoded complex I mutation in a patient with Leigh Syndrome". American Journal of Human Genetics 63(6):1598-1608.

23. van den Heuvel, L., Ruitenbeek, W., Smeets, R., Gelman-Kohan, Z., Elpeleg, O., Loeffen, J., Trijbels, F., Mariman, E., de Bruijn, D. and Smeitink, J. (1998). "Demonstration of a new pathogenic mutation in human complex I deficiency: a 5-bp duplication in the nuclear gene encoding the 18-kD (AQDQ) subunit". American Journal of Human Genetics 62(2):262-268.

24. Bourgeron, T., Rustin, P., Chretien, D., Birch-Machin, M., Bourgeois, M., Viegas-Pequignot, E., Munnich, A. and Rotig, A. (1995). "Mutation of a nuclear succinate dehydrogenase gene results in mitochondrial respiratory chain deficiency". Nature Genetics 11(2):144-149.


The original version of this table was posted in 2006, reproduced with permission from PRINCIPLES AND PRACTICE OF MEDICAL GENETICS, 5/e. © 2006 Elsevier Ltd.

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