Structural Nuclear Genes for Mitochondrial Diseases

Last update: January 2018

Complex	Name	OMIM	Function	Chromosome	Inheritance	Clinical Phenotype	References
Complex I	NDUFS1	157655	IP fraction	2q33-q34	AR	LS	[i]
	NDUFS2	602985	IP fraction	1q23	AR	Encephalopathy, Cardiomyopathy	[ii]
	NDUFS3	603846	IP fraction	11p11.11	AR	LS	[iii]
	NDUFS4	602694	IP fraction	5q11.1	AR	LS	[iv]
	NDUFS6	603848	IP fraction	5pter-p15.33	AR	Fatal Infantile Lactic Acidosis	[v]
	NDUFS7	601825	HP fraction	19p13.3	AR	LS	[vi]
	NDUFS8	602141	HP fraction	11q13	AR	LS	[vii]
	NDUFB3	603839	HP fraction	2q31.3	AR	Fatal Infantile Lactic Acidosis	[viii]
	NDUFB9	601445	HP fraction	8q24.13	AR	Hypotonia, Lactic Acidosis	[ix]
	NDUFB10	603843	HP fraction	16p13.3	AR	Lactic acidosis, cardiomyopathy	[x]
	NDUFB11	300403	HP fraction	Xp11.3	X	Intrauterine growth restriction, Lactic acidosis	[xi]
	NDUFV1	161015	FP fraction	11q13	AR	LS	[xii]
	NDUFV2	600532	FP fraction	18p11	AR	Cardiomyopathy, hypotonia, encephalopathy	[xiii]
	NDUFA1	300078	HP fraction	Xq24	X	LS Progressive neurodegenerative disorder	[xiv]
	NDUFA2	602137	HP fraction	5q31.2	AR	LS	[xv]
	NDUFA9	603834	HP fraction	12p13.32	AR	LS	[xvi]
	NDUFA10	603835	HP fraction	2q37.3	AR	LS	[xvii]
	NDUFA11	612638	IP fraction	19p13.3	AR	Fatal Infantile Lactic Acidosis Encephalocardiomyopathy	[xviii]
	NDUFA12	609653	HP fraction	12q22	AR	LS	[xix]
	NDUFA13	609435	HP fraction	19p13.11	AR	Encephalopathy, Optic atrophy	[xx]
Complex II	SDH-A	600857	FP subunit	5p15	AR	LS	[xxi]
	SDH-B	185470	IP subunit	1p36.1-p35	AD	Phaeochromocytoma and paraganglioma	[xxii]
	SDH-C	602413	Membrane subunit	1q21	AD	Autosomal dominant paraganglioma type 3	[xxiii]
	SDH-D	602690	Membrane subunit	11q23	AD	Autosomal dominant paraganglioma type 1, Pheochromocytoma	[xxiv]
Complex III	UQCRB	191330	electron transfer	8q22	AR	Hypoglycemia, Lactic acidosis	[xxv]
	UQCRQ	612080	electron transfer	5q31.1	AR	Severe neurological phenotype	[xxvi]
Complex IV	COX6A1	602072	Cytochrome oxidase activity	12q24.31	AR	Charcot-Marie-Tooth disease	[xxvii]
	COX6B1	124089	Cytochrome oxidase activity and assembly	19q13.1	AR	Encephalomyopathy	[xxviii]
	COX7B	300885	Cytochrome oxidase activity	Xq21.1	X	Microphthalmia with linear skin lesions	[xxix]
	COX8A	123870	Cytochrome oxidase activity	11q13.1	AR	LS	[xxx]
Complex V	ATP5E	606153	ATPase activity	20q13.3	AR	Lactic acidosis, mental retardation, peripheral neuropathy	[xxxi]
	ATP5A1	164360	ATPase activity	18q21.1	AR	Neonatal encephalopathy	[xxxii]
	ATP8A2	605870	ATPase activity	13q12.13	AR	cerebellar ataxia, mental retardation	[xxxiii]

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ABBREVIATIONS

AD: Autosomal Dominant; AR: Autosomal Recessive; FP: Flavoprotein; HP: Hydrophobic; IP: Iron-Protein; LS: Leigh syndrome; X: X-linked

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REFERENCES

[i] Benit, P., Chretien, D., Kadhom, N., de Lonlay-Debeney, P., Cormier-Daire, V., Cabral, A., Peudenier, S., Rustin, P., Munnich, A., 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, 1344-1352. http://www.ncbi.nlm.nih.gov/pubmed/11349233

[ii] Loeffen, J., Elpeleg, O., Smeitink, J., Smeets, R., Stockler-Ipsiroglu, S., Mandel, H., Sengers, R., Trijbels, F., van den Heuvel, L., 2001. Mutations in the complex I NDUFS2 gene of patients with cardiomyopathy and encephalomyopathy. Annals of Neurology 49, 195-201. http://www.ncbi.nlm.nih.gov/pubmed/11220739

[iii] Benit, P., Slama, A., Cartault, F., Giurgea, I., Chretien, D., Lebon, S., Marsac, C., Munnich, A., Rotig, A., Rustin, P., 2004. Mutant NDUFS3 subunit of mitochondrial complex I causes Leigh syndrome. Journal of Medical Genetics 41, 14-17. http://www.ncbi.nlm.nih.gov/pubmed/14729820

[iv] van den Heuvel, L., Ruitenbeek, W., Smeets, R., Gelman-Kohan, Z., Elpeleg, O., Loeffen, J., Trijbels, F., Mariman, E., de Bruijn, D., 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, 262-268. http://www.ncbi.nlm.nih.gov/pubmed/9463323

[v] 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., Thorburn, D.R., 2004. NDUFS6 mutations are a novel cause of lethal neonatal mitochondrial complex I deficiency. The Journal of Clinical Investigation 114, 837-845. http://www.ncbi.nlm.nih.gov/pubmed/15372108
Spiegel, R., Shaag, A., Mandel, H., Reich, D., Penyakov, M., Hujeirat, Y., Saada, A., Elpeleg, O., Shalev, S.A., 2009. Mutated NDUFS6 is the cause of fatal neonatal lactic acidemia in Caucasus Jews. European Journal of Human Genetics 17, 1200-1203. http://www.ncbi.nlm.nih.gov/pubmed/19259137

[vi] Smeitink, J., van den Heuvel, L., 1999. Human mitochondrial complex I in health and disease. American Journal of Human Genetics 64, 1505-1510. http://www.ncbi.nlm.nih.gov/pubmed/10330338

[vii] Loeffen, J., Smeitink, J., Triepels, R., Smeets, R., Schuelke, M., Sengers, R., Trijbels, F., Hamel, B., Mullaart, R., van den Heuvel, L., 1998. The first nuclear-encoded complex I mutation in a patient with Leigh Syndrome. Ibid. 63, 1598-1608. http://www.ncbi.nlm.nih.gov/pubmed/9837812
Procaccio, V., Wallace, D.C., 2004. Late-onset Leigh syndrome in a patient with mitochondrial complex I NDUFS8 mutations. Neurology 62, 1899-1901. http://www.ncbi.nlm.nih.gov/pubmed/15159508

[viii] 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., 2012. Molecular diagnosis of infantile mitochondrial disease with targeted next-generation sequencing. Science Translational Medicine 4, 118ra110. http://www.ncbi.nlm.nih.gov/pubmed/22277967

[ix] Haack, T.B., Madignier, F., Herzer, M., Lamantea, E., Danhauser, K., Invernizzi, F., Koch, J., Freitag, M., Drost, R., Hillier, I., Haberberger, B., Mayr, J.A., Ahting, U., Tiranti, V., Rotig, A., Iuso, A., Horvath, R., Tesarova, M., Baric, I., Uziel, G., Rolinski, B., Sperl, W., Meitinger, T., Zeviani, M., Freisinger, P., Prokisch, H., 2012. Mutation screening of 75 candidate genes in 152 complex I deficiency cases identifies pathogenic variants in 16 genes including NDUFB9. Journal of Medical Genetics 49, 83-89. https://www.ncbi.nlm.nih.gov/pubmed/22200994

[x] Friederich, M.W., Erdogan, A.J., Coughlin, C.R., 2nd, Elos, M.T., Jiang, H., O'Rourke, C.P., Lovell, M.A., Wartchow, E., Gowan, K., Chatfield, K.C., Chick, W.S., Spector, E.B., Van Hove, J.L.K., Riemer, J., 2017. Mutations in the accessory subunit NDUFB10 result in isolated complex I deficiency and illustrate the critical role of intermembrane space import for complex I holoenzyme assembly. Human Molecular Genetics 26, 702-716. https://www.ncbi.nlm.nih.gov/pubmed/28040730

[xi] Kohda, M., Tokuzawa, Y., Kishita, Y., Nyuzuki, H., Moriyama, Y., Mizuno, Y., Hirata, T., Yatsuka, Y., Yamashita-Sugahara, Y., Nakachi, Y., Kato, H., Okuda, A., Tamaru, S., Borna, N.N., Banshoya, K., Aigaki, T., Sato-Miyata, Y., Ohnuma, K., Suzuki, T., Nagao, A., Maehata, H., Matsuda, F., Higasa, K., Nagasaki, M., Yasuda, J., Yamamoto, M., Fushimi, T., Shimura, M., Kaiho-Ichimoto, K., Harashima, H., Yamazaki, T., Mori, M., Murayama, K., Ohtake, A., Okazaki, Y., 2016. A Comprehensive Genomic Analysis Reveals the Genetic Landscape of Mitochondrial Respiratory Chain Complex Deficiencies. PLoS Genetics 12, e1005679. https://www.ncbi.nlm.nih.gov/pubmed/26741492

[xii] Smeitink, J., van den Heuvel, L., 1999. Human mitochondrial complex I in health and disease. American Journal of Human Genetics 64, 1505-1510. http://www.ncbi.nlm.nih.gov/pubmed/10330338

[xiii] Benit, P., Beugnot, R., Chretien, D., Giurgea, I., De Lonlay-Debeney, P., Issartel, J.P., Corral-Debrinski, M., Kerscher, S., Rustin, P., Rotig, A., Munnich, A., 2003. Mutant NDUFV2 subunit of mitochondrial complex I causes early onset hypertrophic cardiomyopathy and encephalopathy. Human Mutation 21, 582-586. http://www.ncbi.nlm.nih.gov/pubmed/12754703

[xiv] 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., Arenas, J., 2007. X-linked NDUFA1 gene mutations associated with mitochondrial encephalomyopathy. Annals of Neurology 61, 73-83. http://www.ncbi.nlm.nih.gov/pubmed/17262856
Potluri, P., Davila, A., Ruiz-Pesini, E., Mishmar, D., O'Hearn, S., Hancock, S., Simon, M.C., Scheffler, I., Wallace, D.C., Procaccio, V., 2009. A novel NDUFA1 mutation leads to a progressive mitochondrial complex I-specific neurodegenerative disease. Molecular Genetics and Metabolism 96, 189-195. http://www.ncbi.nlm.nih.gov/pubmed/19185523

[xv] 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., van den Heuvel, L.P., 2008. NDUFA2 complex I mutation leads to Leigh disease. American Journal of Human Genetics 82, 1306-1315. http://www.ncbi.nlm.nih.gov/pubmed/18513682

[xvi] van den Bosch, B.J., Gerards, M., Sluiter, W., Stegmann, A.P., Jongen, E.L., Hellebrekers, D.M., Oegema, R., Lambrichs, E.H., Prokisch, H., Danhauser, K., Schoonderwoerd, K., de Coo, I.F., Smeets, H.J., 2012. Defective NDUFA9 as a novel cause of neonatally fatal complex I disease. Journal of Medical Genetics 49, 10-15. https://www.ncbi.nlm.nih.gov/pubmed/22114105

[xvii] Hoefs, S.J., van Spronsen, F.J., Lenssen, E.W., Nijtmans, L.G., Rodenburg, R.J., Smeitink, J.A., van den Heuvel, L.P., 2011. NDUFA10 mutations cause complex I deficiency in a patient with Leigh disease. European Journal of Human Genetics 19, 270-274. http://www.ncbi.nlm.nih.gov/pubmed/21150889

[xviii] Berger, I., Hershkovitz, E., Shaag, A., Edvardson, S., Saada, A., Elpeleg, O., 2008. Mitochondrial complex I deficiency caused by a deleterious NDUFA11 mutation. Annals of Neurology 63, 405-408. http://www.ncbi.nlm.nih.gov/pubmed/18306244

[xix] Ostergaard, E., Rodenburg, R.J., van den Brand, M., Thomsen, L.L., Duno, M., Batbayli, M., Wibrand, F., Nijtmans, L., 2011. Respiratory chain complex I deficiency due to NDUFA12 mutations as a new cause of Leigh syndrome. Journal of Medical Genetics 48, 737-740. https://www.ncbi.nlm.nih.gov/pubmed/21617257

[xx] Angebault, C., Charif, M., Guegen, N., Piro-Megy, C., Mousson de Camaret, B., Procaccio, V., Guichet, P.O., Hebrard, M., Manes, G., Leboucq, N., Rivier, F., Hamel, C.P., Lenaers, G., Roubertie, A., 2015. Mutation in NDUFA13/GRIM19 leads to early onset hypotonia, dyskinesia and sensorial deficiencies, and mitochondrial complex I instability. Human Molecular Genetics 24, 3948-3955. https://www.ncbi.nlm.nih.gov/pubmed/25901006

[xxi] Bourgeron, T., Rustin, P., Chretien, D., Birch-Machin, M., Bourgeois, M., Viegas-Pequignot, E., Munnich, A., Rotig, A., 1995. Mutation of a nuclear succinate dehydrogenase gene results in mitochondrial respiratory chain deficiency. Nature Genetics 11, 144-149. http://www.ncbi.nlm.nih.gov/pubmed/7550341

[xxii] Astuti, D., Latif, F., Dallol, A., Dahia, P.L., Douglas, F., George, E., Skoldberg, F., Husebye, E.S., Eng, C., 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, 49-54. http://www.ncbi.nlm.nih.gov/pubmed/11404820

[xxiii] Niemann, S., Muller, U., 2000. Mutations in SDHC cause autosomal dominant paraganglioma, type 3. Nature Genetics 26, 268-270. http://www.ncbi.nlm.nih.gov/pubmed/11062460

[xxiv] 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., Devlin, B., 2000. Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science 287, 848-851. http://www.ncbi.nlm.nih.gov/pubmed/10657297

[xxv] Haut, S., Brivet, M., Touati, G., Rustin, P., Lebon, S., Garcia-Cazorla, A., Saudubray, J.M., Boutron, A., Legrand, A., 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, 118-122. http://www.ncbi.nlm.nih.gov/pubmed/12709789

[xxvi] Barel, O., Shorer, Z., Flusser, H., Ofir, R., Narkis, G., Finer, G., Shalev, H., Nasasra, A., Saada, A., Birk, O.S., 2008. Mitochondrial complex III deficiency associated with a homozygous mutation in UQCRQ. American Journal of Human Genetics 82, 1211-1216. http://www.ncbi.nlm.nih.gov/pubmed/18439546

[xxvii] Tamiya, G., Makino, S., Hayashi, M., Abe, A., Numakura, C., Ueki, M., Tanaka, A., Ito, C., Toshimori, K., Ogawa, N., Terashima, T., Maegawa, H., Yanagisawa, D., Tooyama, I., Tada, M., Onodera, O., Hayasaka, K., 2014. A mutation of COX6A1 causes a recessive axonal or mixed form of Charcot-Marie-Tooth disease. American Journal of Human Genetics 95, 294-300. https://www.ncbi.nlm.nih.gov/pubmed/25152455

[xxviii] Massa, V., Fernandez-Vizarra, E., Alshahwan, S., Bakhsh, E., Goffrini, P., Ferrero, I., Mereghetti, P., D'Adamo, P., Gasparini, P., 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, 1281-1289. http://www.ncbi.nlm.nih.gov/pubmed/18499082

[xxix] Indrieri, A., van Rahden, V.A., Tiranti, V., Morleo, M., Iaconis, D., Tammaro, R., D'Amato, I., Conte, I., Maystadt, I., Demuth, S., Zvulunov, A., Kutsche, K., Zeviani, M., Franco, B., 2012. Mutations in COX7B cause microphthalmia with linear skin lesions, an unconventional mitochondrial disease. American Journal of Human Genetics 91, 942-949. https://www.ncbi.nlm.nih.gov/pubmed/23122588

[xxx] Hallmann, K., Kudin, A.P., Zsurka, G., Kornblum, C., Reimann, J., Stuve, B., Waltz, S., Hattingen, E., Thiele, H., Nurnberg, P., Rub, C., Voos, W., Kopatz, J., Neumann, H., Kunz, W.S., 2016. Loss of the smallest subunit of cytochrome c oxidase,COX8A, causes Leigh-like syndrome and epilepsy. Brain 139, 338-345. https://www.ncbi.nlm.nih.gov/pubmed/26685157

[xxxi] Mayr, J.A., Havlickova, V., Zimmermann, F., Magler, I., Kaplanova, V., Jesina, P., Pecinova, A., Nuskova, H., Koch, J., Sperl, W., Houstek, J., 2010. Mitochondrial ATP synthase deficiency due to a mutation in the ATP5E gene for the F1 epsilon subunit. Human Molecular Genetics 19, 3430-3439. http://www.ncbi.nlm.nih.gov/pubmed/20566710

[xxxii] Jonckheere, A.I., Renkema, G.H., Bras, M., van den Heuvel, L.P., Hoischen, A., Gilissen, C., Nabuurs, S.B., Huynen, M.A., de Vries, M.C., Smeitink, J.A., Rodenburg, R.J., 2013. A complex V ATP5A1 defect causes fatal neonatal mitochondrial encephalopathy. Brain 136, 1544-1554. https://www.ncbi.nlm.nih.gov/pubmed/23599390

[xxxiii] Onat, O.E., Gulsuner, S., Bilguvar, K., Nazli Basak, A., Topaloglu, H., Tan, M., Tan, U., Gunel, M., Ozcelik, T., 2013. Missense mutation in the ATPase, aminophospholipid transporter protein ATP8A2 is associated with cerebellar atrophy and quadrupedal locomotion. European Journal of Human Genetics 21, 281-285. https://www.ncbi.nlm.nih.gov/pubmed/22892528