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]


ABBREVIATIONS

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


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

Topic revision: r3 - 17 Jan 2018, MarieLott
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