Non-Structural Nuclear Genes in Mitochondrial Disease

Non-Structural Nuclear Genes in Mitochondrial Disease

Complex Assembly

Complex	Gene	OMIM	Function	Chromosome	Inheritance	Clinical Phenotype	References
I	B17.2L	609653	Assembly, chaperone	5q12.1	AR	Early onset progressive encephalopathy (Mitochondrial complex I deficiency)	(22)
III	BCS1L	603647	Assembly	2q33	AR	Encephalopathy, hepatic failure and tubulopathy (Mitochondrial complex III deficiency), LS, GRACILE syndrome	(10,36)
IV	SURF1	185620	Assembly	9q34	AR	LS	(33,37)
IV	SCO1	603644	Copper transport	17p13-p12	AR	Neonatal hepatic failure and encephalopathy	(34)
IV	SCO2	604272	Copper transport	22q13	AR	Neonatal cardioencephalomyopathy due to cytochrome c oxidase deficiency	(24)
IV	COX10	602125	Heme A farnesyltransferase	17p12- p11.2	AR	Neonatal tubulopathy and encephalopathy, LS, cardiomyopathy	(3)
IV	COX15	603646	Heme A synthesis	10q24	AR	Early-onset hypertrophic cardiomyopathy, LS	(4,23)
IV	LRPPRC	607544	Assembly	2p21-p16	AR	French-Canadian LS	(19)
V	ATPAF2	608918	Assembly	17p11.2	AR	Early-onset encephalopathy, Lactic acidosis (Complex V deficiency)	(11)

MtDNA Stability

Gene OMIM
Function
Chromosome Inheritance Clinical Phenotype References

POLG 174763 Polymerase gamma mtDNA replication 15q25 AD/AR Alpers syndrome, AD-PEOA1 and AR-PEO,
male infertility, SANDO syndrome, SCAE (20, 28, 35)

ANT1 103220 Adenine nucleotide translocator isoform 1 4q35 AD AD-PEOA2, multiple mtDNA deletions (15)

C10ORF2 606075 Twinkle helicase 10q24 AD AD-PEOA3, SANDO syndrome (13, 30)

ECGF1 131222 Thymidine phosphorylase 22q13.32-qter AR MNGIE, multiple mtDNA deletions (21)

DGUOK 601465 Deoxyguanosine kinase - Mitochondrial dNTP pool maintenance 2p13 AR Hepatocerebral mtDNA depletion syndrome (17)

TK2 188250 Thymidine kinase -
Mitochondrial dNTP pool maintenance 16q22 AR Myopathic mtDNA depletion (29)

Mitochondrial Import

Gene OMIM
Function
Chromosome Inheritance Clinical Phenotype References

DDP 300356 Protein import Xq22 X-linked Deafness-dystonia or
Mohr-Tranebjaerg syndrome
(14)

Mitochondrial Protein Synthesis

Gene OMIM
Function
Chromosome Inheritance Clinical Phenotype References

EFG1 606639 Elongation factor G1 - mitochondrial translation defect 3q25 AR Severe hepatoencephalopathy and lactic acidosis
(combined oxidative phosphorylation deficiency)
(8)

Iron Homeostasis

Gene OMIM
Function
Chromosome Inheritance Clinical Phenotype References

FRDA 606829 Frataxin Trinucleotide Repeat 9q13 AR Friedreich ataxia, neuropathy, cardiomyopathy, diabetes (6,27)

ABC7 300135 Iron transport Xq13.1-q13.3 X- linked X-linked sideroblastic anemia with ataxia (2)

Chaperone Function

Gene OMIM
Function
Chromosome Inheritance Clinical Phenotype References

SPG7 602783 Paraplegin ATPase protease 16q24.3 AR Spastic paraplegia
(7)

Mitochondrial Integrity

Gene OMIM
Function
Chromosome Inheritance Clinical Phenotype References

OPA1 605290 Dynamin-related protein 3q28-q29 AD AD-Optic atrophy (1,12)

MFN2 608507 Mitofusin - Mitochondrial fusion 1p36.2 AD Charcot- Marie-Tooth disease-2A2 (CMT2A2) (16, 38)

G4.5
(Tafazzin) 300394 Cardiolipin defect Xq28 X-linked Barth syndrome, X-linked dilated cardiomyopathy (5, 9)

RMRP 157660 RNAse Mitochondrial RNA Processing 9p21-p12 AR Metaphyseal chondrodysplasia or Cartilage-hair hypoplasia (25,26)

Mitochondrial Metabolism

Gene OMIM
Function
Chromosome Inheritance Clinical Phenotype References

PDHA1 300502 Pyruvate dehydrogenase
E1-α subunit Xp22.2-p22.1 X-linked X-linked LS (18)

ETHE1 608451 Ethylmalonic acid metabolism 19q13 AR Encephalopathy, ethylmalonic aciduria (31,32)

Abbreviations

AR: Autosomal Recessive; AD: Autosomal Dominant; LS: Leigh Syndrome; SANDO: Sensory Ataxic Neuropathy, Dysarthria, and Ophthalmoparesis; SCAE: Spinocerebellar Ataxia with Epilepsy; GRACILE syndrome: Growth Retardation, Amino aciduria, Cholestasis, Iron overload, Lactic acidosis, and Early death; MNGIE: MyoNeuroGastroIntestinal Encephalopathy

References

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21. Nishino, I., Spinazzola, A. and Hirano, M. (1999). "Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder." Science 283(5402):689- 692.

22. Ogilvie, I., Kennaway, N. G. and Shoubridge, E. A. (2005). "A molecular chaperone for mitochondrial complex I assembly is mutated in a progressive encephalopathy." Journal of Clinical Investigation 115(10):2784-2792.

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31. Tiranti, V., Briem, E., Lamantea, E., Mineri, R., Papaleo, E., Degioia, L., Forlani, F., Rinaldo, P., Dickson, P., Abu-Libdeh, B., Cindro-Heberle, L., Owaidha, M., Jack, R. M., Christensen, E., Burlina, A. and Zeviani, M. (2006). "ETHE1 mutations are specific to ethylmalonic encephalopathy." Journal of Medical Genetics 43(4):340- 346.

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