Non-Structural Nuclear Genes for Mitochondrial Disease

Last update: January 2018

Complex

Name

OMIM

Function

Chromosome

Inheritance

Clinical Phenotype

References
Assembly
Complex I

NDUFAF1(CIA30)

606934

Assembly

15q13.3

AR

Cardioencephalomyopathy

[i]

NDUFAF2 (B17.2L)

609653

Assembly

5q12.1

AR

Early onset progressive encephalopathy

[ii]

NDUFAF3

612911

Assembly

3p21.31

AR

Neonatal encephalopathy

[iii]

NDUFAF4 (HRPAP2)

611776

Assembly

6q16.1

AR

Infantile encephalopathy

[iv]
NDUFAF5 (C20orf7)

612360

Assembly

20p12.1

AR

LS

[v]

NDUFAF6

612392

Assembly

8q22.1

AR

LS

[vi]

NUBPL

613621

Assembly

14q12

AR

Encephalomyopathy

[vii]

FOXRED1

613622

Assembly

11q24.2

AR

LS

[viii]

ACAD9

611103

Assembly and activity

3q26

AR

Hypertrophic cardiopathy encephalopathy

[ix]
Complex II

SDHAF1

612848

Assembly

19q12-q13.2

AR

Leukoencephalopathy

[x]

SDHAF2

613019

Assembly

11q12.2

AD

Autosomal dominant paraganglioma type 2

[xi]
Complex III

BCS1L

603647

Assembly

2q33

AR

Encephalopathy, hepatic failure and tubulopathy, LS, GRACILE syndrome, Bjornstad Syndrome

[xii]

UQCC2

614461

Assembly

6p21.31

AR

lactic acidosis and renal tubular dysfunction

[xiii]

UQCC3

616097

Assembly

11q12.3

AR

lactic acidosis, hypoglycemia, hypotonia

[xiv]
Complex IV

SURF1

185620

Assembly

9q34

AR

LS

[xv]

SCO1

603644

Copper transport

17p13-p12

AR

Neonatal hepatic failure and encephalopathy

[xvi]

SCO2

604272

Copper transport

22q13

AR

Neonatal Cardioencephalomyopathy

[xvii]

COX10

602125

Heme A farnesyltransferase

17p12-p11.2

AR

Neonatal tubulopathy and encephalopathy, LS, cardiomyopathy

[xviii]

COX14 (C12orf62)

614478

COX assembly

12q13.12

AR

Neonatal lactic acidosis

[xix]

COX15

603646

Heme A synthesis

10q24

AR

Early-onset hypertrophic cardiomyopathy, LS

[xx]

COX20

614698

Assembly

1q44

AR

Ataxia, muscle hypotonia

[xxi]

COA3

614775

Assembly

17q21.2

AR

Neuropathy, exercise intolerance

[xxii]

COA5

613920

Assembly

2q11.2

AR

Cardioencephalomyopathy

[xxiii]

COA6

614772

Assembly

1q42.2

AR

Cardioencephalomyopathy

[xxiv]

LRPPRC

220111 607544

Assembly

2p21-p16

AR

French-Canadian LS

[xxv]

FASTKD2

612322

Role in apoptosis

2q33.3

AR

Encephalomyopathy

[xxvi]

TACO1

612958

translational activator of COX1

17q22-q24.2

AR

LS

[xxvii]
Complex V

ATPAF2

608918

Assembly

17p11.2

AR

Early-onset encephalopathy, Lactic acidosis

[xxviii]

TMEM70

604273 612418

Assembly

8q21.11

AR

Neonatal encephalopathy, cardiomyopathy

[xxix]

MtDNA Maintenance

POLG (PEOA1)

174763

Polymerase gamma mtDNA replication

15q25

AD-AR

Alpers syndrome, AD-PEO and AR-PEO, male infertility, SANDO* syndrome, SCAE*

[xxx]

POLG2 (PEOA4)

610131

catalytic subunit of DNA polymerase gamma

17q23-q24

AD

AD-PEO

[xxxi]

ANT1 (PEOA2)

609283

Adenine nucleotide translocator isoform 1

4q35

AD-AR

AD-PEO, multiple mtDNA deletions

[xxxii]

MPV17

137960

regulation of mtDNA copy number

2p23-p21

AR

Hepatocerebral MDDS

[xxxiii]

OPA1

165500

Dynamin-related protein

3q28-q29

AD

AD-Optic Atrophy, Multiple deletions

[xxxiv]

MFN2

609260

Mitofusin
Mitochondrial fusion

1p36-p35

AD

Charcot-Marie-Tooth disease-2A2 (CMT2A2)
Multiple deletions

[xxxv]

C10ORF (PEOA3)

609286

Twinkle helicase

10q24

AD

AD-PEO, SANDO syndrome

[xxxvi]

TYMP (ECGF1)

603041

Thymidine phosphorylase

22q13.32-qter

AR

MNGIE, mtDNA depletion

[xxxvii]

DGUOK

601465

Deoxyguanosine kinase
Mitochondrial dNTP pool maintenance

2p13

AR

Hepatocerebral mtDNA depletion syndrome

[xxxviii]

RRM2B (PEOA5)

604712

ribonucleotide reductase M2 B
dNTP pool

8q23.1

AR

Encephalomyopathic Renal tubulopathy
MNGIE, AD-PEO

[xxxix]

SUCLA2

603921

succinate-CoA ligase, ADP-forming, beta subunit

13q12.2-q13

AR

Encephalomyopathy with methylmalonic aciduria

[xl]

SUCLG1

611224

succinate-CoA ligase, alpha subunit

2p11.2

AR

Encephalomyopathy with methylmalonic aciduria

[xli]

TK2

188250

Thymidine kinase
Mitochondrial dNTP pool maintenance

16q22

AR

Myopathic mtDNA depletion

[xlii]

TFAM

600438

mitochondrial transcription factor A

10q21.1

AR

Encephalomyopathy mtDNA depletion

[xliii]

FBXL4

605654

mtDNA maintenance

6q16.1-q16.2

AR

Encephalomyopathy and myopathy mtDNA depletion

[xliv]

MGME1

615084

mtDNA maintenance

20p11.23

AR

CPEO and Myopathy mtDNA depletion

[xlv]

Mitochondrial Import

DDP

304700

Protein import

Xq22

X-linked

Deafness-dystonia or Mohr-Tranebjaerg syndrome

[xlvi]

DNAJC19

608977

Protein import

3q26.3

AR

Cardiomyopathy, ataxia

[xlvii]

Mitochondrial Protein Synthesis

AARS2

612035

Alanyl-tRNA synthetase

6p21.1

AR

Cardiomyopathy; Leukoencephalopathy

[xlviii]

CARS2

612800

Cysteinyl-tRNA synthetase

13q34

AR

Myoclonic epilepsy

[xlix]

DARS2

611105

aspartyl-tRNA synthetase

1q25.1

AR

Leukoencephalopathy and lactic acidosis

[l]

EARS2

612799

Glutamyl tRNA synthetase

16p12.2

AR

Leukoencephalopathy

[li]

FARS2

611592

Phenylalanyl-tRNA synthetase

6p25.1

AR

Alpers syndrome, spastic paraplegia

[lii]

GARS

600287

glycyl-tRNA synthetase

7p14.3

AD

Charcot-Marie-Tooth disease

[liii]

HARS2

600783

Histidyl-tRNA synthetase

5q31.3

AR

Perrault syndrome

[liv]

IARS2

612801

Isoleucyl tRNA-Synthetase

1q41

AR

Cataract, deafness, neuropathy / Leigh Syndrome

[lv]

KARS

601421

Lysyl-tRNA synthetase

16q23.1

AR

CMT disease/ Deafness

[lvi]

LARS

615438

Leucine-tRNA synthetase

5q32

AR

Hepatopathy

[lvii]

LARS2

604544

Leucyl-tRNA Synthetase

3p21.31

AR

Perrault Syndrome

[lviii]

NARS2

612803

Asparaginyl-tRNA synthetase

11q14.1

AR

Alpers syndrome / Nonsyndromic Deafness and Leigh Syndrome

[lix]

PARS2

612036

Prolyl- tRNA Synthetase

1p32.3

AR

Alpers syndrome

[lx]

RARS2

611523

arginyl-tRNA synthetase

6q16.1

AR

Pontocerebellar hypoplasia

[lxi]

SARS2

612804

seryl-tRNA synthetase

19q13.2

AR

Hyperuricemia, pulmonary hypertension, renal failure

[lxii]

TARS2

612805

Threonyl--tRNA synthetase

1q21.2

AR

Encephalomyopathy

[lxiii]

VARS2

612802

valyl-tRNA synthetase

6p21.33

AR

Encephalomyopathy

[lxiv]

YARS2

610957

tyrosyl-tRNA synthetase

12p11.21

AR

Myopathy, lactic acidosis, and sideroblastic anemia-2

[lxv]

EFG1

609060

Elongation factor G1 mitochondrial translation defect

3q25

AR

Severe hepatoencephalopathy and lactic acidosis

[lxvi]

TSFM

604723

Mitochondrial translation elongation

12q13-q14

AR

Encephalomyopathy, hypertrophic cardiomyopathy

[lxvii]

TUFM

602389

Mitochondrial translation elongation

16p11.2

AR

Leukodystrophy with micropolygyria

[lxviii]

GTPBP3

608536
GTP-binding protein

19p13.11

AR

Cardiomyopathy, encephalopathy

[lxix]

MTFMT

611766

Mitochondrial translation

15q22.31

AR

LS

[lxx]

MTO1

614667

tRNA modification

6q13

AR

Cardiomyopathy

[lxxi]

TRMT5

611023

mitochondrial tRNA methylation

14q23.1

AR

Cardiomyopathy/exercise intolerance

[lxxii]

TRMT10C

615423

TRNA Methyltransferase

3q12.3

AR

Hypotonia, feeding difficulties, deafness

[lxxiii]

TRMU

610230

mitochondrial translation

22q13.31

AR

Liver failure, deafness

[lxxiv]

GFM1

606639

Mitochondrial translationelongation

3q25.32

AR

Encephalopathy/hepatic failure

[lxxv]

GFM2

606544

Mitochondrial translation elongation

5q13.3

AR

Neurodevelopmental disorder, dysmorphic features

[lxxvi]

C12orf65

613541

Mitochondrial translation

12q24.31

AR

Encephalomyopathy, Optic atrophy, axonal neuropathy, paraparesis

[lxxvii]

RMND1

614917

Mitochondrial translation

6q25.1

AR

Encephalopathy

[lxxviii]

MRPL3

607118

Mitochondrial translation

3q22.1

AR

Cardiomyopathy, mental retardation

[lxxix]

MRPS7

611974

Mitochondrial translation

17q25.1

AR

Deafness, hepatic and renal failure

[lxxx]

MRPL12

602375

Mitochondrial translation

17q25.3

AR

Growth retardation, encephalopathy

[lxxxi]

MRPS16

609204

Mitochondrial translation

10q22.1

AR

Neonatal lactic acidosis
corpus callosum agenesis

[lxxxii]

MRPS22

605810

Mitochondrial translation

3q23

AR

Cardiomyopathy, tubulopathy

[lxxxiii]

MRPL44

611849

Mitochondrial translation

2q36.1

AR

Cardiomyopathy

[lxxxiv]

Iron Homeostasis

FRDA (FXN)

606829

Frataxin Trinuc.* Repeat,

9q13

AR

Friedreich ataxia, neuropathy, cardiomyopathy, diabetes

[lxxxv]

ABCB7

301310

Iron transport

Xq13.1-q13.3

X-linked

X-linked sideroblastic anemia with ataxia

[lxxxvi]

GLRX5

205950

Iron-sulfur cluster biosynthesis

3p22.1

AR

Sideroblastic anemia

[lxxxvii]

ISCU

255125

Iron-sulfur cluster biosynthesis

12q23.3

AR

Myopathy, lactic acidosis, exercise intolerance

[lxxxviii]

BOLA3

613183

Iron-sulfur cluster biosynthesis

2p13.1

AR

Encephalomyopathy,

cardiomyopathy

[lxxxix]

NFU1

608100

Iron-sulfur cluster biosynthesis

2p13.3

AR

Lactic acidosis

multiple respiratory chain deficiency

[xc]

ISCA2

615317

Iron-sulfur cluster biosynthesis

14q24.3

AR

Leukodystrophy

[xci]

IBA57

615316

Iron-sulfur cluster biosynthesis

1q42.13

AR

Myopathy, encephalopathy

[xcii]

LYRM4

613311

Iron-sulfur cluster biosynthesis

6p25.1

AR

Lactic acidosis, Failure to thrive

[xciii]

LYRM7

615831

Iron-sulfur cluster biosynthesis

5q23.3-q31.1

AR

Encephalopathy, lactic acidosis

[xciv]

FDXL1

614585

Iron-sulfur cluster biosynthesis

19p13.2

AR

Myopathy, lactic acidosis

[xcv]

Coenzyme Q10 biogenesis

COQ2

609825

CoQ10 deficiency

4q21-q22

AR

Encephalomyopathy, nephropathy

[xcvi]

COQ4

612898

CoQ10 deficiency

9q34.13

AR

Encephalomyopathy, mental retardation

[xcvii]

COQ5

616359

CoQ10 deficiency

12q24.31

AR

Encephalomyopathy, cerebellar ataxia

[xcviii]

COQ6

614647

CoQ10 deficiency

14q24.3

AR

Nephrotic syndrome, deafness

[xcix]

COQ7

601683

CoQ10 deficiency

16p12.3

AR

Hypotonia, cardiac hypertrophy

[c]

COQ9

612837

CoQ10 deficiency

16q13

AR

Neonatal lactic acidosis
Seizures, cardiomyopathy

[ci]

APTX

606350

CoQ10 deficiency

9p13.3

AR

Cerebellar ataxia
Oculomotor apraxia

[cii]

PDSS1

607429

CoQ10 deficiency

10p12.1

AR

Deafness, valvulopathy, mental retardation

[ciii]

PDSS2

610564

CoQ10 deficiency

6q21

AR

LS, nephrotic syndrome

[civ]

CABC1

606980

CoQ10 deficiency

1q42.2

AR

Cerebellar ataxia, lactic acidosis

[cv]

Chaperone Function

SPG7

607259

Paraplegin ATPase protease

16q24.3

AR

Spastic paraplegia

[cvi]

HSPD1

118190

Mitochondrial chaperone

2q33.1

AR

Spastic paraplegia, leukodystrophy

[cvii]

Mitochondrial Integrity

DLP1

603850

Mitochondrial and peroxisomal fission

12p11.21

AD

Microcephaly, abnormal brain development, optic atrophy, lactic acidosis

[cviii]

G4.5 (Tafazzin)

302060

Cardiolipin defect

Xq28

X-linked

Barth syndrome, X-linked dilated cardiomyopathy

[cix]

RMRP

250250

RNAse Mitochondrial RNA Processing

9p13-p12

AR

Metaphyseal chondrodysplasia or Cartilage-hair hypoplasia

[cx]

Mitochondrial Metabolism

PDHA1

308930

Pyruvate dehydrogenase

E1-a subunit

Xp22.2-p22.1

X-linked

LS

[cxi]

ETHE1

602473

Ethylmalonic acid metabolism

19q13

AR

Encephalopathy, ethylmalonic aciduria

[cxii]

PUS1

600462

pseudouridine synthase

12q24.33

AR

myopathy, lactic acidosis, and sideroblastic anemia

[cxiii]

ATAD3

617183

mitochondrial dynamics

1p36.33

AR/AD

Neurodevelopmental disorder, pontocerebellar hypoplasia, encephalopathy

[cxiv]

ABBREVIATIONS

AD: Autosomal Dominant; AR: Autosomal Recessive; 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; MDDS: Mitochondrial DNA Depletion Syndrome


REFERENCES

[i] Dunning, C.J., McKenzie, M., Sugiana, C., Lazarou, M., Silke, J., Connelly, A., Fletcher, J.M., Kirby, D.M., Thorburn, D.R., Ryan, M.T., 2007. Human CIA30 is involved in the early assembly of mitochondrial complex I and mutations in its gene cause disease. EMBO Journal 26, 3227-3237. http://www.ncbi.nlm.nih.gov/pubmed/17557076

[ii] Ogilvie, I., Kennaway, N.G., Shoubridge, E.A., 2005. A molecular chaperone for mitochondrial complex I assembly is mutated in a progressive encephalopathy. The Journal of Clinical Investigation 115, 2784-2792. http://www.ncbi.nlm.nih.gov/pubmed/16200211

[iii] Saada, A., Vogel, R.O., Hoefs, S.J., van den Brand, M.A., Wessels, H.J., Willems, P.H., Venselaar, H., Shaag, A., Barghuti, F., Reish, O., Shohat, M., Huynen, M.A., Smeitink, J.A., van den Heuvel, L.P., Nijtmans, L.G., 2009. Mutations in NDUFAF3 (C3ORF60), encoding an NDUFAF4 (C6ORF66)-interacting complex I assembly protein, cause fatal neonatal mitochondrial disease. American Journal of Human Genetics 84, 718-727. http://www.ncbi.nlm.nih.gov/pubmed/19463981

[iv] Saada, A., Edvardson, S., Rapoport, M., Shaag, A., Amry, K., Miller, C., Lorberboum-Galski, H., Elpeleg, O., 2008. C6ORF66 is an assembly factor of mitochondrial complex I. American Journal of Human Genetics 82, 32-38. http://www.ncbi.nlm.nih.gov/pubmed/18179882

[v] Gerards, M., Sluiter, W., van den Bosch, B.J., de Wit, L.E., Calis, C.M., Frentzen, M., Akbari, H., Schoonderwoerd, K., Scholte, H.R., Jongbloed, R.J., Hendrickx, A.T., de Coo, I.F., Smeets, H.J., 2010. Defective complex I assembly due to C20orf7 mutations as a new cause of Leigh syndrome. Journal of Medical Genetics 47, 507-512. http://www.ncbi.nlm.nih.gov/pubmed/19542079
Sugiana, C., Pagliarini, D.J., McKenzie, M., Kirby, D.M., Salemi, R., Abu-Amero, K.K., Dahl, H.H., Hutchison, W.M., Vascotto, K.A., Smith, S.M., Newbold, R.F., Christodoulou, J., Calvo, S., Mootha, V.K., Ryan, M.T., Thorburn, D.R., 2008. Mutation of C20orf7 disrupts complex I assembly and causes lethal neonatal mitochondrial disease. American Journal of Human Genetics 83, 468-478. http://www.ncbi.nlm.nih.gov/pubmed/18940309

[vi] Bianciardi, L., Imperatore, V., Fernandez-Vizarra, E., Lopomo, A., Falabella, M., Furini, S., Galluzzi, P., Grosso, S., Zeviani, M., Renieri, A., Mari, F., Frullanti, E., 2016. Exome sequencing coupled with mRNA analysis identifies NDUFAF6 as a Leigh gene. Molecular Genetics and Metabolism 119, 214-222. https://www.ncbi.nlm.nih.gov/pubmed/27623250

[vii] Calvo, S.E., Tucker, E.J., Compton, A.G., Kirby, D.M., Crawford, G., Burtt, N.P., Rivas, M., Guiducci, C., Bruno, D.L., Goldberger, O.A., Redman, M.C., Wiltshire, E., Wilson, C.J., Altshuler, D., Gabriel, S.B., Daly, M.J., Thorburn, D.R., Mootha, V.K., 2010. High-throughput, pooled sequencing identifies mutations in NUBPL and FOXRED1 in human complex I deficiency. Nature Genetics 42, 851-858. http://www.ncbi.nlm.nih.gov/pubmed/20818383

[viii] Ibid.

[ix] Haack, T.B., Danhauser, K., Haberberger, B., Hoser, J., Strecker, V., Boehm, D., Uziel, G., Lamantea, E., Invernizzi, F., Poulton, J., Rolinski, B., Iuso, A., Biskup, S., Schmidt, T., Mewes, H.W., Wittig, I., Meitinger, T., Zeviani, M., Prokisch, H., 2010. Exome sequencing identifies ACAD9 mutations as a cause of complex I deficiency. Nature Genetics 42, 1131-1134. http://www.ncbi.nlm.nih.gov/pubmed/21057504

[x] Ghezzi, D., Goffrini, P., Uziel, G., Horvath, R., Klopstock, T., Lochmuller, H., D'Adamo, P., Gasparini, P., Strom, T.M., Prokisch, H., Invernizzi, F., Ferrero, I., Zeviani, M., 2009. SDHAF1, encoding a LYR complex-II specific assembly factor, is mutated in SDH-defective infantile leukoencephalopathy. Nature Genetics 41, 654-656. http://www.ncbi.nlm.nih.gov/pubmed/19465911

[xi] Hao, H.X., Khalimonchuk, O., Schraders, M., Dephoure, N., Bayley, J.P., Kunst, H., Devilee, P., Cremers, C.W., Schiffman, J.D., Bentz, B.G., Gygi, S.P., Winge, D.R., Kremer, H., Rutter, J., 2009. SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma. Science 325, 1139-1142. http://www.ncbi.nlm.nih.gov/pubmed/19628817

[xii] de Lonlay, P., Valnot, I., Barrientos, A., Gorbatyuk, M., Tzagoloff, A., Taanman, J.W., Benayoun, E., Chretien, D., Kadhom, N., Lombes, A., de Baulny, H.O., Niaudet, P., Munnich, A., Rustin, P., Rotig, A., 2001. A mutant mitochondrial respiratory chain assembly protein causes complex III deficiency in patients with tubulopathy, encephalopathy and liver failure. Nature Genetics 29, 57-60. http://www.ncbi.nlm.nih.gov/pubmed/11528392
Hinson, J.T., Fantin, V.R., Schonberger, J., Breivik, N., Siem, G., McDonough, B., Sharma, P., Keogh, I., Godinho, R., Santos, F., Esparza, A., Nicolau, Y., Selvaag, E., Cohen, B.H., Hoppel, C.L., Tranebjaerg, L., Eavey, R.D., Seidman, J.G., Seidman, C.E., 2007. Missense mutations in the BCS1L gene as a cause of the Bjornstad syndrome. The New England Journal of Medicine 356, 809-819. http://www.ncbi.nlm.nih.gov/pubmed/17314340
Visapaa, I., Fellman, V., Vesa, J., Dasvarma, A., Hutton, J.L., Kumar, V., Payne, G.S., Makarow, M., Van Coster, R., Taylor, R.W., Turnbull, D.M., Suomalainen, A., Peltonen, L., 2002. GRACILE syndrome, a lethal metabolic disorder with iron overload, is caused by a point mutation in BCS1L. American Journal of Human Genetics 71, 863-876. http://www.ncbi.nlm.nih.gov/pubmed/12215968

[xiii] Tucker, E.J., Wanschers, B.F., Szklarczyk, R., Mountford, H.S., Wijeyeratne, X.W., van den Brand, M.A., Leenders, A.M., Rodenburg, R.J., Reljic, B., Compton, A.G., Frazier, A.E., Bruno, D.L., Christodoulou, J., Endo, H., Ryan, M.T., Nijtmans, L.G., Huynen, M.A., Thorburn, D.R., 2013. Mutations in the UQCC1-interacting protein, UQCC2, cause human complex III deficiency associated with perturbed cytochrome b protein expression. PLoS Genetics 9, e1004034. https://www.ncbi.nlm.nih.gov/pubmed/24385928

[xiv] Wanschers, B.F., Szklarczyk, R., van den Brand, M.A., Jonckheere, A., Suijskens, J., Smeets, R., Rodenburg, R.J., Stephan, K., Helland, I.B., Elkamil, A., Rootwelt, T., Ott, M., van den Heuvel, L., Nijtmans, L.G., Huynen, M.A., 2014. A mutation in the human CBP4 ortholog UQCC3 impairs complex III assembly, activity and cytochrome b stability. Human Molecular Genetics 23, 6356-6365. https://www.ncbi.nlm.nih.gov/pubmed/25008109

[xv] Tiranti, V., Hoertnagel, K., Carrozzo, R., Galimberti, C., Munaro, M., Granatiero, M., Zelante, L., Gasparini, P., Marzella, R., Rocchi, M., Bayona-Bafaluy, M.P., Enriquez, J.A., Uziel, G., Bertini, E., Dionisi-Vici, C., Franco, B., Meitinger, T., Zeviani, M., 1998. Mutations of SURF-1 in Leigh Disease associated with cytochrome c oxidase deficiency. American Journal of Human Genetics 63, 1609-1621. http://www.ncbi.nlm.nih.gov/pubmed/9837813
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Santos-Cortez, R.L., Lee, K., Azeem, Z., Antonellis, P.J., Pollock, L.M., Khan, S., Irfanullah, Andrade-Elizondo, P.B., Chiu, I., Adams, M.D., Basit, S., Smith, J.D., University of Washington Center for Mendelian, G., Nickerson, D.A., McDermott, B.M., Jr., Ahmad, W., Leal, S.M., 2013. Mutations in KARS, encoding lysyl-tRNA synthetase, cause autosomal-recessive nonsyndromic hearing impairment DFNB89. American Journal of Human Genetics 93, 132-140. https://www.ncbi.nlm.nih.gov/pubmed/23768514

[lvii] Casey, J.P., McGettigan, P., Lynam-Lennon, N., McDermott, M., Regan, R., Conroy, J., Bourke, B., O'Sullivan, J., Crushell, E., Lynch, S., Ennis, S., 2012. Identification of a mutation in LARS as a novel cause of infantile hepatopathy. Molecular Genetics and Metabolism 106, 351-358. https://www.ncbi.nlm.nih.gov/pubmed/22607940

[lviii] Pierce, S.B., Gersak, K., Michaelson-Cohen, R., Walsh, T., Lee, M.K., Malach, D., Klevit, R.E., King, M.C., Levy-Lahad, E., 2013. Mutations in LARS2, encoding mitochondrial leucyl-tRNA synthetase, lead to premature ovarian failure and hearing loss in Perrault syndrome. American Journal of Human Genetics 92, 614-620. https://www.ncbi.nlm.nih.gov/pubmed/23541342

Sofou, K., Kollberg, G., Holmstrom, M., Davila, M., Darin, N., Gustafsson, C.M., Holme, E., Oldfors, A., Tulinius, M., Asin-Cayuela, J., 2015. Whole exome sequencing reveals mutations in NARS2 and PARS2, encoding the mitochondrial asparaginyl-tRNA synthetase and prolyl-tRNA synthetase, in patients with Alpers syndrome. Molecular Genetics and Genomic Medicine 3, 59-68. https://www.ncbi.nlm.nih.gov/pubmed/25629079

[lx] Ibid.

[lxi] Edvardson, S., Shaag, A., Kolesnikova, O., Gomori, J.M., Tarassov, I., Einbinder, T., Saada, A., Elpeleg, O., 2007. Deleterious mutation in the mitochondrial arginyl-transfer RNA synthetase gene is associated with pontocerebellar hypoplasia. American Journal of Human Genetics 81, 857-862. http://www.ncbi.nlm.nih.gov/pubmed/17847012

[lxii] Belostotsky, R., Ben-Shalom, E., Rinat, C., Becker-Cohen, R., Feinstein, S., Zeligson, S., Segel, R., Elpeleg, O., Nassar, S., Frishberg, Y., 2011. Mutations in the mitochondrial seryl-tRNA synthetase cause hyperuricemia, pulmonary hypertension, renal failure in infancy and alkalosis, HUPRA syndrome. American Journal of Human Genetics 88, 193-200. http://www.ncbi.nlm.nih.gov/pubmed/21255763

[lxiii] Diodato, D., Melchionda, L., Haack, T.B., Dallabona, C., Baruffini, E., Donnini, C., Granata, T., Ragona, F., Balestri, P., Margollicci, M., Lamantea, E., Nasca, A., Powell, C.A., Minczuk, M., Strom, T.M., Meitinger, T., Prokisch, H., Lamperti, C., Zeviani, M., Ghezzi, D., 2014. VARS2 and TARS2 mutations in patients with mitochondrial encephalomyopathies. Human Mutation 35, 983-989. https://www.ncbi.nlm.nih.gov/pubmed/24827421

[lxiv] Ibid.

[lxv] Riley, L.G., Cooper, S., Hickey, P., Rudinger-Thirion, J., McKenzie, M., Compton, A., Lim, S.C., Thorburn, D., Ryan, M.T., Giege, R., Bahlo, M., Christodoulou, J., 2010. Mutation of the mitochondrial tyrosyl-tRNA synthetase gene, YARS2, causes myopathy, lactic acidosis, and sideroblastic anemia--MLASA syndrome. American Journal of Human Genetics 87, 52-59. http://www.ncbi.nlm.nih.gov/pubmed/20598274

[lxvi] Coenen, M.J., Antonicka, H., Ugalde, C., Sasarman, F., Rossi, R., Heister, J.G., Newbold, R.F., Trijbels, F.J., van den Heuvel, L.P., Shoubridge, E.A., Smeitink, J.A., 2004. Mutant mitochondrial elongation factor G1 and combined oxidative phosphorylation deficiency. The New England Journal of Medicine 351, 2080-2086. http://www.ncbi.nlm.nih.gov/pubmed/15537906

[lxvii] Smeitink, J.A., Elpeleg, O., Antonicka, H., Diepstra, H., Saada, A., Smits, P., Sasarman, F., Vriend, G., Jacob-Hirsch, J., Shaag, A., Rechavi, G., Welling, B., Horst, J., Rodenburg, R.J., van den Heuvel, B., Shoubridge, E.A., 2006. Distinct clinical phenotypes associated with a mutation in the mitochondrial translation elongation factor EFTs. American Journal of Human Genetics 79, 869-877. http://www.ncbi.nlm.nih.gov/pubmed/17033963

[lxviii] Valente, L., Tiranti, V., Marsano, R.M., Malfatti, E., Fernandez-Vizarra, E., Donnini, C., Mereghetti, P., De Gioia, L., Burlina, A., Castellan, C., Comi, G.P., Savasta, S., Ferrero, I., Zeviani, M., 2007. Infantile encephalopathy and defective mitochondrial DNA translation in patients with mutations of mitochondrial elongation factors EFG1 and EFTu. American Journal of Human Genetics 80, 44-58. Erratum: Am. J. Hum. Genet. 80: 580, 2007. http://www.ncbi.nlm.nih.gov/pubmed/17160893

[lxix] Kopajtich, R., Nicholls, T.J., Rorbach, J., Metodiev, M.D., Freisinger, P., Mandel, H., Vanlander, A., Ghezzi, D., Carrozzo, R., Taylor, R.W., Marquard, K., Murayama, K., Wieland, T., Schwarzmayr, T., Mayr, J.A., Pearce, S.F., Powell, C.A., Saada, A., Ohtake, A., Invernizzi, F., Lamantea, E., Sommerville, E.W., Pyle, A., Chinnery, P.F., Crushell, E., Okazaki, Y., Kohda, M., Kishita, Y., Tokuzawa, Y., Assouline, Z., Rio, M., Feillet, F., Mousson de Camaret, B., Chretien, D., Munnich, A., Menten, B., Sante, T., Smet, J., Regal, L., Lorber, A., Khoury, A., Zeviani, M., Strom, T.M., Meitinger, T., Bertini, E.S., Van Coster, R., Klopstock, T., Rotig, A., Haack, T.B., Minczuk, M., Prokisch, H., 2014. Mutations in GTPBP3 cause a mitochondrial translation defect associated with hypertrophic cardiomyopathy, lactic acidosis, and encephalopathy. American Journal of Human Genetics 95, 708-720. https://www.ncbi.nlm.nih.gov/pubmed/25434004

[lxx] 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., Kuhn, K.A., Ahting, U., Sperl, W., Wilichowski, E., Hoffmann, G.F., Tesarova, M., Hansikova, H., Zeman, J., Plecko, B., Zeviani, M., Wittig, I., Strom, T.M., Schuelke, M., Freisinger, P., Meitinger, T., Prokisch, H., 2012. Molecular diagnosis in mitochondrial complex I deficiency using exome sequencing. Journal of Medical Genetics 49, 277-283. https://www.ncbi.nlm.nih.gov/pubmed/22499348

[lxxi] Ghezzi, D., Baruffini, E., Haack, T.B., Invernizzi, F., Melchionda, L., Dallabona, C., Strom, T.M., Parini, R., Burlina, A.B., Meitinger, T., Prokisch, H., Ferrero, I., Zeviani, M., 2012. Mutations of the mitochondrial-tRNA modifier MTO1 cause hypertrophic cardiomyopathy and lactic acidosis. American Journal of Human Genetics 90, 1079-1087. https://www.ncbi.nlm.nih.gov/pubmed/22608499

[lxxii] Powell, C.A., Kopajtich, R., D'Souza, A.R., Rorbach, J., Kremer, L.S., Husain, R.A., Dallabona, C., Donnini, C., Alston, C.L., Griffin, H., Pyle, A., Chinnery, P.F., Strom, T.M., Meitinger, T., Rodenburg, R.J., Schottmann, G., Schuelke, M., Romain, N., Haller, R.G., Ferrero, I., Haack, T.B., Taylor, R.W., Prokisch, H., Minczuk, M., 2015. TRMT5 mutations cause a defect in post-transcriptional modification of mitochondrial tRNA associated with multiple respiratory-chain deficiencies. American Journal of Human Genetics 97, 319-328. https://www.ncbi.nlm.nih.gov/pubmed/26189817

[lxxiii] Metodiev, M.D., Thompson, K., Alston, C.L., Morris, A.A.M., He, L., Assouline, Z., Rio, M., Bahi-Buisson, N., Pyle, A., Griffin, H., Siira, S., Filipovska, A., Munnich, A., Chinnery, P.F., McFarland, R., Rotig, A., Taylor, R.W., 2016. Recessive mutations in TRMT10C cause defects in mitochondrial RNA processing and multiple respiratory chain deficiencies. American Journal of Human Genetics 98, 993-1000. Erratum: Am. J. Hum. Genet. 1099: 246, 2016. https://www.ncbi.nlm.nih.gov/pubmed/27132592

[lxxiv] Zeharia, A., Shaag, A., Pappo, O., Mager-Heckel, A.M., Saada, A., Beinat, M., Karicheva, O., Mandel, H., Ofek, N., Segel, R., Marom, D., Rotig, A., Tarassov, I., Elpeleg, O., 2009. Acute infantile liver failure due to mutations in the TRMU gene. American Journal of Human Genetics 85, 401-407. https://www.ncbi.nlm.nih.gov/pubmed/19732863

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[lxxvi] Fukumura, S., Ohba, C., Watanabe, T., Minagawa, K., Shimura, M., Murayama, K., Ohtake, A., Saitsu, H., Matsumoto, N., Tsutsumi, H., 2015. Compound heterozygous GFM2 mutations with Leigh syndrome complicated by arthrogryposis multiplex congenita. Journal of Human Genetics 60, 509-513. https://www.ncbi.nlm.nih.gov/pubmed/26016410

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[lxxxv] Campuzano, V., Montermini, L., Molto, M.D., Pianese, L., Cossee, M., Cavalcanti, F., Monros, E., Rodius, F., Duclos, F., Monticelli, A., Zara, F., Canizares, J., Koutnikova, H., Bidichandani, S.I., Gellera, C., Brice, A., Trouillas, P., DeMichele, G., Filla, A., De Frutos, R., Palau, F., Patel, P., DiDonato, S., Mandel, J., Cocozza, S., Koenig, M., Pandolfo, M., 1996. Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science 271, 1423-1427. http://www.ncbi.nlm.nih.gov/pubmed/8596916
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[lxxxvi] Allikmets, R., Raskind, W.H., Hutchinson, A., Schueck, N.D., Dean, M., Koeller, D.M., 1999. Mutation of a putative mitochondrial iron transporter gene (ABC7) in X-linked sideroblastic anemia and ataxia (XLSA/A). Human Molecular Genetics 8, 743-749. http://www.ncbi.nlm.nih.gov/pubmed/10196363

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[lxxxviii] Mochel, F., Knight, M.A., Tong, W.H., Hernandez, D., Ayyad, K., Taivassalo, T., Andersen, P.M., Singleton, A., Rouault, T.A., Fischbeck, K.H., Haller, R.G., 2008. Splice mutation in the iron-sulfur cluster scaffold protein ISCU causes myopathy with exercise intolerance. American Journal of Human Genetics 82, 652-660. http://www.ncbi.nlm.nih.gov/pubmed/18304497

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[xc] Ibid.

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Topic revision: r2 - 17 Jan 2018, MarieLott
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