Mechanisms of mitochondrial diseases

Figures & data

Figure 1. This figure shows human mtDNA represented by a circle. The positions of each of the protein-coding genes as well as the 12S and 16S rRNA genes and the tRNA genes are indicated. The OXPHOS system is shown above in simplified form. The protein-coding genes are color-coded according to the complex to which their product belongs. The non-coding D-loop region is also shown. The two strands of mtDNA are divided into a heavy strand and a light strand. The regions known as origins of heavy and light strand replication (O_H and O_L, respectively) are indicated, as are the transcription promoters for heavy and light strands (HSP and LSP, respectively). In mitochondrial energy conversion, acetyl-coenzyme A (CoA), which can be derived from pyruvate produced in cytoplasmic glycolysis or from mitochondrial fatty acid oxidation, conveys the carbon atoms of the acetyl group into the tricarboxylic acid (TCA) cycle. The enzymes of the TCA cycle oxidize these carbons and generate high-energy electrons that are transferred to the electron carriers nicotinamide adenine dinucleotide (NADH (reduced), NAD⁺ (oxidized)), or flavin adenine dinucleotide (FADH₂ (reduced), FAD (oxidized)). The OXPHOS system comprises five large enzyme complexes, labeled complex I-V. All OXPHOS complexes are embedded in the inner mitochondrial membrane (IMM). Complexes I–IV together constitute the respiratory chain (RC), which uses energy released during electron transfer to pump protons from the matrix into the inter-membrane space (IMS). Complex I (CI) is a NADH oxidase, and complex II (CII) is a succinate dehydrogenase. CII is also a TCA cycle enzyme that oxidizes succinate and uses FADH₂ as the electron carrier. It is the only RC complex that does not pump protons and that does not contain mtDNA-encoded subunits. Both CI and CII transfer electrons onward to the lipid-soluble electron carrier ubiquinone (coenzyme Q₁₀, CoQ₁₀, or Q (oxidized), QH₂ (reduced)) inside the IMM. QH₂ is oxidized by complex III (CIII), and electrons are transferred to cytochrome c (Cyt c), which is a water-soluble electron carrier in the IMS. Complex IV (CIV) catalyzes the final transfer of electrons to molecular oxygen to generate water. The combined action of the RC generates an electrochemical potential difference across the IMM. This is utilized by ATP synthase or complex V (CV) to catalyze the phosphorylation of ADP to ATP.

Table I. This table lists the common mitochondrial syndromes and the main organs that are affected in each case. The syndromes are grouped according to their typical molecular etiology. MELAS, MERRF, NARP, and LHON are caused by mtDNA point mutations. KSS, PS, and PEO are caused by single mtDNA deletions that are either sporadic or maternally inherited; ad/ar PEO, MDS, MNGIE, MIRAS, and AS are caused by defective mtDNA due to mutations in nuclear genes responsible for mtDNA maintenance. LS is typically caused by mutations in mitochondrial or nuclear genes encoding structural proteins or assembly factors of the OXPHOS complexes. The inheritance of LS may thus be maternal, autosomal, or X-linked. Adapted from reference (4).

Abbreviated name	Full name	Typical molecular etiology	Principal affected organs
MELAS	Mitochondrial encephalopathy, lactic acidosis, stroke-like episodes	Mutation in tRNA or protein-coding gene of mtDNA	Skeletal muscle, brain, heart, endocrine pancreas, ear, gut
MERRF	Myoclonus epilepsy with ragged-red fibers	Mutation in tRNA gene of mtDNA	Skeletal muscle, brain, heart
NARP	Neuropathy, ataxia, and retinitis pigmentosa	Mutation in protein-coding gene of mtDNA	Brain, eye
LHON	Leber's hereditary optic neuropathy	mutation in protein-coding gene of mtDNA	Eye, heart
KSS	Kearns–Sayre syndrome	Single mtDNA deletion	Skeletal muscle, brain, heart, eye
PS	Pearson's syndrome	Single mtDNA deletion	Bone-marrow, exocrine pancreas, skeletal muscle, brain
PEO	Progressive external ophthalmoplegia	Single mtDNA deletion	Skeletal muscle (especially extra-ocular), heart
ad/ar PEO	Autosomal-dominant/ recessive PEO	Multiple mtDNA deletions	Skeletal muscle (especially extra-ocular), heart
MDS	mtDNA depletion syndrome	mtDNA depletion	Skeletal muscle, brain, liver, kidney; typically tissue-specific
MNGIE	Mitochondrial neurogastrointestinal encephalopathy	mtDNA depletion, multiple mtDNA deletions and point mutations	Gut, skeletal muscle, brain, peripheral nerve
MIRAS^a	Mitochondrial recessive ataxia syndrome	mtDNA deletions and subtle depletion	Brain, peripheral nerve
AS	Alpers syndrome	mtDNA depletion	Brain, liver
LS	Leigh syndrome	Mutation in protein coding gene of mtDNA or nDNA	Brain, eye, skeletal muscle, peripheral nerve

^aMIRAS is also known as SCA-E (spinocerebellar ataxia with epilepsy) or SANDO (sensory ataxic neuropathy, dysarthria, and ophthalmoparesis).

ad = autosomal-dominant; ar = autosomal-recessive.

Table II. This table lists the disease-associated genes that encode either structural or assembly factors of the OXPHOS complexes. Note that structural proteins are encoded by either nDNA or mtDNA, whereas assembly factors, i.e. proteins needed to make the complex but that are not part of the final complex, are only encoded by nDNA.

Genetic defect		Genes	Major clinical manifestations	Reference
CI	mtDNA-encoded structural gene	ND1 ND2 ND3 ND4 ND4L ND5 ND6	LHON, MELAS, LS	(98)
	nDNA-encoded structural gene	NDUFS1 NDUFS2 NDUFS3 NDUFS4 NDUFS6 NDUFS7 NDUFS8 NDUFV1 NDUFV2 NDUFA1 NDUFA2 NDUFA11	LS, encephalopathy, cardiomyopathy	(20,123,124)
	nDNA-encoded assembly factor	NDUFAF1 NDUFAF2 C6orf66 C20orf7ACAD9 C80RF38	LS, cardioencephalomyopathy, infantile lactic acidosis
CII	nDNA-encoded structural gene	SDH-A SDH-B SDH-C SDH-D	LS, paraganglioma, pheochromocytoma	(123)
	nDNA-encoded assembly factor	SDHAF1 SDHAF2	Infantile leukoencephalopathy, paraganglioma	(125,126)
CIII	mtDNA-encoded structural gene	CYTB	LHON, encephalopathy, cardiomyopathy, myopathy	(31)
	nDNA-encoded structural gene	UQCRB UQCRQ	Hypoglycemia, lactic acidosis or psychomotor retardation with extrapyramidal signs	(31,127)
	nDNA-encoded assembly factor	BCS1L TTC19	Encephalopathy, liver failure, tubulopathy, GRACILE syndrome, Björnstad syndrome	(31,128)
CIV	mtDNA-encoded structural gene	COX1 COX2 COX3	Encephalopathy, myopathy, sideroblastic anemia, myoglobinuria, MELAS	(37)
	nDNA-encoded structural gene	COX6B1 COX4I2	Infantile encephalomyopathy, or exocrine pancreatic insufficiency and anemia	(37,129)
	nDNA-encoded assembly factor	SURF1 SCOl SC02 COX10 COX15 LRPPRC C2orf64	LS, French-Canadian LS, encephalopathy, cardiomyopathy, myopathy, liver failure, tubulopathy	(37,130)
CV	mtDNA-encoded structural gene	ATP6 ATP8	LS, NARP, cardiomyopathy	(98,131)
	nDNA-encoded structural gene	ATP5E	3-methylglutaconic aciduria, lactic acidosis, mild mental retardation, peripheral neuropathy	(48)
	nDNA-encoded assembly factor	ATP12 TMEM70	Encephalopathy, lactic acidosis, cardioencephalomyopathy	(47,132)

Table III. The genes listed in this table encode proteins that are essential for mtDNA maintenance. Mutations in these genes cause mtDNA disease through different mechanisms, as indicated.

Gene	Gene product and its function	Molecular consequence	Clinical consequence	Ref
mtDNA replication:
POLG	Pol γ A, the catalytic subunit of the mtDNA polymerase	MultiplemtDNA deletions mtDNA depletion	ad/arPEOAlpers-type MDS or MIRAS	(56)(55)
POLG2	Pol γ B, the accessory subunit of the mtDNA polymerase	Multiple mtDNA deletions	ad PEO	(58)
C10Orf2	Twinkle, the replicativemtDNA helicase	Multiple mtDNA deletionsmtDNA depletion	adPEOHepatocerebral MDS or IOSCA	(60)(61)
dNTP pool maintenance:
DGUOK	dGK, intramitochondrial salvage of purine nucleosides	mtDNA depletion	Hepatocerebral MDS	(71)
TK2	TK2, intramitochondrial salvage of pyrimidine nucleosides	mtDNA depletion	Myopathic MDS	(72)
TYMP	TP, cytoplasmic breakdown of thymidine nucleosides	mtDNA depletion, deletions, and point mutations	MNGIE	(76)
RRM2B	p53R2, constitutively expressed small subunit of ribonucleotide reductase	mtDNA depletion or mtDNA deletions	Multi-system MDS or adPEO	(73,74)
SLC25A4	ANT1, adenine nucleotide translocator in the IMM	Multiple mtDNA deletions	adPEO	(133)
SUCLG1 SUCLA2	Subunits of succinyl CoA synthetase, citric acid cycle and nucleoside salvage	mtDNA depletion and succinyl-CoA accumulation	Encephalomyopathy	(134,135)
Other or unknown:
OPA1	Protein required for IMM fusion	Multiple mtDNA deletions	adPEO	(136)
MPV17	IMM protein of unknown function	mtDNA depletion	Hepatic MDS	(137)

ad = autosomal-dominant; ar = autosomal-recessive; PEO = progressive external ophthalmoplegia; MDS = mtDNA depletion syndrome; MIRAS = mitochondrial recessive ataxia syndrome; IOSCA = infantile-onset spinocerebellar ataxia; MNGIE = mitochondrial neurogastrointestinal encephalopathy; IMM = inner mitochondrial membrane.

Table IV. Nuclear-encoded mitochondrial translation factors involved in disease.

Function	Gene/protein	Affected tissue	Reference
tRNA modification	PUS1	Skeletal muscle, bone-marrow	(82)
	TRMU	Liver, ear	(84,85)
Elongation factor	GFMl/mtEFG1	Brain, liver	(88)
	TUFW/mtEFTu	Brain	(89)
	TSFM/mtEFTs	Heart or skeletal muscle and brain	(91)
Ribosomal protein	MRPS16	Brain	(86)
	MRPS22	Heart, kidney	(87)
Aminoacyl-tRNA synthetase	RARS2	Brain	(92)
	DARS2	Brain	(93)
	YARS2	Skeletal muscle, bone-marrow	(94)
	SASR2	Kidney, pulmonary circulation	(95)
	HARS2	Ovary, ear	(97)
	AARS2	Heart	(96)
Peptide release factor	C12orf65	Skeletal muscle, brain	(138)

Table V. Disease-associated genes invloved in the biosynthesis of coenzyme Q (CoQ₁₀). Derived from reference (108).

Gene	Protein function/disease mechanism	Phenotype
ADCK3/CABC1	Encodes a putative mitochondrial kinase involved in the regulation of CoQ10 biosynthesis	Encephalomyopathy, juvenile-onset cerebellar ataxia
APTX	Encodes aprataxin, which is involved in DNA repair. Secondary CoQ10 deficiency	Ataxia-oculomotor apraxia 1
COQ2	Encodes para-hydroxybenzoate-polyprenyl transferase, direct role in CoQ10 synthesis	Infantile-onset multi-system syndrome or renal disease
PDSS2	Polyprenyl diphosphate synthase, direct role in CoQ10 biosynthesis	Nephrotic syndrome and LS
PDSS1	Polyprenyl diphosphate synthase, direct role in CoQ10 biosynthesis	Infantile-onset multi-system syndrome
COQ9	Direct role in CoQ10 biosynthesis	Infantile-onset multi-system syndrome
ETFDH	Encodes electron-transferring-flavoprotein dehydrogenase. Also associated with glutaric aciduria type II in which CoQ10 levels in muscle are normal	Myopathy
BRAF	Involved in mitogen-activated protein kinase pathway, CoQ10 deficiency by indirect mechanism	Cardiofaciocutaneous syndrome

McFarland R, Taylor RW, Turnbull DM. The neurology of mitochondrial DNA disease. Lancet Neurol. 2002;1:343–51.

 PubMed Web of Science ®Google Scholar

DiMauro S, Davidzon G. Mitochondrial DNA and disease. Ann Med. 2005;37:222–32.

 PubMed Web of Science ®Google Scholar

Distelmaier F, Koopman WJ, van den Heuvel LP, Rodenburg RJ, Mayatepek E, Willems PH, . Mitochondrial complex I deficiency: from organelle dysfunction to clinical disease. Brain. 2009;132(Pt 4):833–42.

 PubMedGoogle Scholar

Zhu X, Peng X, Guan MX, Yan Q. Pathogenic mutations of nuclear genes associated with mitochondrial disorders. Acta Biochim Biophys Sin (Shanghai). 2009;41:179–87.

 PubMedGoogle Scholar

Haack TB, Danhauser K, Haberberger B, Hoser J, Strecker V, Boehm D, . Exome sequencing identifies ACAD9 mutations as a cause of complex I deficiency. Nat Genet. 2010;42:1131–4.

 PubMed Web of Science ®Google Scholar

Ghezzi D, Goffrini P, Uziel G, Horvath R, Klopstock T, Lochmuller H, . SDHAF1, encoding a LYR complex-II specific assembly factor, is mutated in SDH-defective infantile leukoencephalopathy. Nat Genet. 2009;41:654–6.

 PubMed Web of Science ®Google Scholar

Hao HX, Khalimonchuk O, Schraders M, Dephoure N, Bayley JP, Kunst H, . SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma. Science. 2009;325:1139–42.

 PubMed Web of Science ®Google Scholar

Benit P, Lebon S, Rustin P. Respiratory-chain diseases related to complex III deficiency. Biochim Biophys Acta. 2009;1793:181–5.

 PubMedGoogle Scholar

Barel O, Shorer Z, Flusser H, Ofir R, Narkis G, Finer G, . Mitochondrial complex III deficiency associated with a homozygous mutation in UQCRQ. Am J Hum Genet. 2008;82:1211–6.

 PubMedGoogle Scholar

Ghezzi D, Arzuffi P, Zordan M, Da Re C, Lamperti C, Benna C, . Mutations in TTC19 cause mitochondrial complex III deficiency and neurological impairment in humans and flies. Nat Genet. 2011;43:259–63.

 PubMed Web of Science ®Google Scholar

Diaz F. Cytochrome c oxidase deficiency: patients and animal models. Biochim Biophys Acta. 2010;1802:100–10.

 PubMedGoogle Scholar

Shteyer E, Saada A, Shaag A, Al-Hijawi FA, Kidess R, Revel-Vilk S, . Exocrine pancreatic insufficiency, dyserythropoeitic anemia, and calvarial hyperostosis are caused by a mutation in the COX4I2 gene. Am J Hum Genet. 2009;84:412–7.

 PubMed Web of Science ®Google Scholar

Huigsloot M, Nijtmans LG, Szklarczyk R, Baars MJ, van den Brand MA, Hendriksfranssen MG, . A mutation in c2orf64 causes impaired cytochrome C oxidase assembly and mitochondrial cardiomyopathy. Am J Hum Genet. 2011;88:488–93.

 PubMedGoogle Scholar

Jonckheere AI, Hogeveen M, Nijtmans LG, van den Brand MA, Janssen AJ, Diepstra JH, . A novel mitochondrial ATP8 gene mutation in a patient with apical hypertrophic cardiomyopathy and neuropathy. J Med Genet. 2008;45:129–33.

 PubMed Web of Science ®Google Scholar

Mayr JA, Havlickova V, Zimmermann F, Magler I, Kaplanova V, Jesina P, . Mitochondrial ATP synthase deficiency due to a mutation in the ATP5E gene for the F1 epsilon subunit. Hum Mol Genet. 2010;19:3430–9.

 PubMedGoogle Scholar

De Meirleir L, Seneca S, Lissens W, De Clercq I, Eyskens F, Gerlo E, . Respiratory chain complex V deficiency due to a mutation in the assembly gene ATP12. J Med Genet. 2004;41:120–4.

 PubMedGoogle Scholar

Cizkova A, Stranecky V, Mayr JA, Tesarova M, Havlickova V, Paul J, . TMEM70 mutations cause isolated ATP synthase deficiency and neonatal mitochondrial encephalocardiomyopathy. Nat Genet. 2008;40:1288–90.

 PubMed Web of Science ®Google Scholar

Van Goethem G, Dermaut B, Lofgren A, Martin JJ, Van Broeckhoven C. Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions. Nat Genet. 2001;28:211–2.

 PubMed Web of Science ®Google Scholar

Hakonen AH, Heiskanen S, Juvonen V, Lappalainen I, Luoma PT, Rantamaki M, . Mitochondrial DNA polymerase W748S mutation: a common cause of autosomal recessive ataxia with ancient European origin. Am J Hum Genet. 2005;77:430–41.

 PubMed Web of Science ®Google Scholar

Longley MJ, Clark S, Yu Wai Man C, Hudson G, Durham SE, Taylor RW, . Mutant POLG2 disrupts DNA polymerase gamma subunits and causes progressive external ophthalmoplegia. Am J Hum Genet. 2006;78:1026–34.

 PubMed Web of Science ®Google Scholar

Spelbrink JN, Li FY, Tiranti V, Nikali K, Yuan QP, Tariq M, . Human mitochondrial DNA deletions associated with mutations in the gene encoding Twinkle, a phage T7 gene 4-like protein localized in mitochondria. Nat Genet. 2001;28:223–31.

 PubMed Web of Science ®Google Scholar

Hakonen AH, Isohanni P, Paetau A, Herva R, Suomalainen A, Lonnqvist T. Recessive Twinkle mutations in early onset encephalopathy with mtDNA depletion. Brain. 2007;130(Pt 11):3032–40.

 PubMedGoogle Scholar

Mandel H, Szargel R, Labay V, Elpeleg O, Saada A, Shalata A, . The deoxyguanosine kinase gene is mutated in individuals with depleted hepatocerebral mitochondrial DNA. Nat Genet. 2001;29:337–41.

 PubMed Web of Science ®Google Scholar

Saada A, Shaag A, Mandel H, Nevo Y, Eriksson S, Elpeleg O. Mutant mitochondrial thymidine kinase in mitochondrial DNA depletion myopathy. Nat Genet. 2001;29:342–4.

 PubMed Web of Science ®Google Scholar

Nishino I, Spinazzola A, Hirano M. Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder. Science. 1999;283:689–92.

 PubMed Web of Science ®Google Scholar

Bourdon A, Minai L, Serre V, Jais JP, Sarzi E, Aubert S, . Mutation of RRM2B, encoding p53-controlled ribonucleotide reductase (p53R2), causes severe mitochondrial DNA depletion. Nat Genet. 2007;39:776–80.

 PubMed Web of Science ®Google Scholar

Tyynismaa H, Ylikallio E, Patel M, Molnar MJ, Haller RG, Suomalainen A. A heterozygous truncating mutation in RRM2B causes autosomal-dominant progressive external ophthalmoplegia with multiple mtDNA deletions. Am J Hum Genet. 2009;85:290–5.

 PubMedGoogle Scholar

Kaukonen J, Juselius JK, Tiranti V, Kyttala A, Zeviani M, Comi GP, . Role of adenine nucleotide translocator 1 in mtDNA maintenance. Science. 2000;289:782–5.

 PubMed Web of Science ®Google Scholar

Elpeleg O, Miller C, Hershkovitz E, Bitner-Glindzicz M, Bondi-Rubinstein G, Rahman S, . Deficiency of the ADP-forming succinyl-CoA synthase activity is associated with encephalomyopathy and mitochondrial DNA depletion. Am J Hum Genet. 2005;76:1081–6.

 PubMed Web of Science ®Google Scholar

Ostergaard E, Christensen E, Kristensen E, Mogensen B, Duno M, Shoubridge EA, . Deficiency of the alpha subunit of succinate-coenzyme A ligase causes fatal infantile lactic acidosis with mitochondrial DNA depletion. Am J Hum Genet. 2007;81:383–7.

 PubMed Web of Science ®Google Scholar

Amati-Bonneau P, Valentino ML, Reynier P, Gallardo ME, Bornstein B, Boissiere A, . OPA1 mutations induce mitochondrial DNA instability and optic atrophy ‘plus’ phenotypes. Brain. 2008;131(Pt 2):338–51.

 PubMedGoogle Scholar

Spinazzola A, Viscomi C, Fernandez-Vizarra E, Carrara F, D'Adamo P, Calvo S, . MPV17 encodes an inner mitochondrial membrane protein and is mutated in infantile hepatic mitochondrial DNA depletion. Nat Genet. 2006;38: 570–5.

 PubMed Web of Science ®Google Scholar

Bykhovskaya Y, Casas K, Mengesha E, Inbal A, Fischel-Ghodsian N. Missense mutation in pseudouridine synthase 1 (PUS1) causes mitochondrial myopathy and sideroblastic anemia (MLASA). Am J Hum Genet. 2004;74:1303–8.

 PubMed Web of Science ®Google Scholar

Zeharia A, Shaag A, Pappo O, Mager-Heckel AM, Saada A, Beinat M, . Acute infantile liver failure due to mutations in the TRMU gene. Am J Hum Genet. 2009;85:401–7.

 PubMed Web of Science ®Google Scholar

Guan MX, Yan Q, Li X, Bykhovskaya Y, Gallo-Teran J, Hajek P, . Mutation in TRMU related to transfer RNA modification modulates the phenotypic expression of the deafness-associated mitochondrial 12S ribosomal RNA mutations. Am J Hum Genet. 2006;79:291–302.

 PubMed Web of Science ®Google Scholar

Coenen MJ, Antonicka H, Ugalde C, Sasarman F, Rossi R, Heister JG, . Mutant mitochondrial elongation factor G1 and combined oxidative phosphorylation deficiency. N Engl J Med. 2004;351:2080–6.

 PubMedGoogle Scholar

Valente L, Tiranti V, Marsano RM, Malfatti E, Fernandez-Vizarra E, Donnini C, . Infantile encephalopathy and defective mitochondrial DNA translation in patients with mutations of mitochondrial elongation factors EFG1 and EFTu. Am J Hum Genet. 2007;80:44–58.

 PubMed Web of Science ®Google Scholar

Smeitink JA, Elpeleg O, Antonicka H, Diepstra H, Saada A, Smits P, . Distinct clinical phenotypes associated with a mutation in the mitochondrial translation elongation factor EFTs. Am J Hum Genet. 2006;79:869–77.

 PubMed Web of Science ®Google Scholar

Miller C, Saada A, Shaul N, Shabtai N, Ben-Shalom E, Shaag A, . Defective mitochondrial translation caused by a ribosomal protein (MRPS16) mutation. Ann Neurol. 2004;56:734–8.

 PubMed Web of Science ®Google Scholar

Saada A, Shaag A, Arnon S, Dolfin T, Miller C, Fuchs-Telem D, . Antenatal mitochondrial disease caused by mitochondrial ribosomal protein (MRPS22) mutation. J Med Genet. 2007;44:784–6.

 PubMedGoogle Scholar

Edvardson S, Shaag A, Kolesnikova O, Gomori JM, Tarassov I, Einbinder T, . Deleterious mutation in the mitochondrial arginyl-transfer RNA synthetase gene is associated with pontocerebellar hypoplasia. Am J Hum Genet. 2007;81: 857–62.

 PubMed Web of Science ®Google Scholar

Scheper GC, van der Klok T, van Andel RJ, van Berkel CG, Sissler M, Smet J, . Mitochondrial aspartyl-tRNA synthetase deficiency causes leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation. Nat Genet. 2007;39:534–9.

 PubMed Web of Science ®Google Scholar

Riley LG, Cooper S, Hickey P, Rudinger-Thirion J, McKenzie M, Compton A, . Mutation of the mitochondrial tyrosyl-tRNA synthetase gene, YARS2, causes myopathy, lactic acidosis, and sideroblastic anemia—MLASA syndrome. Am J Hum Genet. 2010;87:52–9.

 PubMed Web of Science ®Google Scholar

Belostotsky R, Ben-Shalom E, Rinat C, Becker-Cohen R, Feinstein S, Zeligson S, . Mutations in the mitochondrial seryl-tRNA synthetase cause hyperuricemia, pulmonary hypertension, renal failure in infancy and alkalosis, HUPRA syndrome. Am J Hum Genet. 2011;88:193–200.

 Google Scholar

Pierce SB, Chisholm KM, Lynch ED, Lee MK, Walsh T, Opitz JM, . Mutations in mitochondrial histidyl tRNA synthetase HARS2 cause ovarian dysgenesis and sensorineural hearing loss of Perrault syndrome. Proc Natl Acad Sci U S A. 2011;108:6543–8.

 PubMed Web of Science ®Google Scholar

Gotz A, Tyynismaa H, Euro L, Ellonen P, Hyotylainen T, Ojala T, . Exome sequencing identifies mitochondrial alanyl-tRNA synthetase mutations in infantile mitochondrial cardiomyopathy. Am J Hum Genet. 2011;88:635–42.

 PubMed Web of Science ®Google Scholar

Antonicka H, Ostergaard E, Sasarman F, Weraarpachai W, Wibrand F, Pedersen AM, . Mutations in C12orf65 in patients with encephalomyopathy and a mitochondrial translation defect. Am J Hum Genet. 2010;87:115–22.

 PubMed Web of Science ®Google Scholar