Abstract
The m.13513G>A transition in the mitochondrial gene encoding the ND5 subunit of respiratory chain complex I, can cause mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) and has been reported to be a frequent cause of Leigh syndrome (LS). We determined the frequency of the mutation in a cohort of 123 patients with reduced complex I activity in muscle (n=113) or fibroblast (n=10) tissue. We describe a Pyrosequencing™ assay for rapid detection and quantification of the m.13513G>A mutation. Two patients with the mutation were identified; both had LS, optical atrophy and a Wolff–Parkinson–White Syndrome (WPWS)-like cardiac conduction defect. The clinical presentation of the m.13513G>A mutation is discussed. We conclude that the m.13513G>A mutation seems not as frequent as previously suggested and is most likely to be present in patients with Leigh (-like) syndrome combined with a complex I deficiency, optic atrophy and/ or WPWS. In addition, we confirmed that the adjacent m.13514A>G mutation is a rare cause of LS or MELAS since no cases with this transition were found.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Smeitink J, van den Heuvel L, DiMauro S : The genetics and pathology of oxidative phosphorylation. Nat Rev Genet 2001; 2: 342–352.
Santorelli FM, Tanji K, Kulikova R, Shanske S, Vilarinho L, Hays AP, DiMauro S : Identification of a novel mutation in the mtDNA ND5 gene associated with MELAS. Biochem Biophys Res Commun 1997; 238: 326–328.
Penisson-Besnier I, Reynier P, Asfar P et al: Recurrent brain hematomas in MELAS associated with an ND5 gene mitochondrial mutation. Neurology 2000; 55: 317–318.
Corona P, Antozzi C, Carrara F et al: A novel mtDNA mutation in the ND5 subunit of complex I in two MELAS patients. Ann Neurol 2001; 49: 106–110.
Pulkes T, Eunson L, Patterson V et al: The mitochondrial DNA G13513A transition in ND5 is associated with a LHON/MELAS overlap syndrome and may be a frequent cause of MELAS. Ann Neurol 1999; 46: 916–919.
Chol M, Lebon S, Benit P et al: The mitochondrial DNA G13513A MELAS mutation in the NADH dehydrogenase 5 gene is a frequent cause of Leigh-like syndrome with isolated complex I deficiency. J Med Genet 2003; 40: 188–191.
Kirby DM, Boneh A, Chow CW et al: Low mutant load of mitochondrial DNA G13513A mutation can cause Leigh's disease. Ann Neurol 2003; 54: 473–478.
Petruzzella V, Di Giacinto G, Scacco S et al: Atypical Leigh syndrome associated with the D393N mutation in the mitochondrial ND5 subunit. Neurology 2003; 61: 1017–1018.
Sudo A, Honzawa S, Nonaka I, Goto Y : Leigh syndrome caused by mitochondrial DNA G13513A mutation: frequency and clinical features in Japan. J Hum Genet 2004; 49: 92–96.
Bugiani M, Invernizzi F, Alberio S et al: Clinical and molecular findings in children with complex I deficiency. Biochim Biophys Acta 2004; 1659 (2–3): 136–147.
Liolitsa D, Rahman S, Benton S, Carr LJ, Hanna MG : Is the mitochondrial complex I ND5 gene a hot-spot for MELAS causing mutations? Ann Neurol 2003; 53: 128–132.
Budde SM, van den Heuvel LP, Smeitink JA : The human complex I NDUFS4 subunit: from gene structure to function and pathology. Mitochondrion 2002; 2 (1–2): 109–115.
Bentlage HA, Wendel U, Schagger H, ter Laak HJ, Janssen AJ, Trijbels JM : Lethal infantile mitochondrial disease with isolated complex I deficiency in fibroblasts but with combined complex I and IV deficiencies in muscle. Neurology 1996; 47: 243–248.
Smeitink J, Sengers R, Trijbels F, van den Heuvel L : Human NADH: ubiquinone oxidoreductase. J Bioenerg Biomembr 2001; 33: 259–266.
Ronaghi M : Pyrosequencing sheds light on DNA sequencing. Genome Res 2001; 11: 3–11.
White HE, Durston VJ, Seller A, Fratter C, Harvey JF, Cross NC : Accurate detection and quantitation of heteroplasmic mitochondrial point mutations by pyrosequencing. Genet Test 2005; 9: 190–199.
Biggin A, Henke R, Bennetts B, Thorburn DR, Christodoulou J : mutation screening of the mitochondrial genome using denaturing high-performance liquid chromatography. Mol Genet Metab 2005; 84 (1): 61–74.
Lowik MM, Hol FA, Steenbergen EJ, Wetzels JF, van den Heuvel LP : Mitochondrial tRNALeu(UUR) mutation in a patient with steroid-resistant nephrotic syndrome and focal segmental glomerulosclerosis. Nephrol Dial Transplant 2005; 20 (2): 336–341.
Mashima Y, Kigasawa K, Hasegawa H, Tani M, Oguchi Y : High incidence of pre-excitation syndrome in Japanese families with Leber's hereditary optic neuropathy. Clin Genet 1996; 50: 535–537.
Nikoskelainen EK, Savontaus ML, Huoponen K, Antila K, Hartiala J : Pre-excitation syndrome in Leber's hereditary optic neuropathy. Lancet 1994; 344: 857–858.
Wilson FH, Hariri A, Farhi A et al: A cluster of metabolic defects caused by mutation in a mitochondrial tRNA. Science 2004; 306: 1190–1194.
Lebon S, Chol M, Benit P et al: Recurrent de novo mitochondrial DNA mutations in respiratory chain deficiency. J Med Genet 2003; 40: 896–899.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Ruiter, E., Siers, M., van den Elzen, C. et al. The mitochondrial 13513G>A mutation is most frequent in Leigh syndrome combined with reduced complex I activity, optic atrophy and/or Wolff–Parkinson–White. Eur J Hum Genet 15, 155–161 (2007). https://doi.org/10.1038/sj.ejhg.5201735
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/sj.ejhg.5201735
Keywords
This article is cited by
-
Induced pluripotent stem cells derived from patients carrying mitochondrial mutations exhibit altered bioenergetics and aberrant differentiation potential
Stem Cell Research & Therapy (2023)
-
Molecular basis of Leigh syndrome: a current look
Orphanet Journal of Rare Diseases (2020)
-
Multisystem mitochondrial diseases due to mutations in mtDNA-encoded subunits of complex I
BMC Pediatrics (2020)
-
Mitochondrial DNA 11777C>A Mutation Associated Leigh Syndrome: Case Report with a Review of the Previously Described Pedigrees
NeuroMolecular Medicine (2010)
-
Acquired mutations in TET2 are common in myelodysplastic syndromes
Nature Genetics (2009)
