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. 1996 Apr;58(4):703–711.

Genetic and biochemical impairment of mitochondrial complex I activity in a family with Leber hereditary optic neuropathy and hereditary spastic dystonia.

D D De Vries 1, L N Went 1, G W Bruyn 1, H R Scholte 1, R M Hofstra 1, P A Bolhuis 1, B A van Oost 1
PMCID: PMC1914692  PMID: 8644732

Abstract

A rare form of Leber hereditary optic neuropathy (LHON) that is associated with hereditary spastic dystonia has been studied in a large Dutch family. Neuropathy and ophthalmological lesions were present together in some family members, whereas only one type of abnormality was found in others. mtDNA mutations previously reported in LHON were not present. Sequence analysis of the protein-coding mitochondrial genes revealed two previously unreported mtDNA mutations. A heteroplasmic A-->G transition at nucleotide position 11696 in the ND4 gene resulted in the substitution of an isoleucine for valine at amino acid position 312. A second mutation, a homoplasmic T-->A transition at nucleotide position 14596 in the ND6 gene, resulted in the substitution of a methionine for the isoleucine at amino acid residue 26. Biochemical analysis of a muscle biopsy revealed a severe complex I deficiency, providing a link between these unique mtDNA mutations and this rare, complex phenotype including Leber optic neuropathy.

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Selected References

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  1. Anderson S., Bankier A. T., Barrell B. G., de Bruijn M. H., Coulson A. R., Drouin J., Eperon I. C., Nierlich D. P., Roe B. A., Sanger F. Sequence and organization of the human mitochondrial genome. Nature. 1981 Apr 9;290(5806):457–465. doi: 10.1038/290457a0. [DOI] [PubMed] [Google Scholar]
  2. Anderson S., de Bruijn M. H., Coulson A. R., Eperon I. C., Sanger F., Young I. G. Complete sequence of bovine mitochondrial DNA. Conserved features of the mammalian mitochondrial genome. J Mol Biol. 1982 Apr 25;156(4):683–717. doi: 10.1016/0022-2836(82)90137-1. [DOI] [PubMed] [Google Scholar]
  3. Arnason U., Gullberg A., Widegren B. The complete nucleotide sequence of the mitochondrial DNA of the fin whale, Balaenoptera physalus. J Mol Evol. 1991 Dec;33(6):556–568. doi: 10.1007/BF02102808. [DOI] [PubMed] [Google Scholar]
  4. Arnason U., Johnsson E. The complete mitochondrial DNA sequence of the harbor seal, Phoca vitulina. J Mol Evol. 1992 Jun;34(6):493–505. doi: 10.1007/BF00160463. [DOI] [PubMed] [Google Scholar]
  5. BRUYN G. W., WENT L. N. A SEX-LINKED HEREDO-DEGENERATIVE NEUROLOGICAL DISORDER, ASSOCIATED WITH LEBER'S OPTIC ATROPHY. I. CLINICAL STUDIES. J Neurol Sci. 1964 Jan-Feb;1(1):59–80. doi: 10.1016/0022-510x(64)90054-1. [DOI] [PubMed] [Google Scholar]
  6. Benecke R., Strümper P., Weiss H. Electron transfer complex I defect in idiopathic dystonia. Ann Neurol. 1992 Nov;32(5):683–686. doi: 10.1002/ana.410320512. [DOI] [PubMed] [Google Scholar]
  7. Bibb M. J., Van Etten R. A., Wright C. T., Walberg M. W., Clayton D. A. Sequence and gene organization of mouse mitochondrial DNA. Cell. 1981 Oct;26(2 Pt 2):167–180. doi: 10.1016/0092-8674(81)90300-7. [DOI] [PubMed] [Google Scholar]
  8. Birky C. W., Jr, Fuerst P., Maruyama T. Organelle gene diversity under migration, mutation, and drift: equilibrium expectations, approach to equilibrium, effects of heteroplasmic cells, and comparison to nuclear genes. Genetics. 1989 Mar;121(3):613–627. doi: 10.1093/genetics/121.3.613. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Bolhuis P. A., Bleeker-Wagemakers E. M., Ponne N. J., Van Schooneveld M. J., Westerveld A., Van den Bogert C., Tabak H. F. Rapid shift in genotype of human mitochondrial DNA in a family with Leber's hereditary optic neuropathy. Biochem Biophys Res Commun. 1990 Aug 16;170(3):994–997. doi: 10.1016/0006-291x(90)90490-e. [DOI] [PubMed] [Google Scholar]
  10. Brown M. D., Voljavec A. S., Lott M. T., MacDonald I., Wallace D. C. Leber's hereditary optic neuropathy: a model for mitochondrial neurodegenerative diseases. FASEB J. 1992 Jul;6(10):2791–2799. doi: 10.1096/fasebj.6.10.1634041. [DOI] [PubMed] [Google Scholar]
  11. Brown M. D., Voljavec A. S., Lott M. T., Torroni A., Yang C. C., Wallace D. C. Mitochondrial DNA complex I and III mutations associated with Leber's hereditary optic neuropathy. Genetics. 1992 Jan;130(1):163–173. doi: 10.1093/genetics/130.1.163. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Brown M. D., Yang C. C., Trounce I., Torroni A., Lott M. T., Wallace D. C. A mitochondrial DNA variant, identified in Leber hereditary optic neuropathy patients, which extends the amino acid sequence of cytochrome c oxidase subunit I. Am J Hum Genet. 1992 Aug;51(2):378–385. [PMC free article] [PubMed] [Google Scholar]
  13. Bruyn G. W., Bots G. T., Went L. N., Klinkhamer P. J. Hereditary spastic dystonia with Leber's hereditary optic neuropathy: neuropathological findings. J Neurol Sci. 1992 Nov;113(1):55–61. doi: 10.1016/0022-510x(92)90265-m. [DOI] [PubMed] [Google Scholar]
  14. Bruyn G. W., Vielvoye G. J., Went L. N. Hereditary spastic dystonia: a new mitochondrial encephalopathy? Putaminal necrosis as a diagnostic sign. J Neurol Sci. 1991 Jun;103(2):195–202. doi: 10.1016/0022-510x(91)90164-3. [DOI] [PubMed] [Google Scholar]
  15. Clary D. O., Wolstenholme D. R. The mitochondrial DNA molecular of Drosophila yakuba: nucleotide sequence, gene organization, and genetic code. J Mol Evol. 1985;22(3):252–271. doi: 10.1007/BF02099755. [DOI] [PubMed] [Google Scholar]
  16. Cornelissen J. C., Wanders R. J., Bolhuis P. A., Bleeker-Wagemakers E., Oostra R. J., Wijburg F. A. Respiratory chain function in Leber's hereditary optic neuropathy: lack of correlation with clinical disease. J Inherit Metab Dis. 1993;16(3):531–533. doi: 10.1007/BF00711673. [DOI] [PubMed] [Google Scholar]
  17. Degli Esposti M., Carelli V., Ghelli A., Ratta M., Crimi M., Sangiorgi S., Montagna P., Lenaz G., Lugaresi E., Cortelli P. Functional alterations of the mitochondrially encoded ND4 subunit associated with Leber's hereditary optic neuropathy. FEBS Lett. 1994 Oct 3;352(3):375–379. doi: 10.1016/0014-5793(94)00971-6. [DOI] [PubMed] [Google Scholar]
  18. Desjardins P., Morais R. Sequence and gene organization of the chicken mitochondrial genome. A novel gene order in higher vertebrates. J Mol Biol. 1990 Apr 20;212(4):599–634. doi: 10.1016/0022-2836(90)90225-B. [DOI] [PubMed] [Google Scholar]
  19. Fearnley I. M., Walker J. E. Conservation of sequences of subunits of mitochondrial complex I and their relationships with other proteins. Biochim Biophys Acta. 1992 Dec 7;1140(2):105–134. doi: 10.1016/0005-2728(92)90001-i. [DOI] [PubMed] [Google Scholar]
  20. Funakawa I., Kato H., Terao A., Ichihashi K., Kawashima S., Hayashi T., Mitani K., Miyazaki S. Cerebellar ataxia in patients with Leber's hereditary optic neuropathy. J Neurol. 1995 Jan;242(2):75–77. doi: 10.1007/BF00887819. [DOI] [PubMed] [Google Scholar]
  21. Gadaleta G., Pepe G., De Candia G., Quagliariello C., Sbisà E., Saccone C. The complete nucleotide sequence of the Rattus norvegicus mitochondrial genome: cryptic signals revealed by comparative analysis between vertebrates. J Mol Evol. 1989 Jun;28(6):497–516. doi: 10.1007/BF02602930. [DOI] [PubMed] [Google Scholar]
  22. Goto Y., Nonaka I., Horai S. A mutation in the tRNA(Leu)(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature. 1990 Dec 13;348(6302):651–653. doi: 10.1038/348651a0. [DOI] [PubMed] [Google Scholar]
  23. Holt I. J., Miller D. H., Harding A. E. Genetic heterogeneity and mitochondrial DNA heteroplasmy in Leber's hereditary optic neuropathy. J Med Genet. 1989 Dec;26(12):739–743. doi: 10.1136/jmg.26.12.739. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Howell N., Bindoff L. A., McCullough D. A., Kubacka I., Poulton J., Mackey D., Taylor L., Turnbull D. M. Leber hereditary optic neuropathy: identification of the same mitochondrial ND1 mutation in six pedigrees. Am J Hum Genet. 1991 Nov;49(5):939–950. [PMC free article] [PubMed] [Google Scholar]
  25. Howell N., Halvorson S., Kubacka I., McCullough D. A., Bindoff L. A., Turnbull D. M. Mitochondrial gene segregation in mammals: is the bottleneck always narrow? Hum Genet. 1992 Sep-Oct;90(1-2):117–120. doi: 10.1007/BF00210753. [DOI] [PubMed] [Google Scholar]
  26. Howell N., Kubacka I., Xu M., McCullough D. A. Leber hereditary optic neuropathy: involvement of the mitochondrial ND1 gene and evidence for an intragenic suppressor mutation. Am J Hum Genet. 1991 May;48(5):935–942. [PMC free article] [PubMed] [Google Scholar]
  27. Huoponen K., Vilkki J., Aula P., Nikoskelainen E. K., Savontaus M. L. A new mtDNA mutation associated with Leber hereditary optic neuroretinopathy. Am J Hum Genet. 1991 Jun;48(6):1147–1153. [PMC free article] [PubMed] [Google Scholar]
  28. Jacobs H. T., Elliott D. J., Math V. B., Farquharson A. Nucleotide sequence and gene organization of sea urchin mitochondrial DNA. J Mol Biol. 1988 Jul 20;202(2):185–217. doi: 10.1016/0022-2836(88)90452-4. [DOI] [PubMed] [Google Scholar]
  29. Johns D. R., Berman J. Alternative, simultaneous complex I mitochondrial DNA mutations in Leber's hereditary optic neuropathy. Biochem Biophys Res Commun. 1991 Feb 14;174(3):1324–1330. doi: 10.1016/0006-291x(91)91567-v. [DOI] [PubMed] [Google Scholar]
  30. Johns D. R., Heher K. L., Miller N. R., Smith K. H. Leber's hereditary optic neuropathy. Clinical manifestations of the 14484 mutation. Arch Ophthalmol. 1993 Apr;111(4):495–498. doi: 10.1001/archopht.1993.01090040087038. [DOI] [PubMed] [Google Scholar]
  31. Johns D. R., Neufeld M. J. Cytochrome b mutations in Leber hereditary optic neuropathy. Biochem Biophys Res Commun. 1991 Dec 31;181(3):1358–1364. doi: 10.1016/0006-291x(91)92088-2. [DOI] [PubMed] [Google Scholar]
  32. Johns D. R., Neufeld M. J., Park R. D. An ND-6 mitochondrial DNA mutation associated with Leber hereditary optic neuropathy. Biochem Biophys Res Commun. 1992 Sep 30;187(3):1551–1557. doi: 10.1016/0006-291x(92)90479-5. [DOI] [PubMed] [Google Scholar]
  33. Jun A. S., Brown M. D., Wallace D. C. A mitochondrial DNA mutation at nucleotide pair 14459 of the NADH dehydrogenase subunit 6 gene associated with maternally inherited Leber hereditary optic neuropathy and dystonia. Proc Natl Acad Sci U S A. 1994 Jun 21;91(13):6206–6210. doi: 10.1073/pnas.91.13.6206. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. King M. P., Attardi G. Human cells lacking mtDNA: repopulation with exogenous mitochondria by complementation. Science. 1989 Oct 27;246(4929):500–503. doi: 10.1126/science.2814477. [DOI] [PubMed] [Google Scholar]
  35. Koehler C. M., Lindberg G. L., Brown D. R., Beitz D. C., Freeman A. E., Mayfield J. E., Myers A. M. Replacement of bovine mitochondrial DNA by a sequence variant within one generation. Genetics. 1991 Sep;129(1):247–255. doi: 10.1093/genetics/129.1.247. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Kohchi T., Shirai H., Fukuzawa H., Sano T., Komano T., Umesono K., Inokuchi H., Ozeki H., Ohyama K. Structure and organization of Marchantia polymorpha chloroplast genome. IV. Inverted repeat and small single copy regions. J Mol Biol. 1988 Sep 20;203(2):353–372. doi: 10.1016/0022-2836(88)90004-6. [DOI] [PubMed] [Google Scholar]
  37. Kuppuswamy M. N., Hoffmann J. W., Kasper C. K., Spitzer S. G., Groce S. L., Bajaj S. P. Single nucleotide primer extension to detect genetic diseases: experimental application to hemophilia B (factor IX) and cystic fibrosis genes. Proc Natl Acad Sci U S A. 1991 Feb 15;88(4):1143–1147. doi: 10.1073/pnas.88.4.1143. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Lamminen T., Majander A., Juvonen V., Wikström M., Aula P., Nikoskelainen E., Savontous M. L. A mitochondrial mutation at nt 9101 in the ATP synthase 6 gene associated with deficient oxidative phosphorylation in a family with Leber hereditary optic neuroretinopathy. Am J Hum Genet. 1995 May;56(5):1238–1240. [PMC free article] [PubMed] [Google Scholar]
  39. Larsson N. G., Andersen O., Holme E., Oldfors A., Wahlström J. Leber's hereditary optic neuropathy and complex I deficiency in muscle. Ann Neurol. 1991 Nov;30(5):701–708. doi: 10.1002/ana.410300511. [DOI] [PubMed] [Google Scholar]
  40. Lee W. J., Kocher T. D. Complete sequence of a sea lamprey (Petromyzon marinus) mitochondrial genome: early establishment of the vertebrate genome organization. Genetics. 1995 Feb;139(2):873–887. doi: 10.1093/genetics/139.2.873. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Lertrit P., Kapsa R. M., Jean-Francois M. J., Thyagarajan D., Noer A. S., Marzuki S., Byrne E. Mitochondrial DNA polymorphism in disease: a possible contributor to respiratory dysfunction. Hum Mol Genet. 1994 Nov;3(11):1973–1981. doi: 10.1093/hmg/3.11.1973. [DOI] [PubMed] [Google Scholar]
  42. Mackey D., Howell N. A variant of Leber hereditary optic neuropathy characterized by recovery of vision and by an unusual mitochondrial genetic etiology. Am J Hum Genet. 1992 Dec;51(6):1218–1228. [PMC free article] [PubMed] [Google Scholar]
  43. Majander A., Huoponen K., Savontaus M. L., Nikoskelainen E., Wikström M. Electron transfer properties of NADH:ubiquinone reductase in the ND1/3460 and the ND4/11778 mutations of the Leber hereditary optic neuroretinopathy (LHON). FEBS Lett. 1991 Nov 4;292(1-2):289–292. doi: 10.1016/0014-5793(91)80886-8. [DOI] [PubMed] [Google Scholar]
  44. Marsden C. D., Lang A. E., Quinn N. P., McDonald W. I., Abdallat A., Nimri S. Familial dystonia and visual failure with striatal CT lucencies. J Neurol Neurosurg Psychiatry. 1986 May;49(5):500–509. doi: 10.1136/jnnp.49.5.500. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Marzuki S., Noer A. S., Lertrit P., Thyagarajan D., Kapsa R., Utthanaphol P., Byrne E. Normal variants of human mitochondrial DNA and translation products: the building of a reference data base. Hum Genet. 1991 Dec;88(2):139–145. doi: 10.1007/BF00206061. [DOI] [PubMed] [Google Scholar]
  46. Miller S. A., Dykes D. D., Polesky H. F. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988 Feb 11;16(3):1215–1215. doi: 10.1093/nar/16.3.1215. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Nakamura M., Ara F., Yamada M., Hotta Y., Hayakawa M., Fujiki K., Kanai A., Sakai J., Inoue M., Yamamoto M. High frequency of mitochondrial ND4 gene mutation in Japanese pedigrees with Leber hereditary optic neuropathy. Jpn J Ophthalmol. 1992;36(1):56–61. [PubMed] [Google Scholar]
  48. Newman N. J. Leber's hereditary optic neuropathy. New genetic considerations. Arch Neurol. 1993 May;50(5):540–548. doi: 10.1001/archneur.1993.00540050082021. [DOI] [PubMed] [Google Scholar]
  49. Newman N. J., Lott M. T., Wallace D. C. The clinical characteristics of pedigrees of Leber's hereditary optic neuropathy with the 11778 mutation. Am J Ophthalmol. 1991 Jun 15;111(6):750–762. doi: 10.1016/s0002-9394(14)76784-4. [DOI] [PubMed] [Google Scholar]
  50. Niki Y., Chigusa S. I., Matsuura E. T. Complete replacement of mitochondrial DNA in Drosophila. Nature. 1989 Oct 12;341(6242):551–552. doi: 10.1038/341551a0. [DOI] [PubMed] [Google Scholar]
  51. Novotny E. J., Jr, Singh G., Wallace D. C., Dorfman L. J., Louis A., Sogg R. L., Steinman L. Leber's disease and dystonia: a mitochondrial disease. Neurology. 1986 Aug;36(8):1053–1060. doi: 10.1212/wnl.36.8.1053. [DOI] [PubMed] [Google Scholar]
  52. Okimoto R., Macfarlane J. L., Clary D. O., Wolstenholme D. R. The mitochondrial genomes of two nematodes, Caenorhabditis elegans and Ascaris suum. Genetics. 1992 Mar;130(3):471–498. doi: 10.1093/genetics/130.3.471. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Parker W. D., Jr, Oley C. A., Parks J. K. A defect in mitochondrial electron-transport activity (NADH-coenzyme Q oxidoreductase) in Leber's hereditary optic neuropathy. N Engl J Med. 1989 May 18;320(20):1331–1333. doi: 10.1056/NEJM198905183202007. [DOI] [PubMed] [Google Scholar]
  54. Pont-Kingdon G. A., Beagley C. T., Okimoto R., Wolstenholme D. R. Mitochondrial DNA of the sea anemone, Metridium senile (Cnidaria): prokaryote-like genes for tRNA(f-Met) and small-subunit ribosomal RNA, and standard genetic code specificities for AGR and ATA codons. J Mol Evol. 1994 Oct;39(4):387–399. doi: 10.1007/BF00160271. [DOI] [PubMed] [Google Scholar]
  55. Roe B. A., Ma D. P., Wilson R. K., Wong J. F. The complete nucleotide sequence of the Xenopus laevis mitochondrial genome. J Biol Chem. 1985 Aug 15;260(17):9759–9774. [PubMed] [Google Scholar]
  56. Scholte H. R., Busch H. F., Bakker H. D., Bogaard J. M., Luyt-Houwen I. E., Kuyt L. P. Riboflavin-responsive complex I deficiency. Biochim Biophys Acta. 1995 May 24;1271(1):75–83. doi: 10.1016/0925-4439(95)00013-t. [DOI] [PubMed] [Google Scholar]
  57. Scholte H. R., Busch H. F., Luyt-Houwen I. E., Vaandrager-Verduin M. H., Przyrembel H., Arts W. F. Defects in oxidative phosphorylation. Biochemical investigations in skeletal muscle and expression of the lesion in other cells. J Inherit Metab Dis. 1987;10 (Suppl 1):81–97. doi: 10.1007/BF01812849. [DOI] [PubMed] [Google Scholar]
  58. Silvestri G., Moraes C. T., Shanske S., Oh S. J., DiMauro S. A new mtDNA mutation in the tRNA(Lys) gene associated with myoclonic epilepsy and ragged-red fibers (MERRF). Am J Hum Genet. 1992 Dec;51(6):1213–1217. [PMC free article] [PubMed] [Google Scholar]
  59. Smith P. R., Cooper J. M., Govan G. G., Harding A. E., Schapira A. H. Platelet mitochondrial function in Leber's hereditary optic neuropathy. J Neurol Sci. 1994 Mar;122(1):80–83. doi: 10.1016/0022-510x(94)90055-8. [DOI] [PubMed] [Google Scholar]
  60. Sweeney M. G., Davis M. B., Lashwood A., Brockington M., Toscano A., Harding A. E. Evidence against an X-linked locus close to DXS7 determining visual loss susceptibility in British and Italian families with Leber hereditary optic neuropathy. Am J Hum Genet. 1992 Oct;51(4):741–748. [PMC free article] [PubMed] [Google Scholar]
  61. Tanaka M., Ino H., Ohno K., Hattori K., Sato W., Ozawa T., Tanaka T., Itoyama S. Mitochondrial mutation in fatal infantile cardiomyopathy. Lancet. 1990 Dec 8;336(8728):1452–1452. doi: 10.1016/0140-6736(90)93162-i. [DOI] [PubMed] [Google Scholar]
  62. Vilkki J., Savontaus M. L., Nikoskelainen E. K. Segregation of mitochondrial genomes in a heteroplasmic lineage with Leber hereditary optic neuroretinopathy. Am J Hum Genet. 1990 Jul;47(1):95–100. [PMC free article] [PubMed] [Google Scholar]
  63. WENT L. N. A SEX-LINKED HEREDO-DEGENERATIVE NEUROLOGICAL DISORDER, ASSOCIATED WITH LEBER'S OPTIC ATROPHY. II. LABORATORY INVESTIGATIONS. J Neurol Sci. 1964 Jan-Feb;1(1):81–87. doi: 10.1016/0022-510x(64)90055-3. [DOI] [PubMed] [Google Scholar]
  64. Walker J. E. The NADH:ubiquinone oxidoreductase (complex I) of respiratory chains. Q Rev Biophys. 1992 Aug;25(3):253–324. doi: 10.1017/s003358350000425x. [DOI] [PubMed] [Google Scholar]
  65. Wallace D. C., Singh G., Lott M. T., Hodge J. A., Schurr T. G., Lezza A. M., Elsas L. J., 2nd, Nikoskelainen E. K. Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. Science. 1988 Dec 9;242(4884):1427–1430. doi: 10.1126/science.3201231. [DOI] [PubMed] [Google Scholar]
  66. Zeviani M., Amati P., Bresolin N., Antozzi C., Piccolo G., Toscano A., DiDonato S. Rapid detection of the A----G(8344) mutation of mtDNA in Italian families with myoclonus epilepsy and ragged-red fibers (MERRF). Am J Hum Genet. 1991 Feb;48(2):203–211. [PMC free article] [PubMed] [Google Scholar]
  67. de Stordeur E., Solignac M., Monnerot M., Mounolou J. C. The generation of transplasmic Drosophila simulans by cytoplasmic injection: effects of segregation and selection on the perpetuation of mitochondrial DNA heteroplasmy. Mol Gen Genet. 1989 Dec;220(1):127–132. doi: 10.1007/BF00260866. [DOI] [PubMed] [Google Scholar]
  68. de Vries D. D., Ruitenbeek W., van Oost B. A. Detection of extremely low levels of wild-type mitochondrial DNA in the liver of a patient with Pearson syndrome by a sensitive PCR assay. J Inherit Metab Dis. 1992;15(3):307–310. doi: 10.1007/BF02435963. [DOI] [PubMed] [Google Scholar]
  69. de Vries D. D., van Engelen B. G., Gabreëls F. J., Ruitenbeek W., van Oost B. A. A second missense mutation in the mitochondrial ATPase 6 gene in Leigh's syndrome. Ann Neurol. 1993 Sep;34(3):410–412. doi: 10.1002/ana.410340319. [DOI] [PubMed] [Google Scholar]
  70. de Vries D., de Wijs I., Ruitenbeek W., Begeer J., Smit P., Bentlage H., van Oost B. Extreme variability of clinical symptoms among sibs in a MELAS family correlated with heteroplasmy for the mitochondrial A3243G mutation. J Neurol Sci. 1994 Jun;124(1):77–82. doi: 10.1016/0022-510x(94)90014-0. [DOI] [PubMed] [Google Scholar]

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