Mitochondrial DNA mutations in multiple sclerosis

Abstract

The presence of mitochondrial DNA mutations, including eight of those frequently associated with Leber's hereditary optic neuropathy (LHON), was investigated by sequencing end restriction endonuclease analysis in randomly selected patients with MS. Class I LHON mutations with primary pathogenic significance for blindness were not detected in any of the MS patients studied. A trend was observed for higher frequency of class II LHON mutations with unknown pathogenic significance in the MS patients than in the controls. Specifically, the mutation at position 4216 and its associated simultaneous mutations occurred with a higher frequency. Eleven of the 53 patients (20.8%) were positive for at least two (4216 and 4917 or 13708) or three (4216, 13 708, 15 257) simultaneous class II LHON mutations, white 7 of the 74 controls (9.5%) carried simultaneous mutations (P=0.036). Earlier studies reported the occurrence of either the 11 778 or 3460 LHON type mutations in MS patients with a positive LHON pedigree and/or with a disease course predominantly involving the optic nerves. The mutations we detected did not correlate with the severity of visual loss in either LHON or MS, rather they seemed to be present in randomly selected MS patients. We conclude that the mutations with primary pathogenic significance for blindness are not shared between LHON and randomly selected MS. However, the presence offurther mitochondrial mutations cannot be excluded in MS. The increased incidence of the simultaneous class II LHON mutations in MS patients (and LHON) vs controls may indicate that certain sets of mitochrondrial DNA mutations/variants are associated with and predispose to MS, a possibility which needs to be investigated further. Alternatively, a biological disadvantage may be associated with the coexistence of the mutations detected.

Keywords

genetic susceptibility mitochrondrial DNA mutations

Get full access to this article

View all access options for this article.

References

1 Seboun E et al. (1989) A susceptibility locus for multiple sclerosis is linked to the T cell receptor β chain complex. Cell 57: 1095–1100.

2 Beall SS et al. (1993) Susceptibility for multiple sclerosis is determined, in part by inheritance of a 175-kb region of the TCR Vβ chain locus and HLA class II genes. J Neuroimmunol 45: 53–60.

3 Takacs K et al. (1990) Association between the lack of HLA DQw6 and the low incidence of multiple sclerosis in Hungarian gypsies. Immunogenetics 31: 383–385.

4 Kalman B et al. (1991) Sclerosis multiplex in gypsies. Acta Neural Scand 84: 181–185.

5 Sadovnick AD , Bulman D , Ebers GC . (1991) Parent — child concordance in multiple sclerosis. Ann Neural 29: 252–255.

6 Lees F , Macdonald A-M , Aldren Turner JW . (1964) Leber's disease with symptoms resembling disseminated sclerosis. J Neural Neurosurg Psychiatr 27: 415–421.

7 Harding AE et al. (1992) Occurrence of multiple sclerosis-like illness in women who have a Leber's hereditary optic neuropathy mitochondrial DNA mutation. Brain 115: 979–989.

8 Flanigan KM , Johns DR . (1993) Association of the 11 778 mitochondrial DNA mutation and demyelinating disease. Neurology 43: 2720–2722.

9 Kellar-Wood H et al. (1994) Leber's hereditary optic neuropathy mitochondrial DNA mutations in multiple sclerosis. Ann Neurol 36: 109–112.

10.

10 Miller NR . (1982) The hereditary optic neuropathies. In: Walsh and Hoyt's Clinical Neuro-Ophthalmology, 4th edn. Williams & Wilkins: Baltimore, pp 311–321.

11.

11 Kermode AG et al. (1989) Magnetic resonance imaging in Leber's optic neuropathy. J Neurol Neurosurg Psychiatr 52: 671–674.

12.

12 Adams HJ , Blackwood W , Wilson J . (1966) Further clinical and pathological observations on Leber's optic atrophy. Brain 89: 15–26.

13.

13 Newman NJ . (1993) Leber's hereditary optic neuropathy. New genetic considerations. Review article. Arch Neurol 50: 540–547.

14.

14 Brown MD et al. (1992) Leber's hereditary optic neuropathy: a model for mitochondrial neurodegenerative diseases. FASEB 6: 2791–2799.

15.

15 Wallace DC et al. (1988) Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. Science 242: 1427–1430.

16.

16 Johns DR , Berman J . (1991) Alternative, simultaneous complex I mitochondrial DNA mutations in Leber's hereditary optic neuropathy. Biochem Biophys Res Commun 174: 1324–1330.

17.

17 Brown MD et al. (1992) Mitochondrial DNA complex I and III mutations associated with Leber's hereditary optic neuropathy. Genetics 130: 163–173.

18.

18 Oostra RJ et al. (1994) Leber's hereditary optic neuropathy: no significant evidence for primary or secondary pathogenicity of the 15257 mutation. Hum Genet 94: 265–270.

19.

19 Anderson S et al. (1981) Sequence and organization of the human mitochondrial genome. Nature 290: 457–464.

20.

20 Howell N et al. (1992) The sequence of human mtDNA: The question of errors versus polymorphism. Am J Hum Genet 50: 1333–1337.

21.

21 Ozawa T et al. (1991) Distinct clustering of point mutations in mitochondrial DNA among patients with mitochondrial encephalomyopathies and Parkinson's disease. Biochem Biophys Res Commun 176: 938–946.

22.

22 Wood DD , Moscarello MA . (1984) Is the myelin membrane abnormal in multiple sclerosis? J Membrane Biol 79: 195–201.

23.

23 Allen IV , Mckeon SR . (1979) A histological, histochemical and biochemical study of the macroscopically normal white matter in multiple sclerosis. J Neurol Sci 41: 81–91.

24.

24 Husted CA et al. (1994) Biochemical alterations in multiple sclerosis lesions and normal-appearing white matter detected by in vivo 31P and 1H spectroscopic imaging. Ann Neurol 36: 157–165.