Multiple Sclerosis (MS) is a multifocal demyelinating central nervous system disorder in which interplay between genes and the environment are supposed to be involved. Mitochondrial DNA (mtDNA) has the only non-coding regions at the displacement loop (D-loop) region that contains two hypervariable segments (HVS-I and HVS-II) with high polymorphism. mtDNA has already been fully sequenced and many subsequent publications have showed polymorphic sites, haplogroups and haplotypes. Haplogroups could have important implications to understand association between mutability of the mitochondrial genome and disease. To assess relationship between mtDNA haplogroups and MS, we have sequenced the mtDNA HVS-I in 54 MS patients and 100 control subjects. We have found that haplogroups A and K are significantly more abundant in MS patients (P=0.042 for haplogroup A and P=0.0005 for haplogroup K). Thus, these two haplogroups might act synergistically to increase the penetrance of MS disease.
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REFERENCES
Anderson, A., Bankier, A. T., Barrel, B. G., de Bruijn, M. H. L., Coulson, A. R., Drouin, J., Eperon, I. C., Nierlich, D. P., Roe, B. A., Sanger, F., Schrier, P. H., Smith, A. J. H., Staden, R., and Young, I. G. (1981). Sequence and organisation of the human mitochondrial genome. Nature 290:457–465.
Andrews, R. M., Kubacka, I., Chinnery, P. F., Lightowlers, R. N., Turnbull, D. M., and Howell, N. (1999). Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA. Nat. Genet. 23(2):147.
Arnestad, M., Opdal, S. H., Musse, M. A., Vege, A., and Rognum, T. O. (2002). Are substitution in the first hypervariable region of mitochondrial DNA displacement-loop in sudden infant death syndrome due to maternal inheritance? Acta. Pediatr. 91:1060–1064.
Brown, M. D., Torroni, A., Reckord, C. L., and Wallace, D. C. (1995). Phylogenetic analysis of Leber's hereditary optic neuropathy mitochondrial DNA's indicates multiple independent occurrences of the common mutations. Hum. Mut. 6:311–325.
Clayton, D. A. (2000). Transcription and replication of mitochondrial DNA. Hum. Reprod. 15(Suppl. 1):11–17.
Compston, A., and Sawcer, S. (2002). Genetic analysis of multiple sclerosis. Curr. Neurol. Neurosci. Rep. 2:259–266.
Graven, L., Passarino, G., Semino, O., Boursot. P., Santachlara-Benerecetti, A. S., et al. (1995). Evolutionary correlation between control region sequence and restriction polymorphisms in the mitochondrial genome of a large Senegalese Mandenka population. Mol. Biol. Evol. 12:334–345.
Hofmann, S., Bezold, R., Jaksch, M., Obermaier-Kusser, B., Mertens, S., Kaufhold, P., Rabl, W., Hecker, W., and Gerbitz, K.-D. (1997a). Wolfram (DIDMOAD) syndrome and Leber hereditary optic neuropathy (LHON) are associated with distinct mitochondrial DNA haplotypes. Genomics 39:8–18.
Hofmann, S., Jaksch, M., Bezold, R., Mertens, S., Aholt, S., Paprotta, A., and Gerbitz, K. D. (1997b). Population genetics and disease susceptibility: Characterization of central European haplogroups by mtDNA gene mutations, correlation with D loop variants and association with disease. Hum. Mol. Genet. 6:1835–1846.
Kalman, B., Albert, R. H., and Leist, T. P. (2002).Genetic of multiple sclerosis: Determinant of autoimmunity and neurodegeneration. Autoimmunity 35:225–234.
Lertrit, P., Kapsa, R. M. I., Jean-Francois, M. J. B., Thyagarajan, D., Noer A. S., Marzuki, S., and Byrne, E. (1994). Mitochondrial DNA polymorphism in disease: A possible contributor to respiratory dysfunction. Hum. Mol. Genet. 3:1973–1981.
Macaulay, V., Richards, M., Hickey, E., Vega, E., Cruciani, F., Guida, V., Scozzari, R., Bonne Tamir, B., Sykes, B., and Torroni, A. (1999). The emerging tree of West Eurasian mtDNAs: A synthesis of control-region sequences and RFLPs . Am J Hum Genet. 64:232–249.
Obermaier-Kusser, B., Lorenz, B., Schubring, S., Paprotta, A., Zerres, K., Meitinger, T., Meire, F., Cochaux, P., Blankenagel, A., Kommerell, G., Jaksch, M., and Gerbitz, K.-D. (1994). Features of mtDNA mutation patterns in European pedigrees and sporadic cases with Leber hereditary optic neuropathy. Am. J. Hum. Genet. 55:1063–1066.
Ozawa, T., Tanaka, M., Ino, H., Ohno, K., Sano, T., Wada, Y., Yoneda, M., Tanno, Y., Miyatake, T., Tanaka, T., Itoyama, S., Ikebe, S., Hattori, N., and Mizuno, Y. (1991). Distinct clustering of point mutations in mitochondrial DNA among patients with mitochondrial encephalomyopathies and with Parkinson's disease. Biochem. Biophys. Res. Commun. 176:938–946.
Poser, C. (1994). The epidemiology of multiple sclerosis. A general overview. Ann. Neurol. 36(Suppl. 2):231–243.
Poser, C. M., Paty, D. W., Scheinberg, L., McDonald, W. I., Davis, F. A., Ebers, G. C., Johnson, K. P., Sibley, W. A., Silberberg, D. H., and Tourtellotte, W. W. (1983). New diagnostic criteria for multiple sclerosis: Guidelines for research protocols. Ann. Neurol. 13:227–231.
Richards, M., Côrte-Real, H., Forster, P., Macaulay, V., Wilkinson-Herbots, H., Demaine, A., Papiha, S., Hedges, R., Bandelt, H.-J., and Sykes, B. (1996). Paleolithic and neolithic lineages in the European mitochondrial gene pool. Am. J. Hum. Genet. 59:185–203.
Shoffner, J. M., Brown, M. D., Torroni, A., Lott, M. T., Cabell, M. F., Mirra, S. S., Beal, M. F., Yang, C.-C., Gearing, M., Salvo, R., Watts, R. L., Juncos, J. L., Hansen, L. A., Crain, B. J., Fayad, M., Reckord, C. L., and Wallace, D. C. (1993). Mitochondrial DNA variants observed in Alzheimer disease and Parkinson disease patients. Genomics 17:171–184.
Stoneking, M., Hedgecock, D., Higuchi, R. G., Vigilant, L., and Erlich, H. A. (1991). Population variation of human mtDNA control region sequences detected by enzymatic amplification and sequence-specific oligonucleotide probes. Am. J. Hum. Genet. 48:370–382.
Torroni, A., Schurr, T. G. Cabeli, M. F., Brown, M. D., Neel, J. V., et al. (1993). Asian affinities and continental radiation of the four founding Native American mtDNA. Am. J. Hum. Genet. 53:563–590.
Torroni, A., Lott, M., Cabell, M., Chen, Y., Lavergne, L., and Wallace, D. C. (1994). MtDNA and the origin of Caucasians: Identification of ancient Caucasian-specific haplogroups, one of which is prone to a recurrent somatic duplication in the D-loop region. Am. J. Hum. Genet. 55:760.
Torroni, A., Houponen, K., Francalacci, P., Petrozzi, M., Morelli, L., Scozzari, R., Obinu, D., Savantous, M. L., and Wallace, D. C. (1996). Classification of European mtDNAs from an analysis of three European populations. Genetics 144:1835–18350
Torroni, A., Petrozzi, M., D’Urbano, L., Sellitto, D., Zeviani, M., Carrara, F., Carducci, C., Leuzzi, V., Carelli, V., Barboni, P., De Negri, A., and Scozzari, R. (1997). Haplotype and phylogenetic analysis suggest that one European-specific mtDNA background plays a role in the expression of Leber hereditary optic neuropathy by increasing the penetrance of the primary mutations 11778 and 14484. Am. J. Hum. Genet. 60:1107–1121.
Weissman, S. M. (1995). Genetic basis for common polygenic diseases. Proc. Natl. Acad. Sci. USA 92:8543–8544.
ACKNOWLEDGMENTS
This work was supported by research project no. 197 from National Research Institute for Genetic Engineering and Biotechnology, Ministry of Science, Research and Technology, Tehran, Iran. We also like to thank patients and their families whose collaboration and understanding let us do this work.
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Kumleh, H.H., Houshmand, M., Panahi, M.S. et al. Mitochondrial D-Loop Variation in Persian Multiple Sclerosis Patients: K and A Haplogroups as a Risk Factor!!. Cell Mol Neurobiol 26, 119–125 (2006). https://doi.org/10.1007/s10571-006-9026-z
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DOI: https://doi.org/10.1007/s10571-006-9026-z