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Mitochondrial NADH dehydrogenase and CYP2D6 genotypes in Lewy‐body Parkinsonism
Author(s) -
Kösel S.,
Lücking C.B.,
Egensperger R.,
Mehraein P.,
Graeber M.B.
Publication year - 1996
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/(sici)1097-4547(19960415)44:2<174::aid-jnr10>3.0.co;2-6
Subject(s) - heteroplasmy , biology , parkinsonism , genetics , substantia nigra , parkinson's disease , mitochondrial dna , pathology , disease , medicine , gene
The cause of nerve‐cell death in sporadic Parkinson's disease remains unknown. Although environmental factors have been traditionally implicated in the etiology of Parkinson's disease, recent studies strongly suggest that there is a genetic contribution to this multifactorial disorder. We studied archival brain tissue from clinically and neuropathologically verified cases of Parkinson's disease, using nonradioactive cycle sequencing and restriction enzymatic analysis of polymerase chain reaction products. Twenty‐one Parkinsonian brains with brain stem Lewy‐bodies and 77 control brains were genotyped at two mitochondrial loci previously implicated in the etiology of neurodegenerative disease. In addition, genotyping was performed for two alleles of the debrisoquine 4‐hydroxylase gene (CYP2D6). A heteroplasmic mtDNA G5460A missense mutation in the ND2 subunit gene of NADH dehydrogenase was three times more frequent in Parkinson cases (4/21) compared to controls (5/77). A homoplasmic mtDNA A4336G transition which alters the mitochondrial tRNA Gln gene product was found in one Parkinson case. Frequencies of the CYP2D6 G1934A and CYP2D6 C2938T alleles were not significantly different between Parkinson cases and controls. Two Parkinsonian brains with high degrees of heteroplasmy for the ND2 G5460A mutation and one CYP2D6 C2938T homozygous case showed very high numbers of Lewy‐bodies in the substantia nigra. The results of this study are in line with the concept that different genetic loci may be involved in Parkinson's disease susceptibility. They provide a hint that the ND2 5460 mutation, in combination with other factors, could play a role in disease pathogenesis in a subset of patients. © 1996 Wiley‐Liss, Inc.