title: Inherited and somatic mitochondrial DNA mutations in Guam amyotrophic lateral sclerosis and parkinsonism-dementia.
abstract: There is increasing evidence for mitochondrial dysfunction in neurodegenerative disorders, although the exact role of mitochondrial DNA (mtDNA) mutations in this process is unresolved. We investigated inherited and somatic mtDNA substitutions and deletions in Guam amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia (PD). Hypervariable segment 1 sequences of Chamorro mtDNA revealed that the odds ratio of a PD or ALS diagnosis was increased for individuals in the E1 haplogroup while individuals in the E2 haplogroup had decreased odds of an ALS or PD diagnosis. Once the disorders were examined separately, it became evident that PD was responsible for these results. When the entire mitochondrial genome was sequenced for a subset of individuals, the nonsynonymous mutation at nucleotide position 9080, shared by all E2 individuals, resulted in a significantly low odds ratio for a diagnosis of ALS or PD. Private polymorphisms found in transfer and ribosomal RNA regions were found only in ALS and PD patients in the E1 haplogroup. Somatic mtDNA deletions in the entire mtDNA genome were not associated with either ALS or PD. We conclude that mtDNA haplogroup effects may result in mitochondrial dysfunction in Guam PD and reflect Guam population history. Thus it is reasonable to consider Guam ALS and PD as complex disorders with both environmental prerequisites and small genetic effects.
authors.affiliation: Laboratory of Biomedical Anthropology and Neurosciences, State University of New York at Binghamton, PO Box 6000, Binghamton, NY 13902-6000, USA. dreiff1@binghamton.edu
authors.forename: Dana M
authors.initials: DM
authors.lastname: Reiff
authors.forename: Rita
authors.initials: R
authors.lastname: Spathis
authors.forename: Chim W
authors.initials: CW
authors.lastname: Chan
authors.forename: Miguel G
authors.initials: MG
authors.lastname: Vilar
authors.forename: Krithivasan
authors.initials: K
authors.lastname: Sankaranarayanan
authors.forename: Daniel
authors.initials: D
authors.lastname: Lynch
authors.forename: Emily
authors.initials: E
authors.lastname: Ehrlich
authors.forename: Samantha
authors.initials: S
authors.lastname: Kerath
authors.forename: Risana
authors.initials: R
authors.lastname: Chowdhury
authors.forename: Leah
authors.initials: L
authors.lastname: Robinowitz
authors.forename: J
authors.initials: J
authors.lastname: Koji Lum
authors.forename: Ralph M
authors.initials: RM
authors.lastname: Garruto
mesh_terms: D000328:Adult; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D004272:DNA, Mitochondrial / Q000235:genetics*; D005787:Gene Frequency; D006239:Haplotypes; D006801:Humans; D008928:Mitochondria / Q000235:genetics*; D009154:Mutation
chemical_list: D004272:DNA, Mitochondrial