Polymorphic Variation in Cytochrome Oxidase Subunit Genes

Article type: Research Article

Authors: Lu, Jianghua^a | Wang, Kaixuan^b | Rodova, Mariana^a | Esteves, Raquel^{a; c} | Berry, Diana^b | E, Lezi^a | Crafter, Adam^a | Barrett, Matthew^b | Cardoso, Sandra M.^c | Onyango, Isaac^{a; d} | Parker, W. Davis^b | Fontes, Joseph^e | Burns, Jeffrey M.^{a; d} | Swerdlow, Russell H.^{a; d; *}

Affiliations: [a] Department of Neurology, University of Kansas School of Medicine, Kansas City, KS, USA | [b] Department of Neurology, University of Virginia Health System, Charlottesville, VA, USA | [c] Centro de Neurociencias e Biologia Celular, Universidade de Coimbra, Coimbra, Portugal | [d] Department Molecular and Integrative Physiology, University of Kansas School of Medicine, KA, USA | [e] Department of Biochemistry, University of Kansas School of Medicine, Kansas City, KA, USA

Correspondence: [*] Correspondence to: Russell H. Swerdlow, MD, University of Kansas School of Medicine, MS 2012, Landon Center on Aging, 3901 Rainbow Boulevard, Kansas City, KA 66160, USA. Tel.: +1 913 588 6970; Fax: +1 913 945 5035; E-mail: [email protected].

Abstract: Cytochrome oxidase (COX) activity varies between individuals and low activities associate with Alzheimer's disease. Whether genetic heterogeneity influences function of this multimeric enzyme is unknown. To explore this we sequenced three mitochondrial DNA (mtDNA) and ten nuclear COX subunit genes from at least 50 individuals. 20% had non-synonymous mtDNA COX gene polymorphisms, 12% had a COX4I1 non-synonymous G to A transition, and other genes rarely contained non-synonymous polymorphisms. Frequent untranslated region (UTR) polymorphisms were seen in COX6A1, COX6B1, COX6C, and COX7A1; heterogeneity in a COX7A1 5' UTR Sp1 site was extensive. Synonymous polymorphisms were common and less frequent in the more conserved COX1 than the less conserved COX3, suggesting at least in mtDNA synonymous polymorphisms experience selection pressure and are not functionally silent. Compound gene variations occurred within individuals. To test whether variations could have functional consequences, we studied the COX4I1 G to A transition and an AGCCCC deletion in the COX7A1 5' UTR Sp1 site. Cells expressing the COX4I1 polymorphism had reduced COX Vmax activity. In reporter construct-transduced cells where green fluorescent protein expression depended on the COX7A1 Sp1 site, AGCCCC deletion reduced fluorescence. Our findings indicate COX subunit gene heterogeneity is pervasive and may mediate COX functional variation.

Keywords: Alzheimer's disease, cytochrome oxidase, mitochondria, mitochondrial DNA, polymorphisms

DOI: 10.3233/JAD-2010-100123

Journal: Journal of Alzheimer's Disease, vol. 21, no. 1, pp. 141-154, 2010