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Mitochondrial DNA 3644T-->C mutation associated with bipolar disorder.

Authors: Munakata, K  Tanaka, M  Mori, K  Washizuka, S  Yoneda, M  Tajima, O  Akiyama, T  Nanko, S  Kunugi, H  Tadokoro, K  Ozaki, N  Inada, T  Sakamoto, K  Fukunaga, T  Iijima, Y  Iwata, N  Tatsumi, M  Yamada, K  Yoshikawa, T  Kato, T 
Citation: Munakata K, etal., Genomics. 2004 Dec;84(6):1041-50.
Pubmed: (View Article at PubMed) PMID:15533721
DOI: Full-text: DOI:10.1016/j.ygeno.2004.08.015

Mitochondrial dysfunction associated with mutant mitochondrial DNA (mtDNA) has been suggested in bipolar disorder, and comorbidity with neurodegenerative diseases was often noted. We examined the entire sequence of mtDNA in six subjects with bipolar disorder having comorbid somatic symptoms suggestive of mitochondrial disorders and found several uncharacterized homoplasmic nonsynonymous nucleotide substitutions of mtDNA. Of these, 3644C was found in 5 of 199 patients with bipolar disorder but in none of 258 controls (p = 0.015). The association was significant in the extended samples [bipolar disorder, 9/630 (1.43%); controls, 1/734 (0.14%); p = 0.007]. On the other hand, only 5 of 25 family members with this mutation developed bipolar disorder, of which 4 patients with 3644C had comorbid physical symptoms. The 3644T-->C mutation converts amino acid 113, valine, to alanine in the NADH-ubiquinone dehydrogenase subunit I, a subunit of complex I, and 113 valine is well conserved from Drosophila to 61 mammalian species. Using transmitochondrial cybrids, 3644T-->C was shown to decrease mitochondrial membrane potential and complex I activity compared with haplogroup-matched controls. According to human mitochondrial genome polymorphism databases, 3644C was not found in centenarians but was found in 3% of patients with Alzheimer disease and 2% with Parkinson disease. The result of modest functional impairment caused by 3644T-->C suggests that this mutation could increase the risk for bipolar disorder.


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RGD Object Information
RGD ID: 5490261
Created: 2011-09-12
Species: All species
Last Modified: 2011-09-12
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.