Mitochondrial DNA 3644T→C mutation associated with bipolar disorder

Kae Munakata, Masashi Tanaka, Kanako Mori, Shinsuke Washizuka, Makoto Yoneda, Osamu Tajima, Tsuyoshi Akiyama, Shinichiro Nanko, Hiroshi Kunugi, Kazuyuki Tadokoro, Norio Ozaki, Toshiya Inada, Kaoru Sakamoto, Takako Fukunaga, Yoshimi Iijima, Nakao Iwata, Masahiko Tatsumi, Kazuo Yamada, Takeo Yoshikawa, Tadafumi Kato

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Abstract

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.

Original languageEnglish
Pages (from-to)1041-1050
Number of pages10
JournalGenomics
Volume84
Issue number6
DOIs
Publication statusPublished - 01-12-2004

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Mitochondrial DNA
Bipolar Disorder
Mutation
Valine
Electron Transport Complex I
Mitochondrial Diseases
Mitochondrial Genome
Mitochondrial Membrane Potential
Human Genome
Neurodegenerative Diseases
Alanine
Drosophila
Parkinson Disease
Comorbidity
Nucleotides
Databases
Amino Acids

All Science Journal Classification (ASJC) codes

  • Genetics

Cite this

Munakata, K., Tanaka, M., Mori, K., Washizuka, S., Yoneda, M., Tajima, O., ... Kato, T. (2004). Mitochondrial DNA 3644T→C mutation associated with bipolar disorder. Genomics, 84(6), 1041-1050. https://doi.org/10.1016/j.ygeno.2004.08.015
Munakata, Kae ; Tanaka, Masashi ; Mori, Kanako ; Washizuka, Shinsuke ; Yoneda, Makoto ; Tajima, Osamu ; Akiyama, Tsuyoshi ; Nanko, Shinichiro ; Kunugi, Hiroshi ; Tadokoro, Kazuyuki ; Ozaki, Norio ; Inada, Toshiya ; Sakamoto, Kaoru ; Fukunaga, Takako ; Iijima, Yoshimi ; Iwata, Nakao ; Tatsumi, Masahiko ; Yamada, Kazuo ; Yoshikawa, Takeo ; Kato, Tadafumi. / Mitochondrial DNA 3644T→C mutation associated with bipolar disorder. In: Genomics. 2004 ; Vol. 84, No. 6. pp. 1041-1050.
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abstract = "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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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 2004, 'Mitochondrial DNA 3644T→C mutation associated with bipolar disorder', Genomics, vol. 84, no. 6, pp. 1041-1050. https://doi.org/10.1016/j.ygeno.2004.08.015

Mitochondrial DNA 3644T→C mutation associated with bipolar disorder. / Munakata, Kae; Tanaka, Masashi; Mori, Kanako; Washizuka, Shinsuke; Yoneda, Makoto; Tajima, Osamu; Akiyama, Tsuyoshi; Nanko, Shinichiro; Kunugi, Hiroshi; Tadokoro, Kazuyuki; Ozaki, Norio; Inada, Toshiya; Sakamoto, Kaoru; Fukunaga, Takako; Iijima, Yoshimi; Iwata, Nakao; Tatsumi, Masahiko; Yamada, Kazuo; Yoshikawa, Takeo; Kato, Tadafumi.

In: Genomics, Vol. 84, No. 6, 01.12.2004, p. 1041-1050.

Research output: Contribution to journalArticle

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T1 - Mitochondrial DNA 3644T→C mutation associated with bipolar disorder

AU - Munakata, Kae

AU - Tanaka, Masashi

AU - Mori, Kanako

AU - Washizuka, Shinsuke

AU - Yoneda, Makoto

AU - Tajima, Osamu

AU - Akiyama, Tsuyoshi

AU - Nanko, Shinichiro

AU - Kunugi, Hiroshi

AU - Tadokoro, Kazuyuki

AU - Ozaki, Norio

AU - Inada, Toshiya

AU - Sakamoto, Kaoru

AU - Fukunaga, Takako

AU - Iijima, Yoshimi

AU - Iwata, Nakao

AU - Tatsumi, Masahiko

AU - Yamada, Kazuo

AU - Yoshikawa, Takeo

AU - Kato, Tadafumi

PY - 2004/12/1

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N2 - 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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Munakata K, Tanaka M, Mori K, Washizuka S, Yoneda M, Tajima O et al. Mitochondrial DNA 3644T→C mutation associated with bipolar disorder. Genomics. 2004 Dec 1;84(6):1041-1050. https://doi.org/10.1016/j.ygeno.2004.08.015