Mutations in COQ2 in familial and sporadic multiple-system atrophy the multiple-system atrophy research collaboration

Jun Mitsui, Takashi Matsukawa, Hiroyuki Ishiura, Yoko Fukuda, Yaeko Ichikawa, Hidetoshi Date, Budrul Ahsan, Yasuo Nakahara, Yoshio Momose, Yuji Takahashi, Atsushi Iwata, Jun Goto, Yorihiro Yamamoto, Makiko Komata, Katsuhiko Shirahige, Kenju Hara, Akiyoshi Kakita, Mitsunori Yamada, Hitoshi Takahashi, Osamu Onodera & 54 others Masatoyo Nishizawa, Hiroshi Takashima, Ryozo Kuwano, Hirohisa Watanabe, Mizuki Ito, Gen Sobue, Hiroyuki Soma, Ichiro Yabe, Hidenao Sasaki, Masashi Aoki, Kinya Ishikawa, Hidehiro Mizusawa, Kazuaki Kanai, Takamichi Hattori, Satoshi Kuwabara, Kimihito Arai, Shigeru Koyano, Yoshiyuki Kuroiwa, Kazuko Hasegawa, Tatsuhiko Yuasa, Kenichi Yasui, Kenji Nakashima, Hijiri Ito, Yuishin Izumi, Ryuji Kaji, Takeo Kato, Susumu Kusunoki, Yasushi Osaki, Masahiro Horiuchi, Tomoyoshi Kondo, Shigeo Murayama, Nobutaka Hattori, Mitsutoshi Yamamoto, Miho Murata, Wataru Satake, Tatsushi Toda, Alexandra Dürr, Alexis Brice, Alessandro Filla, Thomas Klockgether, Ullrich Wallner, Garth Nicholson, Sid Gilman, Clifford W. Shults, Caroline M. Tanner, Walter A. Kukull, Virginia M Y Lee, Eliezer Masliah, Phillip A. Low, Paola Sandroni, John Q. Trojanowski, Laurie Ozelius, Tatiana Foroud, Shoji Tsuji

Research output: Contribution to journalArticle

155 Citations (Scopus)

Abstract

BACKGROUND: Multiple-system atrophy is an intractable neurodegenerative disease characterized by autonomic failure in addition to various combinations of parkinsonism, cerebellar ataxia, and pyramidal dysfunction. Although multiple-system atrophy is widely considered to be a nongenetic disorder, we previously identified multiplex families with this disease, which indicates the involvement of genetic components. METHODS: In combination with linkage analysis, we performed whole-genome sequencing of a sample obtained from a member of a multiplex family in whom multiple-system atrophy had been diagnosed on autopsy. We also performed mutational analysis of samples from members of five other multiplex families and from a Japanese series (363 patients and two sets of controls, one of 520 persons and one of 2383 persons), a European series (223 patients and 315 controls), and a North American series (172 patients and 294 controls). On the basis of these analyses, we used a yeast complementation assay and measured enzyme activity of parahydroxybenzoate-polyprenyl transferase. This enzyme is encoded by the gene COQ2 and is essential for the biosynthesis of coenzyme Q10. Levels of coenzyme Q10 in lymphoblastoid cells and brain tissue were measured on high-performance liquid chromatography. RESULTS: We identified a homozygous mutation (M78V-V343A/M78V-V343A) and compound heterozygous mutations (R337X/V343A) in COQ2 in two multiplex families. Furthermore, we found that a common variant (V343A) and multiple rare variants in COQ2, all of which are functionally impaired, are associated with sporadic multiple-system atrophy. The V343A variant was exclusively observed in the Japanese population. CONCLUSIONS: Functionally impaired variants of COQ2 were associated with an increased risk of multiple-system atrophy in multiplex families and patients with sporadic disease, providing evidence of a role of impaired COQ2 activities in the pathogenesis of this disease.

Original languageEnglish
Pages (from-to)233-244
Number of pages12
JournalNew England Journal of Medicine
Volume369
Issue number3
DOIs
StatePublished - 2013

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Multiple System Atrophy
coenzyme Q10
Mutation
Research
Cerebellar Ataxia
Enzyme Assays
Parkinsonian Disorders
Transferases
Neurodegenerative Diseases
Autopsy
Yeasts
High Pressure Liquid Chromatography
Genome
Brain
Enzymes
Population
Genes

ASJC Scopus subject areas

  • Medicine(all)

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Mutations in COQ2 in familial and sporadic multiple-system atrophy the multiple-system atrophy research collaboration. / Mitsui, Jun; Matsukawa, Takashi; Ishiura, Hiroyuki; Fukuda, Yoko; Ichikawa, Yaeko; Date, Hidetoshi; Ahsan, Budrul; Nakahara, Yasuo; Momose, Yoshio; Takahashi, Yuji; Iwata, Atsushi; Goto, Jun; Yamamoto, Yorihiro; Komata, Makiko; Shirahige, Katsuhiko; Hara, Kenju; Kakita, Akiyoshi; Yamada, Mitsunori; Takahashi, Hitoshi; Onodera, Osamu; Nishizawa, Masatoyo; Takashima, Hiroshi; Kuwano, Ryozo; Watanabe, Hirohisa; Ito, Mizuki; Sobue, Gen; Soma, Hiroyuki; Yabe, Ichiro; Sasaki, Hidenao; Aoki, Masashi; Ishikawa, Kinya; Mizusawa, Hidehiro; Kanai, Kazuaki; Hattori, Takamichi; Kuwabara, Satoshi; Arai, Kimihito; Koyano, Shigeru; Kuroiwa, Yoshiyuki; Hasegawa, Kazuko; Yuasa, Tatsuhiko; Yasui, Kenichi; Nakashima, Kenji; Ito, Hijiri; Izumi, Yuishin; Kaji, Ryuji; Kato, Takeo; Kusunoki, Susumu; Osaki, Yasushi; Horiuchi, Masahiro; Kondo, Tomoyoshi; Murayama, Shigeo; Hattori, Nobutaka; Yamamoto, Mitsutoshi; Murata, Miho; Satake, Wataru; Toda, Tatsushi; Dürr, Alexandra; Brice, Alexis; Filla, Alessandro; Klockgether, Thomas; Wallner, Ullrich; Nicholson, Garth; Gilman, Sid; Shults, Clifford W.; Tanner, Caroline M.; Kukull, Walter A.; Lee, Virginia M Y; Masliah, Eliezer; Low, Phillip A.; Sandroni, Paola; Trojanowski, John Q.; Ozelius, Laurie; Foroud, Tatiana; Tsuji, Shoji.

In: New England Journal of Medicine, Vol. 369, No. 3, 2013, p. 233-244.

Research output: Contribution to journalArticle

Mitsui, J, Matsukawa, T, Ishiura, H, Fukuda, Y, Ichikawa, Y, Date, H, Ahsan, B, Nakahara, Y, Momose, Y, Takahashi, Y, Iwata, A, Goto, J, Yamamoto, Y, Komata, M, Shirahige, K, Hara, K, Kakita, A, Yamada, M, Takahashi, H, Onodera, O, Nishizawa, M, Takashima, H, Kuwano, R, Watanabe, H, Ito, M, Sobue, G, Soma, H, Yabe, I, Sasaki, H, Aoki, M, Ishikawa, K, Mizusawa, H, Kanai, K, Hattori, T, Kuwabara, S, Arai, K, Koyano, S, Kuroiwa, Y, Hasegawa, K, Yuasa, T, Yasui, K, Nakashima, K, Ito, H, Izumi, Y, Kaji, R, Kato, T, Kusunoki, S, Osaki, Y, Horiuchi, M, Kondo, T, Murayama, S, Hattori, N, Yamamoto, M, Murata, M, Satake, W, Toda, T, Dürr, A, Brice, A, Filla, A, Klockgether, T, Wallner, U, Nicholson, G, Gilman, S, Shults, CW, Tanner, CM, Kukull, WA, Lee, VMY, Masliah, E, Low, PA, Sandroni, P, Trojanowski, JQ, Ozelius, L, Foroud, T & Tsuji, S 2013, 'Mutations in COQ2 in familial and sporadic multiple-system atrophy the multiple-system atrophy research collaboration', New England Journal of Medicine, vol. 369, no. 3, pp. 233-244. https://doi.org/10.1056/NEJMoa1212115
Mitsui, Jun ; Matsukawa, Takashi ; Ishiura, Hiroyuki ; Fukuda, Yoko ; Ichikawa, Yaeko ; Date, Hidetoshi ; Ahsan, Budrul ; Nakahara, Yasuo ; Momose, Yoshio ; Takahashi, Yuji ; Iwata, Atsushi ; Goto, Jun ; Yamamoto, Yorihiro ; Komata, Makiko ; Shirahige, Katsuhiko ; Hara, Kenju ; Kakita, Akiyoshi ; Yamada, Mitsunori ; Takahashi, Hitoshi ; Onodera, Osamu ; Nishizawa, Masatoyo ; Takashima, Hiroshi ; Kuwano, Ryozo ; Watanabe, Hirohisa ; Ito, Mizuki ; Sobue, Gen ; Soma, Hiroyuki ; Yabe, Ichiro ; Sasaki, Hidenao ; Aoki, Masashi ; Ishikawa, Kinya ; Mizusawa, Hidehiro ; Kanai, Kazuaki ; Hattori, Takamichi ; Kuwabara, Satoshi ; Arai, Kimihito ; Koyano, Shigeru ; Kuroiwa, Yoshiyuki ; Hasegawa, Kazuko ; Yuasa, Tatsuhiko ; Yasui, Kenichi ; Nakashima, Kenji ; Ito, Hijiri ; Izumi, Yuishin ; Kaji, Ryuji ; Kato, Takeo ; Kusunoki, Susumu ; Osaki, Yasushi ; Horiuchi, Masahiro ; Kondo, Tomoyoshi ; Murayama, Shigeo ; Hattori, Nobutaka ; Yamamoto, Mitsutoshi ; Murata, Miho ; Satake, Wataru ; Toda, Tatsushi ; Dürr, Alexandra ; Brice, Alexis ; Filla, Alessandro ; Klockgether, Thomas ; Wallner, Ullrich ; Nicholson, Garth ; Gilman, Sid ; Shults, Clifford W. ; Tanner, Caroline M. ; Kukull, Walter A. ; Lee, Virginia M Y ; Masliah, Eliezer ; Low, Phillip A. ; Sandroni, Paola ; Trojanowski, John Q. ; Ozelius, Laurie ; Foroud, Tatiana ; Tsuji, Shoji. / Mutations in COQ2 in familial and sporadic multiple-system atrophy the multiple-system atrophy research collaboration. In: New England Journal of Medicine. 2013 ; Vol. 369, No. 3. pp. 233-244.
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abstract = "BACKGROUND: Multiple-system atrophy is an intractable neurodegenerative disease characterized by autonomic failure in addition to various combinations of parkinsonism, cerebellar ataxia, and pyramidal dysfunction. Although multiple-system atrophy is widely considered to be a nongenetic disorder, we previously identified multiplex families with this disease, which indicates the involvement of genetic components. METHODS: In combination with linkage analysis, we performed whole-genome sequencing of a sample obtained from a member of a multiplex family in whom multiple-system atrophy had been diagnosed on autopsy. We also performed mutational analysis of samples from members of five other multiplex families and from a Japanese series (363 patients and two sets of controls, one of 520 persons and one of 2383 persons), a European series (223 patients and 315 controls), and a North American series (172 patients and 294 controls). On the basis of these analyses, we used a yeast complementation assay and measured enzyme activity of parahydroxybenzoate-polyprenyl transferase. This enzyme is encoded by the gene COQ2 and is essential for the biosynthesis of coenzyme Q10. Levels of coenzyme Q10 in lymphoblastoid cells and brain tissue were measured on high-performance liquid chromatography. RESULTS: We identified a homozygous mutation (M78V-V343A/M78V-V343A) and compound heterozygous mutations (R337X/V343A) in COQ2 in two multiplex families. Furthermore, we found that a common variant (V343A) and multiple rare variants in COQ2, all of which are functionally impaired, are associated with sporadic multiple-system atrophy. The V343A variant was exclusively observed in the Japanese population. CONCLUSIONS: Functionally impaired variants of COQ2 were associated with an increased risk of multiple-system atrophy in multiplex families and patients with sporadic disease, providing evidence of a role of impaired COQ2 activities in the pathogenesis of this disease.",
author = "Jun Mitsui and Takashi Matsukawa and Hiroyuki Ishiura and Yoko Fukuda and Yaeko Ichikawa and Hidetoshi Date and Budrul Ahsan and Yasuo Nakahara and Yoshio Momose and Yuji Takahashi and Atsushi Iwata and Jun Goto and Yorihiro Yamamoto and Makiko Komata and Katsuhiko Shirahige and Kenju Hara and Akiyoshi Kakita and Mitsunori Yamada and Hitoshi Takahashi and Osamu Onodera and Masatoyo Nishizawa and Hiroshi Takashima and Ryozo Kuwano and Hirohisa Watanabe and Mizuki Ito and Gen Sobue and Hiroyuki Soma and Ichiro Yabe and Hidenao Sasaki and Masashi Aoki and Kinya Ishikawa and Hidehiro Mizusawa and Kazuaki Kanai and Takamichi Hattori and Satoshi Kuwabara and Kimihito Arai and Shigeru Koyano and Yoshiyuki Kuroiwa and Kazuko Hasegawa and Tatsuhiko Yuasa and Kenichi Yasui and Kenji Nakashima and Hijiri Ito and Yuishin Izumi and Ryuji Kaji and Takeo Kato and Susumu Kusunoki and Yasushi Osaki and Masahiro Horiuchi and Tomoyoshi Kondo and Shigeo Murayama and Nobutaka Hattori and Mitsutoshi Yamamoto and Miho Murata and Wataru Satake and Tatsushi Toda and Alexandra D{\"u}rr and Alexis Brice and Alessandro Filla and Thomas Klockgether and Ullrich Wallner and Garth Nicholson and Sid Gilman and Shults, {Clifford W.} and Tanner, {Caroline M.} and Kukull, {Walter A.} and Lee, {Virginia M Y} and Eliezer Masliah and Low, {Phillip A.} and Paola Sandroni and Trojanowski, {John Q.} and Laurie Ozelius and Tatiana Foroud and Shoji Tsuji",
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T1 - Mutations in COQ2 in familial and sporadic multiple-system atrophy the multiple-system atrophy research collaboration

AU - Mitsui, Jun

AU - Matsukawa, Takashi

AU - Ishiura, Hiroyuki

AU - Fukuda, Yoko

AU - Ichikawa, Yaeko

AU - Date, Hidetoshi

AU - Ahsan, Budrul

AU - Nakahara, Yasuo

AU - Momose, Yoshio

AU - Takahashi, Yuji

AU - Iwata, Atsushi

AU - Goto, Jun

AU - Yamamoto, Yorihiro

AU - Komata, Makiko

AU - Shirahige, Katsuhiko

AU - Hara, Kenju

AU - Kakita, Akiyoshi

AU - Yamada, Mitsunori

AU - Takahashi, Hitoshi

AU - Onodera, Osamu

AU - Nishizawa, Masatoyo

AU - Takashima, Hiroshi

AU - Kuwano, Ryozo

AU - Watanabe, Hirohisa

AU - Ito, Mizuki

AU - Sobue, Gen

AU - Soma, Hiroyuki

AU - Yabe, Ichiro

AU - Sasaki, Hidenao

AU - Aoki, Masashi

AU - Ishikawa, Kinya

AU - Mizusawa, Hidehiro

AU - Kanai, Kazuaki

AU - Hattori, Takamichi

AU - Kuwabara, Satoshi

AU - Arai, Kimihito

AU - Koyano, Shigeru

AU - Kuroiwa, Yoshiyuki

AU - Hasegawa, Kazuko

AU - Yuasa, Tatsuhiko

AU - Yasui, Kenichi

AU - Nakashima, Kenji

AU - Ito, Hijiri

AU - Izumi, Yuishin

AU - Kaji, Ryuji

AU - Kato, Takeo

AU - Kusunoki, Susumu

AU - Osaki, Yasushi

AU - Horiuchi, Masahiro

AU - Kondo, Tomoyoshi

AU - Murayama, Shigeo

AU - Hattori, Nobutaka

AU - Yamamoto, Mitsutoshi

AU - Murata, Miho

AU - Satake, Wataru

AU - Toda, Tatsushi

AU - Dürr, Alexandra

AU - Brice, Alexis

AU - Filla, Alessandro

AU - Klockgether, Thomas

AU - Wallner, Ullrich

AU - Nicholson, Garth

AU - Gilman, Sid

AU - Shults, Clifford W.

AU - Tanner, Caroline M.

AU - Kukull, Walter A.

AU - Lee, Virginia M Y

AU - Masliah, Eliezer

AU - Low, Phillip A.

AU - Sandroni, Paola

AU - Trojanowski, John Q.

AU - Ozelius, Laurie

AU - Foroud, Tatiana

AU - Tsuji, Shoji

PY - 2013

Y1 - 2013

N2 - BACKGROUND: Multiple-system atrophy is an intractable neurodegenerative disease characterized by autonomic failure in addition to various combinations of parkinsonism, cerebellar ataxia, and pyramidal dysfunction. Although multiple-system atrophy is widely considered to be a nongenetic disorder, we previously identified multiplex families with this disease, which indicates the involvement of genetic components. METHODS: In combination with linkage analysis, we performed whole-genome sequencing of a sample obtained from a member of a multiplex family in whom multiple-system atrophy had been diagnosed on autopsy. We also performed mutational analysis of samples from members of five other multiplex families and from a Japanese series (363 patients and two sets of controls, one of 520 persons and one of 2383 persons), a European series (223 patients and 315 controls), and a North American series (172 patients and 294 controls). On the basis of these analyses, we used a yeast complementation assay and measured enzyme activity of parahydroxybenzoate-polyprenyl transferase. This enzyme is encoded by the gene COQ2 and is essential for the biosynthesis of coenzyme Q10. Levels of coenzyme Q10 in lymphoblastoid cells and brain tissue were measured on high-performance liquid chromatography. RESULTS: We identified a homozygous mutation (M78V-V343A/M78V-V343A) and compound heterozygous mutations (R337X/V343A) in COQ2 in two multiplex families. Furthermore, we found that a common variant (V343A) and multiple rare variants in COQ2, all of which are functionally impaired, are associated with sporadic multiple-system atrophy. The V343A variant was exclusively observed in the Japanese population. CONCLUSIONS: Functionally impaired variants of COQ2 were associated with an increased risk of multiple-system atrophy in multiplex families and patients with sporadic disease, providing evidence of a role of impaired COQ2 activities in the pathogenesis of this disease.

AB - BACKGROUND: Multiple-system atrophy is an intractable neurodegenerative disease characterized by autonomic failure in addition to various combinations of parkinsonism, cerebellar ataxia, and pyramidal dysfunction. Although multiple-system atrophy is widely considered to be a nongenetic disorder, we previously identified multiplex families with this disease, which indicates the involvement of genetic components. METHODS: In combination with linkage analysis, we performed whole-genome sequencing of a sample obtained from a member of a multiplex family in whom multiple-system atrophy had been diagnosed on autopsy. We also performed mutational analysis of samples from members of five other multiplex families and from a Japanese series (363 patients and two sets of controls, one of 520 persons and one of 2383 persons), a European series (223 patients and 315 controls), and a North American series (172 patients and 294 controls). On the basis of these analyses, we used a yeast complementation assay and measured enzyme activity of parahydroxybenzoate-polyprenyl transferase. This enzyme is encoded by the gene COQ2 and is essential for the biosynthesis of coenzyme Q10. Levels of coenzyme Q10 in lymphoblastoid cells and brain tissue were measured on high-performance liquid chromatography. RESULTS: We identified a homozygous mutation (M78V-V343A/M78V-V343A) and compound heterozygous mutations (R337X/V343A) in COQ2 in two multiplex families. Furthermore, we found that a common variant (V343A) and multiple rare variants in COQ2, all of which are functionally impaired, are associated with sporadic multiple-system atrophy. The V343A variant was exclusively observed in the Japanese population. CONCLUSIONS: Functionally impaired variants of COQ2 were associated with an increased risk of multiple-system atrophy in multiplex families and patients with sporadic disease, providing evidence of a role of impaired COQ2 activities in the pathogenesis of this disease.

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DO - 10.1056/NEJMoa1212115

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JF - New England Journal of Medicine

SN - 0028-4793

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