title: A Comprehensive Genomic Analysis Reveals the Genetic Landscape of Mitochondrial Respiratory Chain Complex Deficiencies.
abstract: Mitochondrial disorders have the highest incidence among congenital metabolic disorders characterized by biochemical respiratory chain complex deficiencies. It occurs at a rate of 1 in 5,000 births, and has phenotypic and genetic heterogeneity. Mutations in about 1,500 nuclear encoded mitochondrial proteins may cause mitochondrial dysfunction of energy production and mitochondrial disorders. More than 250 genes that cause mitochondrial disorders have been reported to date. However exact genetic diagnosis for patients still remained largely unknown. To reveal this heterogeneity, we performed comprehensive genomic analyses for 142 patients with childhood-onset mitochondrial respiratory chain complex deficiencies. The approach includes whole mtDNA and exome analyses using high-throughput sequencing, and chromosomal aberration analyses using high-density oligonucleotide arrays. We identified 37 novel mutations in known mitochondrial disease genes and 3 mitochondria-related genes (MRPS23, QRSL1, and PNPLA4) as novel causative genes. We also identified 2 genes known to cause monogenic diseases (MECP2 and TNNI3) and 3 chromosomal aberrations (6q24.3-q25.1, 17p12, and 22q11.21) as causes in this cohort. Our approaches enhance the ability to identify pathogenic gene mutations in patients with biochemically defined mitochondrial respiratory chain complex deficiencies in clinical settings. They also underscore clinical and genetic heterogeneity and will improve patient care of this complex disorder.
authors.affiliation: Division of Translational Research, Research Center for Genomic Medicine, Saitama Medical University, Hidaka-shi, Saitama, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Kohda
authors.affiliation: Division of Functional Genomics & Systems Medicine, Research Center for Genomic Medicine, Saitama Medical University, Hidaka-shi, Saitama, Japan.
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Tokuzawa
authors.affiliation: Division of Functional Genomics & Systems Medicine, Research Center for Genomic Medicine, Saitama Medical University, Hidaka-shi, Saitama, Japan.
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Kishita
authors.affiliation: Division of Functional Genomics & Systems Medicine, Research Center for Genomic Medicine, Saitama Medical University, Hidaka-shi, Saitama, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Nyuzuki
authors.affiliation: Division of Functional Genomics & Systems Medicine, Research Center for Genomic Medicine, Saitama Medical University, Hidaka-shi, Saitama, Japan.|Division of Developmental Biology, Research Center for Genomic Medicine, Saitama Medical University, Hidaka-shi, Saitama, Japan.
authors.forename: Yohsuke
authors.initials: Y
authors.lastname: Moriyama
authors.affiliation: Division of Functional Genomics & Systems Medicine, Research Center for Genomic Medicine, Saitama Medical University, Hidaka-shi, Saitama, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Mizuno
authors.affiliation: Division of Translational Research, Research Center for Genomic Medicine, Saitama Medical University, Hidaka-shi, Saitama, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Hirata
authors.affiliation: Division of Functional Genomics & Systems Medicine, Research Center for Genomic Medicine, Saitama Medical University, Hidaka-shi, Saitama, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Yatsuka
authors.affiliation: Division of Functional Genomics & Systems Medicine, Research Center for Genomic Medicine, Saitama Medical University, Hidaka-shi, Saitama, Japan.
authors.forename: Yzumi
authors.initials: Y
authors.lastname: Yamashita-Sugahara
authors.affiliation: Division of Translational Research, Research Center for Genomic Medicine, Saitama Medical University, Hidaka-shi, Saitama, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Nakachi
authors.affiliation: Division of Translational Research, Research Center for Genomic Medicine, Saitama Medical University, Hidaka-shi, Saitama, Japan.|Division of Developmental Biology, Research Center for Genomic Medicine, Saitama Medical University, Hidaka-shi, Saitama, Japan.
authors.forename: Hidemasa
authors.initials: H
authors.lastname: Kato
authors.affiliation: Division of Developmental Biology, Research Center for Genomic Medicine, Saitama Medical University, Hidaka-shi, Saitama, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Okuda
authors.affiliation: Division of Functional Genomics & Systems Medicine, Research Center for Genomic Medicine, Saitama Medical University, Hidaka-shi, Saitama, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Tamaru
authors.affiliation: Division of Functional Genomics & Systems Medicine, Research Center for Genomic Medicine, Saitama Medical University, Hidaka-shi, Saitama, Japan.
authors.forename: Nurun Nahar
authors.initials: NN
authors.lastname: Borna
authors.affiliation: Division of Functional Genomics & Systems Medicine, Research Center for Genomic Medicine, Saitama Medical University, Hidaka-shi, Saitama, Japan.|Chemicals Assessment and Research Center, Chemicals Evaluation and Research Institute, Japan (CERI), Sugito-machi, Kitakatsushika-gun, Saitama, Japan.
authors.forename: Kengo
authors.initials: K
authors.lastname: Banshoya
authors.affiliation: Department of Biological Sciences, Tokyo Metropolitan University, Hachioji, Tokyo, Japan.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Aigaki
authors.affiliation: Department of Biological Sciences, Tokyo Metropolitan University, Hachioji, Tokyo, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Sato-Miyata
authors.affiliation: Department of Biological Sciences, Tokyo Metropolitan University, Hachioji, Tokyo, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Ohnuma
authors.affiliation: Department of Chemistry and Biotechnology, Graduate School of Engineering, University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Department of Chemistry and Biotechnology, Graduate School of Engineering, University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Asuteka
authors.initials: A
authors.lastname: Nagao
authors.affiliation: Department of Chemistry and Biotechnology, Graduate School of Engineering, University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Hazuki
authors.initials: H
authors.lastname: Maehata
authors.affiliation: Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan.
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Matsuda
authors.affiliation: Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Higasa
authors.affiliation: Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Aoba-ku, Sendai, Miyagi, Japan.|Graduate School of Medicine, Tohoku University, Aoba-ku, Sendai, Miyagi, Japan.|Graduate School of Information Sciences, Tohoku University, Sendai, Miyagi, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Nagasaki
authors.affiliation: Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Aoba-ku, Sendai, Miyagi, Japan.|Graduate School of Medicine, Tohoku University, Aoba-ku, Sendai, Miyagi, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Yasuda
authors.affiliation: Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Aoba-ku, Sendai, Miyagi, Japan.|Graduate School of Medicine, Tohoku University, Aoba-ku, Sendai, Miyagi, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: Department of Metabolism, Chiba Children's Hospital, Midori, Chiba, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Fushimi
authors.affiliation: Department of Metabolism, Chiba Children's Hospital, Midori, Chiba, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Shimura
authors.affiliation: Department of Metabolism, Chiba Children's Hospital, Midori, Chiba, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Kaiho-Ichimoto
authors.affiliation: Department of Pediatrics, Saitama Medical University, Moroyama-machi, Iruma-gun, Saitama, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Harashima
authors.affiliation: Department of Pediatrics, Saitama Medical University, Moroyama-machi, Iruma-gun, Saitama, Japan.
authors.forename: Taro
authors.initials: T
authors.lastname: Yamazaki
authors.affiliation: Department of Pediatrics, Matsudo City Hospital, Matsudo-shi, Chiba, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Mori
authors.affiliation: Department of Metabolism, Chiba Children's Hospital, Midori, Chiba, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Murayama
authors.affiliation: Department of Pediatrics, Saitama Medical University, Moroyama-machi, Iruma-gun, Saitama, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Ohtake
authors.affiliation: Division of Translational Research, Research Center for Genomic Medicine, Saitama Medical University, Hidaka-shi, Saitama, Japan.|Division of Functional Genomics & Systems Medicine, Research Center for Genomic Medicine, Saitama Medical University, Hidaka-shi, Saitama, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Okazaki
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D002869:Chromosome Aberrations; D004272:DNA, Mitochondrial / Q000235:genetics; D059472:Exome / Q000235:genetics*; D005260:Female; D005347:Fibroblasts; D018740:Genetic Heterogeneity; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D054643:INDEL Mutation / Q000235:genetics; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008928:Mitochondria / Q000235:genetics* / Q000473:pathology; D028361:Mitochondrial Diseases / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
chemical_list: D004272:DNA, Mitochondrial