IBA57 mutations abrogate iron-sulfur cluster assembly leading to cavitating leukoencephalopathy

Akihiko Ishiyama, Chika Sakai, Yuichi Matsushima, Satoru Noguchi, Satomi Mitsuhashi, Yukari Endo, Yukiko K. Hayashi, Yoshiaki Saito, Eiji Nakagawa, Hirofumi Komaki, Kenji Sugai, Masayuki Sasaki, Noriko Sato, Ikuya Nonaka, Yu Ichi Goto, Ichizo Nishino

研究成果: ジャーナルへの寄稿記事

5 引用 (Scopus)

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Objective: To determine the molecular factors contributing to progressive cavitating leukoencephalopathy (PCL) to help resolve the underlying genotype-phenotype associations in the mitochondrial iron-sulfur cluster (ISC) assembly system. Methods: The subjects were 3 patients from 2 families who showed no inconsistencies in either clinical or brain MRI findings as PCL. We used exome sequencing, immunoblotting, and enzyme activity assays to establish a molecular diagnosis and determine the roles of ISC-associated factors in PCL. Results: We performed genetic analyses on these 3 patients and identified compound heterozygosity for the IBA57 gene, which encodes the mitochondrial iron-sulfur protein assembly factor. Protein expression analysis revealed substantial decreases in IBA57 protein expression in myoblasts and fibroblasts. Immunoblotting revealed substantially reduced expression of SDHB, a subunit of complex II, and lipoic acid synthetase (LIAS). Levels of pyruvate dehydrogenase complex-E2 and a-ketoglutarate dehydrogenase-E2, which use lipoic acid as a cofactor, were also reduced. In activity staining, SDH activity was clearly reduced, but it was ameliorated in mitochondrial fractions from rescued myoblasts. In addition, NFU1 protein expression was also decreased, which is required for the assembly of a subset of iron-sulfur proteins to SDH and LIAS in the mitochondrial ISC assembly system. Conclusions: Defects in IBA57 essentially regulate NFU1 expression, and aberrant NFU1 ultimately affects SDH activity and LIAS expression in the ISC biogenesis pathway. This study provides new insights into the role of the iron-sulfur protein assembly system in disorders related to mitochondrial energy metabolism associated with leukoencephalopathy with cavities.

元の言語英語
記事番号e184
ジャーナルNeurology: Genetics
3
発行部数5
DOI
出版物ステータス出版済み - 10 1 2017

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Leukoencephalopathies
Thioctic Acid
Iron-Sulfur Proteins
Sulfur
Ligases
Iron
Mutation
Myoblasts
Immunoblotting
Dihydrolipoyllysine-Residue Acetyltransferase
Exome
Proteins
Mitochondrial Proteins
Enzyme Assays
Genetic Association Studies
Energy Metabolism
Oxidoreductases
Fibroblasts
Staining and Labeling
Brain

All Science Journal Classification (ASJC) codes

  • Clinical Neurology
  • Genetics(clinical)

これを引用

IBA57 mutations abrogate iron-sulfur cluster assembly leading to cavitating leukoencephalopathy. / Ishiyama, Akihiko; Sakai, Chika; Matsushima, Yuichi; Noguchi, Satoru; Mitsuhashi, Satomi; Endo, Yukari; Hayashi, Yukiko K.; Saito, Yoshiaki; Nakagawa, Eiji; Komaki, Hirofumi; Sugai, Kenji; Sasaki, Masayuki; Sato, Noriko; Nonaka, Ikuya; Goto, Yu Ichi; Nishino, Ichizo.

:: Neurology: Genetics, 巻 3, 番号 5, e184, 01.10.2017.

研究成果: ジャーナルへの寄稿記事

Ishiyama, A, Sakai, C, Matsushima, Y, Noguchi, S, Mitsuhashi, S, Endo, Y, Hayashi, YK, Saito, Y, Nakagawa, E, Komaki, H, Sugai, K, Sasaki, M, Sato, N, Nonaka, I, Goto, YI & Nishino, I 2017, 'IBA57 mutations abrogate iron-sulfur cluster assembly leading to cavitating leukoencephalopathy', Neurology: Genetics, 巻. 3, 番号 5, e184. https://doi.org/10.1212/NXG.0000000000000184
Ishiyama, Akihiko ; Sakai, Chika ; Matsushima, Yuichi ; Noguchi, Satoru ; Mitsuhashi, Satomi ; Endo, Yukari ; Hayashi, Yukiko K. ; Saito, Yoshiaki ; Nakagawa, Eiji ; Komaki, Hirofumi ; Sugai, Kenji ; Sasaki, Masayuki ; Sato, Noriko ; Nonaka, Ikuya ; Goto, Yu Ichi ; Nishino, Ichizo. / IBA57 mutations abrogate iron-sulfur cluster assembly leading to cavitating leukoencephalopathy. :: Neurology: Genetics. 2017 ; 巻 3, 番号 5.
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abstract = "Objective: To determine the molecular factors contributing to progressive cavitating leukoencephalopathy (PCL) to help resolve the underlying genotype-phenotype associations in the mitochondrial iron-sulfur cluster (ISC) assembly system. Methods: The subjects were 3 patients from 2 families who showed no inconsistencies in either clinical or brain MRI findings as PCL. We used exome sequencing, immunoblotting, and enzyme activity assays to establish a molecular diagnosis and determine the roles of ISC-associated factors in PCL. Results: We performed genetic analyses on these 3 patients and identified compound heterozygosity for the IBA57 gene, which encodes the mitochondrial iron-sulfur protein assembly factor. Protein expression analysis revealed substantial decreases in IBA57 protein expression in myoblasts and fibroblasts. Immunoblotting revealed substantially reduced expression of SDHB, a subunit of complex II, and lipoic acid synthetase (LIAS). Levels of pyruvate dehydrogenase complex-E2 and a-ketoglutarate dehydrogenase-E2, which use lipoic acid as a cofactor, were also reduced. In activity staining, SDH activity was clearly reduced, but it was ameliorated in mitochondrial fractions from rescued myoblasts. In addition, NFU1 protein expression was also decreased, which is required for the assembly of a subset of iron-sulfur proteins to SDH and LIAS in the mitochondrial ISC assembly system. Conclusions: Defects in IBA57 essentially regulate NFU1 expression, and aberrant NFU1 ultimately affects SDH activity and LIAS expression in the ISC biogenesis pathway. This study provides new insights into the role of the iron-sulfur protein assembly system in disorders related to mitochondrial energy metabolism associated with leukoencephalopathy with cavities.",
author = "Akihiko Ishiyama and Chika Sakai and Yuichi Matsushima and Satoru Noguchi and Satomi Mitsuhashi and Yukari Endo and Hayashi, {Yukiko K.} and Yoshiaki Saito and Eiji Nakagawa and Hirofumi Komaki and Kenji Sugai and Masayuki Sasaki and Noriko Sato and Ikuya Nonaka and Goto, {Yu Ichi} and Ichizo Nishino",
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T1 - IBA57 mutations abrogate iron-sulfur cluster assembly leading to cavitating leukoencephalopathy

AU - Ishiyama, Akihiko

AU - Sakai, Chika

AU - Matsushima, Yuichi

AU - Noguchi, Satoru

AU - Mitsuhashi, Satomi

AU - Endo, Yukari

AU - Hayashi, Yukiko K.

AU - Saito, Yoshiaki

AU - Nakagawa, Eiji

AU - Komaki, Hirofumi

AU - Sugai, Kenji

AU - Sasaki, Masayuki

AU - Sato, Noriko

AU - Nonaka, Ikuya

AU - Goto, Yu Ichi

AU - Nishino, Ichizo

PY - 2017/10/1

Y1 - 2017/10/1

N2 - Objective: To determine the molecular factors contributing to progressive cavitating leukoencephalopathy (PCL) to help resolve the underlying genotype-phenotype associations in the mitochondrial iron-sulfur cluster (ISC) assembly system. Methods: The subjects were 3 patients from 2 families who showed no inconsistencies in either clinical or brain MRI findings as PCL. We used exome sequencing, immunoblotting, and enzyme activity assays to establish a molecular diagnosis and determine the roles of ISC-associated factors in PCL. Results: We performed genetic analyses on these 3 patients and identified compound heterozygosity for the IBA57 gene, which encodes the mitochondrial iron-sulfur protein assembly factor. Protein expression analysis revealed substantial decreases in IBA57 protein expression in myoblasts and fibroblasts. Immunoblotting revealed substantially reduced expression of SDHB, a subunit of complex II, and lipoic acid synthetase (LIAS). Levels of pyruvate dehydrogenase complex-E2 and a-ketoglutarate dehydrogenase-E2, which use lipoic acid as a cofactor, were also reduced. In activity staining, SDH activity was clearly reduced, but it was ameliorated in mitochondrial fractions from rescued myoblasts. In addition, NFU1 protein expression was also decreased, which is required for the assembly of a subset of iron-sulfur proteins to SDH and LIAS in the mitochondrial ISC assembly system. Conclusions: Defects in IBA57 essentially regulate NFU1 expression, and aberrant NFU1 ultimately affects SDH activity and LIAS expression in the ISC biogenesis pathway. This study provides new insights into the role of the iron-sulfur protein assembly system in disorders related to mitochondrial energy metabolism associated with leukoencephalopathy with cavities.

AB - Objective: To determine the molecular factors contributing to progressive cavitating leukoencephalopathy (PCL) to help resolve the underlying genotype-phenotype associations in the mitochondrial iron-sulfur cluster (ISC) assembly system. Methods: The subjects were 3 patients from 2 families who showed no inconsistencies in either clinical or brain MRI findings as PCL. We used exome sequencing, immunoblotting, and enzyme activity assays to establish a molecular diagnosis and determine the roles of ISC-associated factors in PCL. Results: We performed genetic analyses on these 3 patients and identified compound heterozygosity for the IBA57 gene, which encodes the mitochondrial iron-sulfur protein assembly factor. Protein expression analysis revealed substantial decreases in IBA57 protein expression in myoblasts and fibroblasts. Immunoblotting revealed substantially reduced expression of SDHB, a subunit of complex II, and lipoic acid synthetase (LIAS). Levels of pyruvate dehydrogenase complex-E2 and a-ketoglutarate dehydrogenase-E2, which use lipoic acid as a cofactor, were also reduced. In activity staining, SDH activity was clearly reduced, but it was ameliorated in mitochondrial fractions from rescued myoblasts. In addition, NFU1 protein expression was also decreased, which is required for the assembly of a subset of iron-sulfur proteins to SDH and LIAS in the mitochondrial ISC assembly system. Conclusions: Defects in IBA57 essentially regulate NFU1 expression, and aberrant NFU1 ultimately affects SDH activity and LIAS expression in the ISC biogenesis pathway. This study provides new insights into the role of the iron-sulfur protein assembly system in disorders related to mitochondrial energy metabolism associated with leukoencephalopathy with cavities.

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U2 - 10.1212/NXG.0000000000000184

DO - 10.1212/NXG.0000000000000184

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