Identification of novel compound heterozygous mutations in ACO2 in a patient with progressive cerebral and cerebellar atrophy
Abstract Background The tricarboxylic acid (TCA) cycle is a sequence of catabolic reactions within the mitochondrial matrix, and is a central pathway for cellular energy metabolism. Genetic defects affecting the TCA cycle are known to cause severe multisystem disorders. Methods We performed whole ex...
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doaj-61d99489bb1e4106bf9ccef9fc2a59952020-11-25T02:07:50ZengWileyMolecular Genetics & Genomic Medicine2324-92692019-07-0177n/an/a10.1002/mgg3.698Identification of novel compound heterozygous mutations in ACO2 in a patient with progressive cerebral and cerebellar atrophyMasahide Fukada0Keitaro Yamada1Shima Eda2Ken Inoue3Chihiro Ohba4Naomichi Matsumoto5Hirotomo Saitsu6Atsuo Nakayama7Department of Embryology Institute for Developmental Research, Aichi Human Service Center Kasugai JapanDepartment of Pediatric Neurology Aichi Prefectural Colony Central Hospital, Aichi Human Service Center Kasugai JapanDepartment of Embryology Institute for Developmental Research, Aichi Human Service Center Kasugai JapanDepartment of Mental Retardation and Birth Defect Research National Center of Neurology and Psychiatry Kodaira, Tokyo JapanDepartment of Human Genetics Yokohama City University Graduate School of Medicine Yokohama JapanDepartment of Human Genetics Yokohama City University Graduate School of Medicine Yokohama JapanDepartment of Biochemistry Hamamatsu University School of Medicine Hamamatsu JapanDepartment of Embryology Institute for Developmental Research, Aichi Human Service Center Kasugai JapanAbstract Background The tricarboxylic acid (TCA) cycle is a sequence of catabolic reactions within the mitochondrial matrix, and is a central pathway for cellular energy metabolism. Genetic defects affecting the TCA cycle are known to cause severe multisystem disorders. Methods We performed whole exome sequencing of genomic DNA of a patient with progressive cerebellar and cerebral atrophy, hypotonia, ataxia, seizure disorder, developmental delay, ophthalmological abnormalities and hearing loss. We also performed biochemical studies using patient fibroblasts. Results We identified new compound heterozygous mutations (c.1534G > A, p.Asp512Asn and c.1997G > C, p.Gly666Ala) in ACO2, which encodes aconitase 2, a component of the TCA cycle. In patient fibroblasts, the aconitase activity was reduced to 15% of that of the control, and the aconitase 2 level decreased to 36% of that of the control. As such a decrease in aconitase 2 in patient fibroblasts was partially restored by proteasome inhibition, mutant aconitase 2 was suggested to be relatively unstable and rapidly degraded after being synthesized. In addition, the activity of the father‐derived variant of aconitase 2 (p.Gly666Ala), which had a mutation near the active center, was 55% of that of wild‐type. Conclusion The marked reduction of aconitase activity in patient fibroblasts was due to the combination of decreased aconitase 2 amount and activity due to mutations. Reduced aconitase activity directly suppresses the TCA cycle, resulting in mitochondrial dysfunction, which may lead to symptoms similar to those observed in mitochondrial diseases.https://doi.org/10.1002/mgg3.698ACO2aconitaseTCA cyclemitochondriabrain atrophyataxia |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Masahide Fukada Keitaro Yamada Shima Eda Ken Inoue Chihiro Ohba Naomichi Matsumoto Hirotomo Saitsu Atsuo Nakayama |
spellingShingle |
Masahide Fukada Keitaro Yamada Shima Eda Ken Inoue Chihiro Ohba Naomichi Matsumoto Hirotomo Saitsu Atsuo Nakayama Identification of novel compound heterozygous mutations in ACO2 in a patient with progressive cerebral and cerebellar atrophy Molecular Genetics & Genomic Medicine ACO2 aconitase TCA cycle mitochondria brain atrophy ataxia |
author_facet |
Masahide Fukada Keitaro Yamada Shima Eda Ken Inoue Chihiro Ohba Naomichi Matsumoto Hirotomo Saitsu Atsuo Nakayama |
author_sort |
Masahide Fukada |
title |
Identification of novel compound heterozygous mutations in ACO2 in a patient with progressive cerebral and cerebellar atrophy |
title_short |
Identification of novel compound heterozygous mutations in ACO2 in a patient with progressive cerebral and cerebellar atrophy |
title_full |
Identification of novel compound heterozygous mutations in ACO2 in a patient with progressive cerebral and cerebellar atrophy |
title_fullStr |
Identification of novel compound heterozygous mutations in ACO2 in a patient with progressive cerebral and cerebellar atrophy |
title_full_unstemmed |
Identification of novel compound heterozygous mutations in ACO2 in a patient with progressive cerebral and cerebellar atrophy |
title_sort |
identification of novel compound heterozygous mutations in aco2 in a patient with progressive cerebral and cerebellar atrophy |
publisher |
Wiley |
series |
Molecular Genetics & Genomic Medicine |
issn |
2324-9269 |
publishDate |
2019-07-01 |
description |
Abstract Background The tricarboxylic acid (TCA) cycle is a sequence of catabolic reactions within the mitochondrial matrix, and is a central pathway for cellular energy metabolism. Genetic defects affecting the TCA cycle are known to cause severe multisystem disorders. Methods We performed whole exome sequencing of genomic DNA of a patient with progressive cerebellar and cerebral atrophy, hypotonia, ataxia, seizure disorder, developmental delay, ophthalmological abnormalities and hearing loss. We also performed biochemical studies using patient fibroblasts. Results We identified new compound heterozygous mutations (c.1534G > A, p.Asp512Asn and c.1997G > C, p.Gly666Ala) in ACO2, which encodes aconitase 2, a component of the TCA cycle. In patient fibroblasts, the aconitase activity was reduced to 15% of that of the control, and the aconitase 2 level decreased to 36% of that of the control. As such a decrease in aconitase 2 in patient fibroblasts was partially restored by proteasome inhibition, mutant aconitase 2 was suggested to be relatively unstable and rapidly degraded after being synthesized. In addition, the activity of the father‐derived variant of aconitase 2 (p.Gly666Ala), which had a mutation near the active center, was 55% of that of wild‐type. Conclusion The marked reduction of aconitase activity in patient fibroblasts was due to the combination of decreased aconitase 2 amount and activity due to mutations. Reduced aconitase activity directly suppresses the TCA cycle, resulting in mitochondrial dysfunction, which may lead to symptoms similar to those observed in mitochondrial diseases. |
topic |
ACO2 aconitase TCA cycle mitochondria brain atrophy ataxia |
url |
https://doi.org/10.1002/mgg3.698 |
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