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Bilateral striatal necrosis due to homoplasmic mitochondrial 3697G>A mutation presents with incomplete penetrance and sex bias

BACKGROUND: Heteroplasmic mitochondrial 3697G>A mutation has been associated with leber hereditary optic neuropathy (LHON), mitochondrial encephalopathy, lactic acidosis and stroke‐like episodes (MELAS), and LHON/MELAS overlap syndrome. However, homoplasmic m.3697G>A mutation was only found in...

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Autores principales: Zhong, Shanshan, Wen, Shumeng, Qiu, Yusen, Yu, Yanyan, Xin, Ling, He, Yang, Gao, Xuguang, Fang, Hezhi, Hong, Daojun, Zhang, Jun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6418351/
https://www.ncbi.nlm.nih.gov/pubmed/30623604
http://dx.doi.org/10.1002/mgg3.541
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author Zhong, Shanshan
Wen, Shumeng
Qiu, Yusen
Yu, Yanyan
Xin, Ling
He, Yang
Gao, Xuguang
Fang, Hezhi
Hong, Daojun
Zhang, Jun
author_facet Zhong, Shanshan
Wen, Shumeng
Qiu, Yusen
Yu, Yanyan
Xin, Ling
He, Yang
Gao, Xuguang
Fang, Hezhi
Hong, Daojun
Zhang, Jun
author_sort Zhong, Shanshan
collection PubMed
description BACKGROUND: Heteroplasmic mitochondrial 3697G>A mutation has been associated with leber hereditary optic neuropathy (LHON), mitochondrial encephalopathy, lactic acidosis and stroke‐like episodes (MELAS), and LHON/MELAS overlap syndrome. However, homoplasmic m.3697G>A mutation was only found in a family with Leigh syndrome, and the phenotype and pathogenicity of this homoplasmic mutation still need to be investigated in new patients. METHODS: The clinical interviews were conducted in 12 individuals from a multiple‐generation inherited family. Mutations were screened through exome next‐generation sequencing and subsequently confirmed by PCR‐restriction fragment length polymorphism. Mitochondrial complex activities and ATP production rate were measured by biochemical analysis. RESULTS: The male offspring with bilateral striatal necrosis (BSN) were characterized by severe spastic dystonia and complete penetrance, while the female offspring presented with mild symptom and low penetrance. All offspring carried homoplasmic mutation of NC_012920.1: m.3697G>A, p.(Gly131Ser). Biochemical analysis revealed an isolated defect of complex I, but the magnitude of the defect was higher in the male patients than that in the female ones. The ATP production rate also exhibited a similar pattern. However, no possible modifier genes on the X chromosome were identified. CONCLUSION: Homoplasmic m.3697G>A mutation could be associated with BSN, which expanded the clinical spectrum of m.3697G>A. Our preliminary investigations had not found the underlying modifiers to support the double hit hypothesis, while the high level of estrogens in the female patients might exert a potential compensatory effect on mutant cell metabolism.
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spelling pubmed-64183512019-03-27 Bilateral striatal necrosis due to homoplasmic mitochondrial 3697G>A mutation presents with incomplete penetrance and sex bias Zhong, Shanshan Wen, Shumeng Qiu, Yusen Yu, Yanyan Xin, Ling He, Yang Gao, Xuguang Fang, Hezhi Hong, Daojun Zhang, Jun Mol Genet Genomic Med Original Articles BACKGROUND: Heteroplasmic mitochondrial 3697G>A mutation has been associated with leber hereditary optic neuropathy (LHON), mitochondrial encephalopathy, lactic acidosis and stroke‐like episodes (MELAS), and LHON/MELAS overlap syndrome. However, homoplasmic m.3697G>A mutation was only found in a family with Leigh syndrome, and the phenotype and pathogenicity of this homoplasmic mutation still need to be investigated in new patients. METHODS: The clinical interviews were conducted in 12 individuals from a multiple‐generation inherited family. Mutations were screened through exome next‐generation sequencing and subsequently confirmed by PCR‐restriction fragment length polymorphism. Mitochondrial complex activities and ATP production rate were measured by biochemical analysis. RESULTS: The male offspring with bilateral striatal necrosis (BSN) were characterized by severe spastic dystonia and complete penetrance, while the female offspring presented with mild symptom and low penetrance. All offspring carried homoplasmic mutation of NC_012920.1: m.3697G>A, p.(Gly131Ser). Biochemical analysis revealed an isolated defect of complex I, but the magnitude of the defect was higher in the male patients than that in the female ones. The ATP production rate also exhibited a similar pattern. However, no possible modifier genes on the X chromosome were identified. CONCLUSION: Homoplasmic m.3697G>A mutation could be associated with BSN, which expanded the clinical spectrum of m.3697G>A. Our preliminary investigations had not found the underlying modifiers to support the double hit hypothesis, while the high level of estrogens in the female patients might exert a potential compensatory effect on mutant cell metabolism. John Wiley and Sons Inc. 2019-01-08 /pmc/articles/PMC6418351/ /pubmed/30623604 http://dx.doi.org/10.1002/mgg3.541 Text en © 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Zhong, Shanshan
Wen, Shumeng
Qiu, Yusen
Yu, Yanyan
Xin, Ling
He, Yang
Gao, Xuguang
Fang, Hezhi
Hong, Daojun
Zhang, Jun
Bilateral striatal necrosis due to homoplasmic mitochondrial 3697G>A mutation presents with incomplete penetrance and sex bias
title Bilateral striatal necrosis due to homoplasmic mitochondrial 3697G>A mutation presents with incomplete penetrance and sex bias
title_full Bilateral striatal necrosis due to homoplasmic mitochondrial 3697G>A mutation presents with incomplete penetrance and sex bias
title_fullStr Bilateral striatal necrosis due to homoplasmic mitochondrial 3697G>A mutation presents with incomplete penetrance and sex bias
title_full_unstemmed Bilateral striatal necrosis due to homoplasmic mitochondrial 3697G>A mutation presents with incomplete penetrance and sex bias
title_short Bilateral striatal necrosis due to homoplasmic mitochondrial 3697G>A mutation presents with incomplete penetrance and sex bias
title_sort bilateral striatal necrosis due to homoplasmic mitochondrial 3697g>a mutation presents with incomplete penetrance and sex bias
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6418351/
https://www.ncbi.nlm.nih.gov/pubmed/30623604
http://dx.doi.org/10.1002/mgg3.541
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