A Novel Variation in the Mitochondrial Complex I Assembly Factor NDUFAF5 Causes Isolated Bilateral Striatal Necrosis in Childhood

Background: Bilateral striatal necrosis (BSN) is characterized by symmetrical degeneration, predominantly of the caudate and putamen nucleus, in the basal ganglia. It is associated with numerous acquired and hereditary neuro-developmental and motor dysfunction-related pathological conditions. BSN re...

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Autores principales:	Hongyan Bi, Hui Guo, Qianfei Wang, Xiao Zhang, Yaming Zhao, Jimei Li, Weiqin Zhao, Houzhen Tuo, Yongbo Zhang
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	bilateral striatal necrosis NDUFAF5 mitochondrial complex I deficiency whole-exome sequencing novel variation Neurology. Diseases of the nervous system RC346-429
Acceso en línea:	https://doaj.org/article/2250786dd9e444e2a7c31cad979b8bcd
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spelling	oai:doaj.org-article:2250786dd9e444e2a7c31cad979b8bcd2021-11-08T13:39:36ZA Novel Variation in the Mitochondrial Complex I Assembly Factor NDUFAF5 Causes Isolated Bilateral Striatal Necrosis in Childhood1664-229510.3389/fneur.2021.675616https://doaj.org/article/2250786dd9e444e2a7c31cad979b8bcd2021-06-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fneur.2021.675616/fullhttps://doaj.org/toc/1664-2295Background: Bilateral striatal necrosis (BSN) is characterized by symmetrical degeneration, predominantly of the caudate and putamen nucleus, in the basal ganglia. It is associated with numerous acquired and hereditary neuro-developmental and motor dysfunction-related pathological conditions. BSN results in high morbidity and mortality among infants and children, and its diagnosis is clinically challenging due to several overlapping disease phenotypes. Therefore, a precise genetic diagnosis is urgently needed for accurate genetic counseling and improved prognostic outcomes as well.Objective: To identify novel missense mutations in the NDUFAF5 gene as a cause of childhood BSN in members of a Chinese family and summarize the clinical characteristics of patients with the NDUFAF5 gene mutations.Methods: This study included a large family living in a remote northwestern area of China. Three siblings developed a neurological disorder characterized by generalized dystonia within the first decade of their lives. Cerebral computed tomography (CT) and magnetic resonance imaging (MRI) showed bilateral lesions of the putamen. Biochemical and genetic approaches were used to identify the cause of BSN.Results: Sequence analysis showed no pathogenic variation in PANK2, SLC25A19, SLC19A3, and NUP62 genes and in the entire mitochondrial genome as well. Whole-exome sequencing revealed compound heterozygous mutations consisting of NDUFAF5:c.425A > C(p.E142A) and c.836T > G (p.M279R). The father, a healthy sister, and a healthy brother of the affected siblings carried the c.836T > G mutation, and the mother carried the c.425A > C mutation. These variants were absent in 100 ethnically matched non-BSN controls. In silico analysis demonstrated that the E142A and M279R mutations in NDUFAF5 protein significantly perturbed the normal conformation of the protein due to alterations in the hydrogen bonding patterns around the evolutionarily conserved catalytic domains, leading to its loss of function in the early stage of mitochondrial complex I assembly.Conclusions: We identified a novel compound heterozygous mutation (c.425A > C and c.836T > G) in the NDUFAF5 gene as the potential cause of autosomal recessive childhood BSN, which extended the pathogenic variation spectrum of the NDUFAF5 gene. This study provides substantial evidence for further improvement of genetic counseling and better clinical management of BSN affected individuals.Hongyan BiHui GuoQianfei WangXiao ZhangYaming ZhaoJimei LiWeiqin ZhaoHouzhen TuoYongbo ZhangFrontiers Media S.A.articlebilateral striatal necrosisNDUFAF5mitochondrial complex I deficiencywhole-exome sequencingnovel variationNeurology. Diseases of the nervous systemRC346-429ENFrontiers in Neurology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	bilateral striatal necrosis NDUFAF5 mitochondrial complex I deficiency whole-exome sequencing novel variation Neurology. Diseases of the nervous system RC346-429
spellingShingle	bilateral striatal necrosis NDUFAF5 mitochondrial complex I deficiency whole-exome sequencing novel variation Neurology. Diseases of the nervous system RC346-429 Hongyan Bi Hui Guo Qianfei Wang Xiao Zhang Yaming Zhao Jimei Li Weiqin Zhao Houzhen Tuo Yongbo Zhang A Novel Variation in the Mitochondrial Complex I Assembly Factor NDUFAF5 Causes Isolated Bilateral Striatal Necrosis in Childhood
description	Background: Bilateral striatal necrosis (BSN) is characterized by symmetrical degeneration, predominantly of the caudate and putamen nucleus, in the basal ganglia. It is associated with numerous acquired and hereditary neuro-developmental and motor dysfunction-related pathological conditions. BSN results in high morbidity and mortality among infants and children, and its diagnosis is clinically challenging due to several overlapping disease phenotypes. Therefore, a precise genetic diagnosis is urgently needed for accurate genetic counseling and improved prognostic outcomes as well.Objective: To identify novel missense mutations in the NDUFAF5 gene as a cause of childhood BSN in members of a Chinese family and summarize the clinical characteristics of patients with the NDUFAF5 gene mutations.Methods: This study included a large family living in a remote northwestern area of China. Three siblings developed a neurological disorder characterized by generalized dystonia within the first decade of their lives. Cerebral computed tomography (CT) and magnetic resonance imaging (MRI) showed bilateral lesions of the putamen. Biochemical and genetic approaches were used to identify the cause of BSN.Results: Sequence analysis showed no pathogenic variation in PANK2, SLC25A19, SLC19A3, and NUP62 genes and in the entire mitochondrial genome as well. Whole-exome sequencing revealed compound heterozygous mutations consisting of NDUFAF5:c.425A > C(p.E142A) and c.836T > G (p.M279R). The father, a healthy sister, and a healthy brother of the affected siblings carried the c.836T > G mutation, and the mother carried the c.425A > C mutation. These variants were absent in 100 ethnically matched non-BSN controls. In silico analysis demonstrated that the E142A and M279R mutations in NDUFAF5 protein significantly perturbed the normal conformation of the protein due to alterations in the hydrogen bonding patterns around the evolutionarily conserved catalytic domains, leading to its loss of function in the early stage of mitochondrial complex I assembly.Conclusions: We identified a novel compound heterozygous mutation (c.425A > C and c.836T > G) in the NDUFAF5 gene as the potential cause of autosomal recessive childhood BSN, which extended the pathogenic variation spectrum of the NDUFAF5 gene. This study provides substantial evidence for further improvement of genetic counseling and better clinical management of BSN affected individuals.
format	article
author	Hongyan Bi Hui Guo Qianfei Wang Xiao Zhang Yaming Zhao Jimei Li Weiqin Zhao Houzhen Tuo Yongbo Zhang
author_facet	Hongyan Bi Hui Guo Qianfei Wang Xiao Zhang Yaming Zhao Jimei Li Weiqin Zhao Houzhen Tuo Yongbo Zhang
author_sort	Hongyan Bi
title	A Novel Variation in the Mitochondrial Complex I Assembly Factor NDUFAF5 Causes Isolated Bilateral Striatal Necrosis in Childhood
title_short	A Novel Variation in the Mitochondrial Complex I Assembly Factor NDUFAF5 Causes Isolated Bilateral Striatal Necrosis in Childhood
title_full	A Novel Variation in the Mitochondrial Complex I Assembly Factor NDUFAF5 Causes Isolated Bilateral Striatal Necrosis in Childhood
title_fullStr	A Novel Variation in the Mitochondrial Complex I Assembly Factor NDUFAF5 Causes Isolated Bilateral Striatal Necrosis in Childhood
title_full_unstemmed	A Novel Variation in the Mitochondrial Complex I Assembly Factor NDUFAF5 Causes Isolated Bilateral Striatal Necrosis in Childhood
title_sort	novel variation in the mitochondrial complex i assembly factor ndufaf5 causes isolated bilateral striatal necrosis in childhood
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/2250786dd9e444e2a7c31cad979b8bcd
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A Novel Variation in the Mitochondrial Complex I Assembly Factor NDUFAF5 Causes Isolated Bilateral Striatal Necrosis in Childhood

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