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

ABSTRACT: 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.

SUBMITTER: Zhong S

PROVIDER: S-EPMC6418351 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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

Zhong Shanshan S Wen Shumeng S Qiu Yusen Y Yu Yanyan Y Xin Ling L He Yang Y Gao Xuguang X Fang Hezhi H Hong Daojun D Zhang Jun J

Molecular genetics & genomic medicine 20190108 3

<h4>Background</h4>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.<h4>Methods</h4>The clinical interviews were conducted in ...[more]

PMID: 30623604

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Project description:PurposeTo identify the molecular mechanisms of the development of autosomal dominant retinitis pigmentosa (adRP) with incomplete penetrance in an Israeli Muslim Arab family.MethodsTwo patients with adRP underwent a detailed ophthalmic evaluation, including funduscopic examination, visual field testing, optical coherence tomography, and electroretinography. Genetic analysis was performed using a combination of whole exome sequencing (WES) and Sanger sequencing. The pathogenicity of the identified intronic variant was evaluated in silico using several web-based tools, in vitro using a minigene-based assay, and in vivo using reverse transcription PCR analysis of lymphocyte-derived RNA. The relative abundance of alternatively spliced transcripts was evaluated using amplicon-based next-generation sequencing. The relative expression levels of PRPF31 and CNOT3 were measured using quantitative PCR (qPCR) analysis.ResultsThe two patients recruited in this study had childhood-onset RP, with night blindness as the initial symptom, followed by concentric restriction of the visual field. The funduscopic findings included narrowed retinal blood vessels and peripheral bone spicule pigmentation. By the third decade of life, the full-field electroretinography findings had been remarkably attenuated. In these patients, we identified a novel heterozygous intronic variant at position +5 of PRPF31 intron 11 (c.1146+5G>T). The same variant was also detected in one asymptomatic family member. Through in silico analysis, the variant was predicted to alter the splicing of intron 11. An in vitro splicing assay and a reverse transcription PCR analysis of lymphocyte-derived RNA revealed that the mutant allele yielded mainly a shorter transcript in which exon 11 was skipped. The skipping of exon 11 was expected to cause a frameshift and an aberrant truncated protein (p.Tyr359Serfs*29). The qPCR analysis revealed reduced PRPF31 expression levels in the mutation carriers, without a significant difference between the affected patient and his asymptomatic brother. We evaluated several factors that have been suggested to correlate with non-penetrance of PRPF31 mutations, including the number of cis-acting MSR1 elements adjacent to the PRPF31 core promoter, CNOT3 expression level, and CNOT3 rs4806718 single-nucleotide polymorphism. None of these factors correlated with non-penetrance in the family in this study.ConclusionsWe report a novel intronic mutation in PRPF31 underlying adRP. This report expands the spectrum of pathogenic mutations in PRPF31 and further demonstrates the importance of intronic mutations. Moreover, it demonstrates the phenomenon of incomplete penetrance previously associated with PRPF31 mutations. The fact that the non-penetrance in the family in this study could not be explained by any of the known mechanisms suggests the possible contribution of a novel modifier of PRPF31 penetrance.

Project 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.

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

Publications

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

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