Deep sequencing discovery of causal mtDNA mutations in a patient with unspecific neurological disease

Spangenberg, Lucía; Graña, Martín; Mansilla, Santiago; Martínez, Jennyfer; Tapié, Alejandra; Greif, Gonzalo; Montano, Nélida; Vaglio, Alicia; Gueçaimburú, Rosario; Robello, Carlos; Castro, Laura; Quijano, Celia; Raggio, Víctor; Naya, Hugo

doi:10.1016/j.mito.2018.09.004

Cited by 6 publications

(2 citation statements)

References 39 publications

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“…We wondered if compensatory processes, such as an increase in mitochondrial biogenesis, could be taking place in PBMCs [ 7 , 49 – 52 ]. To explore this possibility, we determined the number of copies of mtDNA in PBMCs, from the patient and control individuals, but found lower or similar levels in the patient.…”

Section: Discussionmentioning

confidence: 99%

Computational and mitochondrial functional studies of novel compound heterozygous variants in SPATA5 gene support a causal link with epileptogenic encephalopathy

et al. 2023

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The SPATA5 gene encodes a 892 amino-acids long protein that has a putative mitochondrial targeting sequence and has been proposed to function in maintenance of mitochondrial function and integrity during mouse spermatogenesis. Several studies have associated homozygous or compound heterozygous mutations in SPATA5 gene to microcephaly, intellectual disability, seizures and hearing loss. This suggests a role of the SPATA5 gene also in neuronal development. Recently, our group presented results validating the use of blood cells for the assessment of mitochondrial function for diagnosis and follow-up of mitochondrial disease, minimizing the need for invasive procedures such as muscle biopsy. In this study, we were able to diagnose a patient with epileptogenic encephalopathy using next generation sequencing. We found two novel compound heterozygous variants in SPATA5 that are most likely causative. To analyze the impact of SPATA5 mutations on mitochondrial functional studies directly on the patients' mononuclear cells and platelets were undertaken. Oxygen consumption rates in platelets and PBMCs were impaired in the patient when compared to a healthy control. Also, a decrease in mitochondrial mass was observed in the patient monocytes with respect to the control. This suggests a true pathogenic effect of the mutations in mitochondrial function, especially in energy production and possibly biogenesis, leading to the observed phenotype.

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Section: Discussionmentioning

confidence: 99%

Computational and mitochondrial functional studies of novel compound heterozygous variants in SPATA5 gene support a causal link with epileptogenic encephalopathy

et al. 2023

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“…How to score of the 37 individual genes encoded on the mtDNA was exceptionally difficult to determine. Multiple mtDNA genes have previously been reported to be associated with CVS, yet variants in different mtDNA genes generally have highly overlapping phenotypes (24)(25)(26)(27)(28)(29). Thus, it was decided to consider the mtDNA as a single gene in terms of this study.…”

Section: Development Of the Paroxysmal Gene Listmentioning

confidence: 99%

Whole exome/genome sequencing in cyclic vomiting syndrome reveals multiple candidate genes, suggesting a model of elevated intracellular cations and mitochondrial dysfunction

Bar¹,

Ebenau²,

Weiner³

et al. 2023

Front. Neurol.

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ObjectiveTo utilize whole exome or genome sequencing and the scientific literature for identifying candidate genes for cyclic vomiting syndrome (CVS), an idiopathic migraine variant with paroxysmal nausea and vomiting.MethodsA retrospective chart review of 80 unrelated participants, ascertained by a quaternary care CVS specialist, was conducted. Genes associated with paroxysmal symptoms were identified querying the literature for genes associated with dominant cases of intermittent vomiting or both discomfort and disability; among which the raw genetic sequence was reviewed. “Qualifying” variants were defined as coding, rare, and conserved. Additionally, “Key Qualifying” variants were Pathogenic/Likely Pathogenic, or “Clinical” based upon the presence of a corresponding diagnosis. Candidate association to CVS was based on a point system.ResultsThirty-five paroxysmal genes were identified per the literature review. Among these, 12 genes were scored as “Highly likely” (SCN4A, CACNA1A, CACNA1S, RYR2, TRAP1, MEFV) or “Likely” (SCN9A, TNFRSF1A, POLG, SCN10A, POGZ, TRPA1) CVS related. Nine additional genes (OTC, ATP1A3, ATP1A2, GFAP, SLC2A1, TUBB3, PPM1D, CHAMP1, HMBS) had sufficient evidence in the literature but not from our study participants. Candidate status for mitochondrial DNA was confirmed by the literature and our study data. Among the above-listed 22 CVS candidate genes, a Key Qualifying variant was identified in 31/80 (34%), and any Qualifying variant was present in 61/80 (76%) of participants. These findings were highly statistically significant (p < 0.0001, p = 0.004, respectively) compared to an alternative hypothesis/control group regarding brain neurotransmitter receptor genes. Additional, post-analyses, less-intensive review of all genes (exome) outside our paroxysmal genes identified 13 additional genes as “Possibly” CVS related.ConclusionAll 22 CVS candidate genes are associated with either cation transport or energy metabolism (14 directly, 8 indirectly). Our findings suggest a cellular model in which aberrant ion gradients lead to mitochondrial dysfunction, or vice versa, in a pathogenic vicious cycle of cellular hyperexcitability. Among the non-paroxysmal genes identified, 5 are known causes of peripheral neuropathy. Our model is consistent with multiple current hypotheses of CVS.

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Quantitative multi-omics analysis of the effects of mitochondrial dysfunction on lipid metabolism in Saccharomyces cerevisiae

Guo

Zhang

Gao

et al. 2019

Appl Microbiol Biotechnol

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Deep sequencing discovery of causal mtDNA mutations in a patient with unspecific neurological disease

Cited by 6 publications

References 39 publications

Computational and mitochondrial functional studies of novel compound heterozygous variants in SPATA5 gene support a causal link with epileptogenic encephalopathy

Computational and mitochondrial functional studies of novel compound heterozygous variants in SPATA5 gene support a causal link with epileptogenic encephalopathy

Whole exome/genome sequencing in cyclic vomiting syndrome reveals multiple candidate genes, suggesting a model of elevated intracellular cations and mitochondrial dysfunction

Quantitative multi-omics analysis of the effects of mitochondrial dysfunction on lipid metabolism in Saccharomyces cerevisiae

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