Abstract:We have used whole-exome sequencing in ten individuals from four unrelated pedigrees to identify biallelic missense mutations in the nuclear-encoded mitochondrial inorganic pyrophosphatase (PPA2) that are associated with mitochondrial disease. These individuals show a range of severity, indicating that PPA2 mutations may cause a spectrum of mitochondrial disease phenotypes. Severe symptoms include seizures, lactic acidosis, cardiac arrhythmia, and death within days of birth. In the index family, presentation w… Show more
Background
Sudden death in children is a tragic event that often remains unexplained after comprehensive investigation. We report two asymptomatic siblings who died unexpectedly at approximately 1 year of age found to have biallelic (compound heterozygous) variants in PPA2.
Methods
The index case, parents, and sister were enrolled in the Sudden Unexplained Death in Childhood Registry and Research Collaborative, which included next‐generation genetic screening. Prior published cases of PPA2 variants, along with the known biology of PPA2, were also summarized.
Results
Whole exome sequencing in both siblings revealed biallelic rare missense variants in PPA2: c.182C > T (p.Ser61Phe) and c.380G > T (p.Arg127Leu). PPA2 encodes a mitochondrially located inorganic pyrophosphatase implicated in progressive and lethal cardiomyopathies. As a regulator and supplier of inorganic phosphate, PPA2 is central to phosphate metabolism. Biological roles include the following: mtDNA maintenance; oxidative phosphorylation and generation of ATP; reactive oxygen species homeostasis; mitochondrial membrane potential regulation; and possibly, retrograde signaling between mitochondria and nucleus.
Conclusions
Two healthy and asymptomatic sisters died unexpectedly at ages 12 and 10 months, and were diagnosed by molecular autopsy to carry biallelic variants in PPA2. Our cases add additional details to those reported thus far, and broaden the spectrum of clinical and molecular features of PPA2 variants.
Background
Sudden death in children is a tragic event that often remains unexplained after comprehensive investigation. We report two asymptomatic siblings who died unexpectedly at approximately 1 year of age found to have biallelic (compound heterozygous) variants in PPA2.
Methods
The index case, parents, and sister were enrolled in the Sudden Unexplained Death in Childhood Registry and Research Collaborative, which included next‐generation genetic screening. Prior published cases of PPA2 variants, along with the known biology of PPA2, were also summarized.
Results
Whole exome sequencing in both siblings revealed biallelic rare missense variants in PPA2: c.182C > T (p.Ser61Phe) and c.380G > T (p.Arg127Leu). PPA2 encodes a mitochondrially located inorganic pyrophosphatase implicated in progressive and lethal cardiomyopathies. As a regulator and supplier of inorganic phosphate, PPA2 is central to phosphate metabolism. Biological roles include the following: mtDNA maintenance; oxidative phosphorylation and generation of ATP; reactive oxygen species homeostasis; mitochondrial membrane potential regulation; and possibly, retrograde signaling between mitochondria and nucleus.
Conclusions
Two healthy and asymptomatic sisters died unexpectedly at ages 12 and 10 months, and were diagnosed by molecular autopsy to carry biallelic variants in PPA2. Our cases add additional details to those reported thus far, and broaden the spectrum of clinical and molecular features of PPA2 variants.
“…Ppa2 hydrolyzes inorganic pyrophosphate (PPi) into two phosphates, which is an essential activity for diverse biosynthetic reactions and for cellular energy metabolism (Guimier et al, ). Knockdown of Ppa2 has been shown to result in growth defects and loss of mitochondrial DNA in S. cerevisiae (Lundin et al, ), while Ppa2‐deficient cells might have limited ATP synthesis (Kennedy et al, ). In this study, Ppa2 was found to be downregulated suggesting that the failure of energy metabolism may be a fundamental mechanism in ICH.…”
IntroductionIntracerebral hemorrhage (ICH) is a lethal cerebrovascular disorder with a high mortality and morbidity. The pathophysiological mechanisms underlying ICH‐induced secondary injury remain unclear.MethodsTo examine one of the gaps in the knowledge about ICH pathological mechanisms, isobaric tag for relative and absolute quantification (iTRAQ)‐based liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) was used in collagenase‐induced ICH rats on the 2nd day.ResultsA total of 6,456 proteins were identified with a 1% false discovery rate (FDR). Of these proteins, 126 and 75 differentially expressed proteins (DEPs) were substantially increased and decreased, respectively. Based on Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and STRING analyses, the protein changes in cerebral hemorrhage were comprehensively evaluated, and the energy metabolism in ICH was anchored. The core position of the nitrogen metabolism pathway in brain metabolism in ICH was found for the first time. Carbonic anhydrase 1 (Ca1), carbonic anhydrase 2 (Ca2), and glutamine synthetase (Glul) participated in this pathway. We constructed the protein–protein interaction (PPI) networks for the energy metabolism of ICH, including the Atp6v1a‐Atp6v0c‐Atp6v0d1‐Ppa2‐Atp6ap2 network.ConclusionsIt seems that dysregulation of energy metabolism, especially nitrogen metabolism, may be a major cause in secondary ICH injury. This information provides novel insights into secondary events following ICH.
“…Cardiac conduction defects have been reported frequently in children and adults with KSS, and complete heart block may be a life‐threatening event in these individuals, indicating a need for regular screening ECGs [81]. Sudden death is also a feature of PPA2 mutations, and implantation of a cardiac defibrillator may be life‐preserving in affected individuals [82]. Wolff–Parkinson–White has been reported in LHON, MELAS and Leigh syndrome caused by the m.13513G>A mutation [44,58,83].…”
Section: Other Phenotypes: a Systems Approach To Mitochondrial Diseasmentioning
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