PPA2 was evaluated for autosomal recessive (AR) dilated cardiomyopathy. PPA2 is a nuclear gene related to mitochondrial function. PPA2 plays roles in mtDNA maintenance, oxidative phosphorylation, generation of ATP, ROS homeostasis, and mitochondrial membrane potential (Phoon et. al, 2020, PMID: 31705601). At the time of this review, dilated cardiomyopathy is the only condition that has been associated with this gene.
Human genetic evidence for this gene-disease relationship contains case-level data. At least 9 variants (including missense, nonsense, and frameshift variants) have been reported in humans with DCM in 4 separate publications (Vasilescu et. al, 2018, PMID: 30384889; Zhao et. al, 2021, PMID: 33826954; Guimier et. al, 2021, PMID: 34400813; Manzanilla-Romero et. al, 2023; PMID: 37269378). All cases reported in the literature were infant onset, often in the presence of viral illness, or in teenage/young adulthood in the presence of alcohol consumption. Several cases presented with sudden cardiac death, with limited phenotype information available on autopsy or due to the patient’s young age and were not scored for DCM (Kennedy et. al, 2016, PMID: 27523597; Guimier et. al, 2016, PMID: 27523598; Sanford et. al, 2020, PMID: 33028643; Guimer et. al, 2021, PMID: 34400813; Genthe et. al, 2023, PMID: 37869221; Graham et. al, 2023, PMID: 37249496; González et. al, 2024, PMID: 38582264).
In addition, this gene-disease assertion is supported by expression studies and functional alteration. Expression of PPA2 in human heart tissue was demonstrated by northern blot (Curbo et. al, 2006, PMID: 16300924). Decreased expression of PPA2 was demonstrated in western blot of patient homogenates (Kennedy et. al, 2016, PMID: 27523597). In addition, functional alterations were shown in both patient and non-patient cells. Increased oxygen consumption rates were found in PPA2-deficient fibroblasts (Kennedy et. al, 2016, PMID: 27523597). Additionally, yeast PPA2 knockouts showed increased diamide sensitivity, suggesting reduced levels of antioxidants (Kennedy et. al, 2016, PMID: 27523597).
In summary, there is strong evidence to support the relationship between PPA2 and AR DCM. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on 05/16/2025 (SOP Version 10).
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