Sudden cardiac death due to deficiency of the mitochondrial inorganic pyrophosphatase PPA2.
Am. J. Hum. Genet. 99, 674-682 (2016)
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 was milder and manifested as cardiac fibrosis and an exquisite sensitivity to alcohol, leading to sudden arrhythmic cardiac death in the second decade of life. Comparison of normal and mutant PPA2-containing mitochondria from fibroblasts showed that the activity of inorganic pyrophosphatase was significantly reduced in affected individuals. Recombinant PPA2 enzymes modeling hypomorphic missense mutations had decreased activity that correlated with disease severity. These findings confirm the pathogenicity of PPA2 mutations and suggest that PPA2 is a cardiomyopathy-associated protein, which has a greater physiological importance in mitochondrial function than previously recognized.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Atp Synthase Deficiency; Saccharomyces-cerevisiae; Mutations; Gene; Depletion; Subunit; Acetate; Liver; Heart
ISSN (print) / ISBN 0002-9297
Zeitschrift American Journal of Human Genetics, The
Quellenangaben Band: 99, Heft: 3, Seiten: 674-682
Verlag Elsevier ; Cell Press
Verlagsort New York, NY
Institut(e) Institute of Human Genetics (IHG)