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Kennedy, H.* ; Haack, T.B. ; Hartill, V.L.* ; Matakovic, L.* ; Baumgartner, E.R.* ; Potter, H.* ; Mackay, R.* ; Alston, C.L.* ; O'Sullivan, S.* ; McFarland, R.* ; Connolly, G.* ; Gannon, C.* ; King, R.* ; Mead, S.* ; Crozier, I.* ; Chan, W.* ; Florkowski, C.M.* ; Sage, M.* ; Höfken, T.* ; Alhaddad, B. ; Kremer, L.S. ; Kopajtich, R. ; Feichtinger, R.G.* ; Sperl, W.* ; Rodenburg, R.J.* ; Minet, J.C.* ; Dobbie, A.* ; Strom, T.M. ; Meitinger, T. ; George, P.M.* ; Johnson, C.A.* ; Taylor, R.W.* ; Prokisch, H. ; Doudney, K.* ; Mayr, J.A.*

Sudden cardiac death due to deficiency of the mitochondrial inorganic pyrophosphatase PPA2.

Am. J. Hum. Genet. 99, 674-682 (2016)
Verlagsversion Anhang DOI PMC
Creative Commons Lizenzvertrag
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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
Korrespondenzautor
Schlagwörter Atp Synthase Deficiency; Saccharomyces-cerevisiae; Mutations; Gene; Depletion; Subunit; Acetate; Liver; Heart
ISSN (print) / ISBN 0002-9297
e-ISSN 1537-6605
Zeitschrift American Journal of Human Genetics, The
Quellenangaben Band: 99, Heft: 3, Seiten: 674-682 Artikelnummer: , Supplement: ,
Verlag Elsevier
Verlagsort New York, NY
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Human Genetics (IHG)