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Saoura, M.* ; Powell, C.A.* ; Kopajtich, R. ; Alahmad, A.* ; Al-Balool, H.H.* ; Albash, B.* ; Alfadhel, M.* ; Alston, C.L.* ; Bertini, E.* ; Bonnen, P.* ; Bratkovic, D.* ; Carrozzo, R.* ; Donati, M.A.* ; Nottia, M.D.* ; Ghezzi, D.* ; Goldstein, A.* ; Haan, E.* ; Horvath, R.* ; Hughes, J.* ; Invernizzi, F.* ; Lamantea, E.* ; Lucas, B.* ; Pinnock, K.G.* ; Pujantell, M.* ; Rahman, S.* ; Rebelo-Guiomar, P.* ; Santra, S.* ; Verrigni, D.* ; McFarland, R. ; Prokisch, H. ; Taylor, R.W.* ; Levinger, L.* ; Minczuk, M.*

Mutations in ELAC2 associated with hypertrophic cardiomyopathy impair mitochondrial tRNA 3 '-end processing.

Hum. Mutat. 40, 1731-1748 (2019)
Postprint DOI PMC
Open Access Green
Mutations in either the mitochondrial or nuclear genomes are associated with a diverse group of human disorders characterized by impaired mitochondrial respiration. Within this group, an increasing number of mutations have been identified in nuclear genes involved in mitochondrial RNA metabolism, including ELAC2. The ELAC2 gene codes for the mitochondrial RNase Z, responsible for endonucleolytic cleavage of the 3 ' ends of mitochondrial pre-tRNAs. Here, we report the identification of 16 novel ELAC2 variants in individuals presenting with mitochondrial respiratory chain deficiency, hypertrophic cardiomyopathy (HCM), and lactic acidosis. We provide evidence for the pathogenicity of the novel missense variants by studying the RNase Z activity in an in vitro system. We also modeled the residues affected by a missense mutation in solved RNase Z structures, providing insight into enzyme structure and function. Finally, we show that primary fibroblasts from the affected individuals have elevated levels of unprocessed mitochondrial RNA precursors. Our study thus broadly confirms the correlation of ELAC2 variants with severe infantile-onset forms of HCM and mitochondrial respiratory chain dysfunction. One rare missense variant associated with the occurrence of prostate cancer (p.Arg781His) impairs the mitochondrial RNase Z activity of ELAC2, suggesting a functional link between tumorigenesis and mitochondrial RNA metabolism
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Cardiomyopathy ; Mitochondria ; Mitochondrial Disease ; Rna ; Rnase Z; Cancer Susceptibility Gene; Substrate Recognition; Sideroblastic Anemia; Trnase-z; Residues; Defect; Metabolism; Maturation; Catalysis
ISSN (print) / ISBN 1059-7794
e-ISSN 1098-1004
Zeitschrift Human Mutation
Quellenangaben Band: 40, Heft: 10, Seiten: 1731-1748 Artikelnummer: , Supplement: ,
Verlag Wiley
Verlagsort 111 River St, Hoboken 07030-5774, Nj Usa
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Human Genetics (IHG)