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Exome sequencing identifies mitochondrial alanyl-tRNA synthetase mutations in infantile mitochondrial cardiomyopathy
Research Programs Unit, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland.
Research Programs Unit, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland.
Research Programs Unit, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland.
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
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2011 (English)In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 88, no 5, p. 635-642Article in journal (Refereed) Published
Abstract [en]

Infantile cardiomyopathies are devastating fatal disorders of the neonatal period or the first year of life. Mitochondrial dysfunction is a common cause of this group of diseases, but the underlying gene defects have been characterized in only a minority of cases, because tissue specificity of the manifestation hampers functional cloning and the heterogeneity of causative factors hinders collection of informative family materials. We sequenced the exome of a patient who died at the age of 10 months of hypertrophic mitochondrial cardiomyopathy with combined cardiac respiratory chain complex I and IV deficiency. Rigorous data analysis allowed us to identify a homozygous missense mutation in AARS2, which we showed to encode the mitochondrial alanyl-tRNA synthetase (mtAlaRS). Two siblings from another family, both of whom died perinatally of hypertrophic cardiomyopathy, had the same mutation, compound heterozygous with another missense mutation. Protein structure modeling of mtAlaRS suggested that one of the mutations affected a unique tRNA recognition site in the editing domain, leading to incorrect tRNA aminoacylation, whereas the second mutation severely disturbed the catalytic function, preventing tRNA aminoacylation. We show here that mutations in AARS2 cause perinatal or infantile cardiomyopathy with near-total combined mitochondrial respiratory chain deficiency in the heart. Our results indicate that exome sequencing is a powerful tool for identifying mutations in single patients and allows recognition of the genetic background in single-gene disorders of variable clinical manifestation and tissue-specific disease. Furthermore, we show that mitochondrial disorders extend to prenatal life and are an important cause of early infantile cardiac failure.

Place, publisher, year, edition, pages
Cell Press , 2011. Vol. 88, no 5, p. 635-642
National Category
Medical Genetics
Identifiers
URN: urn:nbn:se:oru:diva-63649DOI: 10.1016/j.ajhg.2011.04.006ISI: 000290832100012PubMedID: 21549344Scopus ID: 2-s2.0-79955797332OAI: oai:DiVA.org:oru-63649DiVA, id: diva2:1169213
Funder
Academy of Finland
Note

Funding agencies:

Jane and Aatos Erkko Foundation

Sigrid Juselius Foundation

University of Helsinki

Graduate School of Biotechnology and Molecular Biology

Finnish Cultural Foundation

Available from: 2017-12-22 Created: 2017-12-22 Last updated: 2018-09-12Bibliographically approved

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Oresic, Matej

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