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Sökning: id:"swepub:oai:DiVA.org:oru-63649" > Exome sequencing id...

Exome sequencing identifies mitochondrial alanyl-tRNA synthetase mutations in infantile mitochondrial cardiomyopathy

Götz, Alexandra (författare)
Research Programs Unit, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland
Tyynismaa, Henna (författare)
Research Programs Unit, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland
Euro, Liliya (författare)
Research Programs Unit, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland
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Ellonen, Pekka (författare)
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
Hyötyläinen, Tuulia, 1971- (författare)
VTT Technical Research Centre of Finland, Espoo, Finland
Ojala, Tiina (författare)
Department of Pediatric Cardiology, Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland
Hämäläinen, Riikka H (författare)
Research Programs Unit, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland
Tommiska, Johanna (författare)
Institute of Biomedicine, Department of Physiology, University of Helsinki, Helsinki, Finland; Children's Hospital, Helsinki University Central Hospital, Helsinki, Finland g
Raivio, Taneli (författare)
Institute of Biomedicine, Department of Physiology, University of Helsinki, Helsinki, Finland; Children's Hospital, Helsinki University Central Hospital, Helsinki, Finland
Oresic, Matej, 1967- (författare)
Örebro universitet,Institutionen för medicinska vetenskaper,VTT Technical Research Centre of Finland, Espoo, Finland
Karikoski, Riitta (författare)
Department of Pathology, University of Helsinki, Helsinki, Finland; Helsinki University Central Hospital, Helsinki, Finland
Tammela, Outi (författare)
Pediatric Research Centre, Tampere University Hospital, Tampere, Finland
Simola, Kalle O J (författare)
Genetics Outpatient Clinic, Department of Pediatrics, Tampere University Hospital, Tampere, Finland
Paetau, Anders (författare)
Department of Pathology, University of Helsinki, Helsinki, Finland; Helsinki University Central Hospital, Helsinki, Finland
Tyni, Tiina (författare)
Research Programs Unit, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland; Department of Pediatric Neurology, Helsinki University Central Hospital, Helsinki, Finland
Suomalainen, Anu (författare)
Research Programs Unit, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland; Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland
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 (creator_code:org_t)
Cell Press, 2011
2011
Engelska.
Ingår i: American Journal of Human Genetics. - : Cell Press. - 0002-9297 .- 1537-6605. ; 88:5, s. 635-642
Relaterad länk:
http://www.cell.com/...
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https://urn.kb.se/re...
https://doi.org/10.1...
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  • Tidskriftsartikel (refereegranskat)
Abstract Ämnesord
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  • 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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Medical Genetics (hsv//eng)

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