Bi-allelic missense disease-causing variants in RPL3L associate neonatal dilated cardiomyopathy with muscle-specific ribosome biogenesis

  1. Ganapathi, Mythily ORCID logo
  2. Argyriou, Loukas ORCID logo
  3. Martínez-Azorín, Francisco ORCID logo
  4. Morlot, Susanne ORCID logo
  5. Yigit, Gökhan ORCID logo
  6. Lee, Teresa ORCID logo
  7. Auber, Bernd ORCID logo
  8. von Gise, Alexander ORCID logo
  9. Petrey, Donald S.
  10. Thiele, Holger ORCID logo
  11. Cyganek, Lukas ORCID logo
  12. Sabater-Molina, Maria ORCID logo
  13. Ahimaz, Priyanka
  14. Cabezas-Herrera, Juan ORCID logo
  15. Sorlí García , Moises ORCID logo
  16. Zibat, Arne ORCID logo
  17. Siegelin, Markus ORCID logo
  18. Burfeind, Peter ORCID logo
  19. Buchovecky, Christie M.
  20. Hasenfuss, Gerd ORCID logo
  21. Honig, Barry ORCID logo
  22. Li, Yun
  23. Iglesias, Alejandro ORCID logo
  24. Wollnik, Bernd ORCID logo

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1000 Titel
  • Bi-allelic missense disease-causing variants in RPL3L associate neonatal dilated cardiomyopathy with muscle-specific ribosome biogenesis
1000 Autor/in
  1. Ganapathi, Mythily |
  2. Argyriou, Loukas |
  3. Martínez-Azorín, Francisco |
  4. Morlot, Susanne |
  5. Yigit, Gökhan |
  6. Lee, Teresa |
  7. Auber, Bernd |
  8. von Gise, Alexander |
  9. Petrey, Donald S. |
  10. Thiele, Holger |
  11. Cyganek, Lukas |
  12. Sabater-Molina, Maria |
  13. Ahimaz, Priyanka |
  14. Cabezas-Herrera, Juan |
  15. Sorlí García , Moises |
  16. Zibat, Arne |
  17. Siegelin, Markus |
  18. Burfeind, Peter |
  19. Buchovecky, Christie M. |
  20. Hasenfuss, Gerd |
  21. Honig, Barry |
  22. Li, Yun |
  23. Iglesias, Alejandro |
  24. Wollnik, Bernd |
1000 Erscheinungsjahr 2020
1000 Publikationstyp
  1. Artikel |
1000 Online veröffentlicht
  • 2020-06-08
1000 Erschienen in
1000 Quellenangabe
  • 139(11):1443-1454
1000 Copyrightjahr
  • 2020
1000 Lizenz
1000 Verlagsversion
  • https://doi.org/10.1007/s00439-020-02188-6 |
  • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519902/ |
1000 Publikationsstatus
1000 Sprache der Publikation
1000 Abstract/Summary
  • Dilated cardiomyopathy (DCM) belongs to the most frequent forms of cardiomyopathy mainly characterized by cardiac dilatation and reduced systolic function. Although most cases of DCM are classified as sporadic, 20-30% of cases show a heritable pattern. Familial forms of DCM are genetically heterogeneous, and mutations in several genes have been identified that most commonly play a role in cytoskeleton and sarcomere-associated processes. Still, a large number of familial cases remain unsolved. Here, we report five individuals from three independent families who presented with severe dilated cardiomyopathy during the neonatal period. Using whole-exome sequencing (WES), we identified causative, compound heterozygous missense variants in RPL3L (ribosomal protein L3-like) in all the affected individuals. The identified variants co-segregated with the disease in each of the three families and were absent or very rare in the human population, in line with an autosomal recessive inheritance pattern. They are located within the conserved RPL3 domain of the protein and were classified as deleterious by several in silico prediction software applications. RPL3L is one of the four non-canonical riboprotein genes and it encodes the 60S ribosomal protein L3-like protein that is highly expressed only in cardiac and skeletal muscle. Three-dimensional homology modeling and in silico analysis of the affected residues in RPL3L indicate that the identified changes specifically alter the interaction of RPL3L with the RNA components of the 60S ribosomal subunit and thus destabilize its binding to the 60S subunit. In conclusion, we report that bi-allelic pathogenic variants in RPL3L are causative of an early-onset, severe neonatal form of dilated cardiomyopathy, and we show for the first time that cytoplasmic ribosomal proteins are involved in the pathogenesis of non-syndromic cardiomyopathies.
1000 Sacherschließung
lokal Infant, Newborn [MeSH]
lokal Female [MeSH]
lokal Cardiomyopathy, Dilated/genetics [MeSH]
lokal Mutation, Missense/genetics [MeSH]
lokal Humans [MeSH]
lokal Ribosomes/genetics [MeSH]
lokal Molecular Medicine
lokal Heart/physiopathology [MeSH]
lokal Muscle, Skeletal/physiopathology [MeSH]
lokal Original Investigation
lokal Pedigree [MeSH]
lokal RNA/genetics [MeSH]
lokal Ribosomal Protein L3 [MeSH]
lokal Infant [MeSH]
lokal Male [MeSH]
lokal Metabolic Diseases
lokal Ribosomal Proteins/genetics [MeSH]
lokal Gene Function
lokal Phenotype [MeSH]
lokal Alleles [MeSH]
lokal Exome/genetics [MeSH]
lokal Human Genetics
1000 Liste der Beteiligten
  1. https://orcid.org/0000-0003-2834-0843|https://orcid.org/0000-0002-9816-2109|https://orcid.org/0000-0001-6250-7745|https://orcid.org/0000-0002-5966-9070|https://orcid.org/0000-0003-2777-0198|https://orcid.org/0000-0001-7409-6832|https://orcid.org/0000-0003-1880-291X|https://orcid.org/0000-0001-7886-3031|https://frl.publisso.de/adhoc/uri/UGV0cmV5LCBEb25hbGQgUy4=|https://orcid.org/0000-0002-0169-998X|https://orcid.org/0000-0001-9120-1382|https://orcid.org/0000-0003-1352-1748|https://frl.publisso.de/adhoc/uri/QWhpbWF6LCBQcml5YW5rYQ==|https://orcid.org/0000-0001-9053-5380|https://orcid.org/0000-0003-0888-7112|https://orcid.org/0000-0002-0837-3050|https://orcid.org/0000-0001-7113-3634|https://orcid.org/0000-0003-4480-5276|https://frl.publisso.de/adhoc/uri/QnVjaG92ZWNreSwgQ2hyaXN0aWUgTS4=|https://orcid.org/0000-0002-5942-361X|https://orcid.org/0000-0002-1835-1031|https://frl.publisso.de/adhoc/uri/TGksIFl1bg==|https://orcid.org/0000-0002-6487-436X|https://orcid.org/0000-0003-2589-0364
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