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Title: | Incomplete penetrance for isolated congenital asplenia in humans with mutations in translated and untranslated RPSA exons | Authors: | Bolze, Alexandre Boisson, Bertrand Bosch, Barbara Antipenko, Alexander Bouaziz, Matthieu Sackstein, Paul Chaker-Margot, Malik Barlogis, Vincent Briggs, Tracy Colino, Elena Elmore, Aurora C. Fischer, Alain Genel, Ferah Hewlett, Angela Jedidi, Maher Kelecic, Jadranka Krüger, Renate Ku, Cheng Lung Kumararatne, Dinakantha Lefevre-Utile, Alain Loughlin, Sam Mahlaoui, Nizar Markus, Susanne Garcia, Juan Miguel Nizon, Mathilde Oleastro, Matias Pac, Malgorzata Picard, Capucine Pollard, Andrew J. Rodriguez-Gallego, Carlos Thomas, Caroline Bernuth, Horst Von Worth, Austen Meyts, Isabelle Risolino, Maurizio Selleri, Licia Puel, Anne Klinge, Sebastian Abel, Laurent Casanova, Jean Laurent |
UNESCO Clasification: | 32 Ciencias médicas 3205 Medicina interna |
Keywords: | Isolated congenital asplenia Spleen incomplete penetranceI Ribosomopathy RPSA |
Issue Date: | 2018 | Journal: | Proceedings of the National Academy of Sciences of the United States of America | Abstract: | Isolated congenital asplenia (ICA) is the only known human developmental defect exclusively affecting a lymphoid organ. In 2013, we showed that private deleterious mutations in the protein-coding region of RPSA, encoding ribosomal protein SA, caused ICA by haploinsufficiency with complete penetrance. We reported seven heterozygous protein-coding mutations in 8 of the 23 kindreds studied, including 6 of the 8 multiplex kindreds. We have since enrolled 33 new kindreds, 5 of which are multiplex. We describe here 11 new heterozygous ICA-causing RPSA protein-coding mutations, and the first two mutations in the 5′-UTR of this gene, which disrupt mRNA splicing. Overall, 40 of the 73 ICA patients (55%) and 23 of the 56 kindreds (41%) carry mutations located in translated or untranslated exons of RPSA. Eleven of the 43 kindreds affected by sporadic disease (26%) carry RPSA mutations, whereas 12 of the 13 multiplex kindreds (92%) carry RPSA mutations. We also report that 6 of 18 (33%) protein-coding mutations and the two (100%) 5′-UTR mutations display incomplete penetrance. Three mutations were identified in two independent kindreds, due to a hotspot or a founder effect. Finally, RPSA ICA-causing mutations were demonstrated to be de novo in 7 of the 23 probands. Mutations in RPSA exons can affect the translated or untranslated regions and can underlie ICA with complete or incomplete penetrance | URI: | http://hdl.handle.net/10553/48610 | ISSN: | 0027-8424 | DOI: | 10.1073/pnas.1805437115 | Source: | Proceedings of the National Academy of Sciences of the United States of America[ISSN 0027-8424],v. 115, p. E8007-E8016 |
Appears in Collections: | Artículos |
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