Incomplete penetrance for isolated congenital asplenia in humans with mutations in translated and untranslated RPSA exons

Alexandre Bolze, Bertrand Boisson, Barbara Bosch, Alexander Antipenko, Matthieu Bouaziz, Paul Sackstein, Malik Chaker-Margot, Vincent Barlogis, Tracy Briggs, Elena Colino, Aurora C. Elmore, Alain Fischer, Ferah Genel, Angela Hewlett, Maher Jedidi, Jadranka Kelecic, Renate Krüger, Cheng Lung Ku, Dinakantha Kumararatne, Alain Lefevre-UtileSam Loughlin, Nizar Mahlaoui, Susanne Markus, Juan Miguel Garcia, Mathilde Nizon, Matias Oleastro, Malgorzata Pac, Capucine Picard, Andrew J. Pollard, Carlos Rodriguez-Gallego, Caroline Thomas, Horst Von Bernuth, Austen Worth, Isabelle Meyts, Maurizio Risolino, Licia Selleri, Anne Puel, Sebastian Klinge, Laurent Abel, Jean Laurent Casanova

Research output: Contribution to journalArticle

13 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)E8007-E8016
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number34
DOIs
StatePublished - Aug 21 2018

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Keywords

  • Incomplete penetrance
  • Isolated congenital asplenia
  • RPSA
  • Ribosomopathy
  • Spleen

ASJC Scopus subject areas

  • General

Cite this

Bolze, A., Boisson, B., Bosch, B., Antipenko, A., Bouaziz, M., Sackstein, P., Chaker-Margot, M., Barlogis, V., Briggs, T., Colino, E., Elmore, A. C., Fischer, A., Genel, F., Hewlett, A., Jedidi, M., Kelecic, J., Krüger, R., Ku, C. L., Kumararatne, D., ... Casanova, J. L. (2018). Incomplete penetrance for isolated congenital asplenia in humans with mutations in translated and untranslated RPSA exons. Proceedings of the National Academy of Sciences of the United States of America, 115(34), E8007-E8016. https://doi.org/10.1073/pnas.1805437115