Incomplete penetrance for isolated congenital asplenia in humans with mutations in translated and untranslated RPSA exons
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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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National Academy of Sciences
2018
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| _version_ | 1797081146467549184 |
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| author | Bolze, A Boisson, B Bosch, B Antipenko, A Bouaziz, M Sackstein, P Chaker-Margot, M Barlogis, V Briggs, T Colino, E Elmore, A Fischer, A Genel, F Hewlett, A Jedidi, M Kelecic, J Krüger, R Ku, C Kumararatne, D Lefevre-Utile, A Loughlin, S Mahlaoui, N Markus, S Garcia, J Nizon, M Oleastro, M Pac, M Picard, C Pollard, A Rodriguez-Gallego, C Thomas, C Von Bernuth, H Worth, A Meyts, I Risolino, M Selleri, L Puel, A Klinge, S Abel, L Casanova, J |
| author_facet | Bolze, A Boisson, B Bosch, B Antipenko, A Bouaziz, M Sackstein, P Chaker-Margot, M Barlogis, V Briggs, T Colino, E Elmore, A Fischer, A Genel, F Hewlett, A Jedidi, M Kelecic, J Krüger, R Ku, C Kumararatne, D Lefevre-Utile, A Loughlin, S Mahlaoui, N Markus, S Garcia, J Nizon, M Oleastro, M Pac, M Picard, C Pollard, A Rodriguez-Gallego, C Thomas, C Von Bernuth, H Worth, A Meyts, I Risolino, M Selleri, L Puel, A Klinge, S Abel, L Casanova, J |
| author_sort | Bolze, A |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T01:10:24Z |
| format | Journal article |
| id | oxford-uuid:8ccdba3e-046b-41e1-a0ed-28363edfec95 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T01:10:24Z |
| publishDate | 2018 |
| publisher | National Academy of Sciences |
| record_format | dspace |
| spelling | oxford-uuid:8ccdba3e-046b-41e1-a0ed-28363edfec952022-03-26T22:46:58ZIncomplete penetrance for isolated congenital asplenia in humans with mutations in translated and untranslated RPSA exonsJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:8ccdba3e-046b-41e1-a0ed-28363edfec95EnglishSymplectic Elements at OxfordNational Academy of Sciences2018Bolze, ABoisson, BBosch, BAntipenko, ABouaziz, MSackstein, PChaker-Margot, MBarlogis, VBriggs, TColino, EElmore, AFischer, AGenel, FHewlett, AJedidi, MKelecic, JKrüger, RKu, CKumararatne, DLefevre-Utile, ALoughlin, SMahlaoui, NMarkus, SGarcia, JNizon, MOleastro, MPac, MPicard, CPollard, ARodriguez-Gallego, CThomas, CVon Bernuth, HWorth, AMeyts, IRisolino, MSelleri, LPuel, AKlinge, SAbel, LCasanova, JIsolated 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. |
| spellingShingle | Bolze, A Boisson, B Bosch, B Antipenko, A Bouaziz, M Sackstein, P Chaker-Margot, M Barlogis, V Briggs, T Colino, E Elmore, A Fischer, A Genel, F Hewlett, A Jedidi, M Kelecic, J Krüger, R Ku, C Kumararatne, D Lefevre-Utile, A Loughlin, S Mahlaoui, N Markus, S Garcia, J Nizon, M Oleastro, M Pac, M Picard, C Pollard, A Rodriguez-Gallego, C Thomas, C Von Bernuth, H Worth, A Meyts, I Risolino, M Selleri, L Puel, A Klinge, S Abel, L Casanova, J Incomplete penetrance for isolated congenital asplenia in humans with mutations in translated and untranslated RPSA exons |
| title | Incomplete penetrance for isolated congenital asplenia in humans with mutations in translated and untranslated RPSA exons |
| title_full | Incomplete penetrance for isolated congenital asplenia in humans with mutations in translated and untranslated RPSA exons |
| title_fullStr | Incomplete penetrance for isolated congenital asplenia in humans with mutations in translated and untranslated RPSA exons |
| title_full_unstemmed | Incomplete penetrance for isolated congenital asplenia in humans with mutations in translated and untranslated RPSA exons |
| title_short | Incomplete penetrance for isolated congenital asplenia in humans with mutations in translated and untranslated RPSA exons |
| title_sort | incomplete penetrance for isolated congenital asplenia in humans with mutations in translated and untranslated rpsa exons |
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