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. 2018 Aug 21;115(34):E8007-E8016.
doi: 10.1073/pnas.1805437115. Epub 2018 Aug 2.

Incomplete Penetrance for Isolated Congenital Asplenia in Humans With Mutations in Translated and Untranslated RPSA Exons

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Free PMC article

Incomplete Penetrance for Isolated Congenital Asplenia in Humans With Mutations in Translated and Untranslated RPSA Exons

Alexandre Bolze et al. Proc Natl Acad Sci U S A. .
Free PMC article

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.

Keywords: RPSA; incomplete penetrance; isolated congenital asplenia; ribosomopathy; spleen.

Conflict of interest statement

Conflict of interest statement: A.B. works at Helix.

Figures

Fig. 1.
Fig. 1.
Overview of the 23 ICA kindreds in our cohort who carry mutations in RPSA. (A) Eight kindreds were reported in our initial publication: All had nonsynonymous and fully penetrant mutations for ICA. (B and C) Twelve newly recruited kindreds had novel nonsynonymous mutations, displaying complete (B) or incomplete penetrance (C) for ICA. (D) Three ICA kindreds with mutations in the 5′-UTR of RPSA. (E) Schematic view of all of the ICA-causing mutations in RPSA. Mutations reported in our initial study are indicated above the gene schema. New mutations identified and reported in this study are indicated underneath the gene schema. Alternate white and gray color indicates the seven different exons from the canonical transcript of the gene (ENST00000301821).
Fig. 2.
Fig. 2.
Several mutations in RPSA display incomplete penetrance for ICA. (A) Comparative CADD score between RPSA coding-mutations leading to complete or incomplete penetrance. (B) Structure of the human small ribosomal subunit (PDB ID code 6EK0). The 18S ribosomal RNA is colored in gray, ribosomal proteins are colored in light blue, and RPSA is highlighted in green. (CE) Detailed view of RPSA with colored spheres highlighting RPSA missense mutations leading to complete (red spheres) or incomplete (orange spheres) penetrance. Each amino acid found mutated in the ICA cohort is indicated based on human RPSA.
Fig. 3.
Fig. 3.
Impact of the two 5′-UTR mutations on RPSA mRNA structure. The two 5′-UTR mutations identified in ICA patients impair the splicing of intron 1 and lead to an intron retention of 70 or 67 bp at the end exon 1. (A) Sashimi plots of RNAseq results for ICA-AO (c.-39_-34+3del), ICA-G (c.-34+5G>C), and ICA-H (variant c.-47C>T). In ICA-AO and ICA-G the mutations lead to a 67- or 70-bp intronic retention, respectively (red), whereas variant c.-47C>T does not impact mRNA structure (ICA-H). (B) Quantification of the allelic ratio. About half of the transcripts show the splicing defect in ICA-AO and ICA-G patients.

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