Aberrant splicing due to a novel RPS7 variant causes Diamond-Blackfan Anemia associated with spontaneous remission and meningocele.

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Abstrakt

Tytuł:: Aberrant splicing due to a novel RPS7 variant causes Diamond-Blackfan Anemia associated with spontaneous remission and meningocele.
Autorzy:: Akram T; Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE-C)-PIEAS, Faisalabad, Pakistan.; Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, BMC Box 815, Uppsala, Sweden.
Fatima A; Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, BMC Box 815, Uppsala, Sweden.
Klar J; Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, BMC Box 815, Uppsala, Sweden.
Hoeber J; Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, BMC Box 815, Uppsala, Sweden.
Zakaria M; Center for Human Genetics, Hazara University, Mansehra, Pakistan.
Tariq M; Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE-C)-PIEAS, Faisalabad, Pakistan.
Baig SM; Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE-C)-PIEAS, Faisalabad, Pakistan.
Schuster J; Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, BMC Box 815, Uppsala, Sweden.
Dahl N; Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, BMC Box 815, Uppsala, Sweden. .
Źródło:: International journal of hematology [Int J Hematol] 2020 Dec; Vol. 112 (6), pp. 894-899. Date of Electronic Publication: 2020 Aug 09.
Typ publikacji:: Case Reports; Journal Article
Język:: English
Imprint Name(s):: Publication: 2008- : Tokyo : Springer Japan
Original Publication: Amsterdam : Elsevier Science Publishers, c1991-
MeSH Terms:: Chromosome Aberrations*
Genetic Association Studies*
Anemia, Diamond-Blackfan/*genetics
Genetic Variation/*genetics
Meningocele/*genetics
RNA Splicing/*genetics
Ribosomal Proteins/*genetics
Adolescent ; Adult ; Anemia, Diamond-Blackfan/etiology ; Child ; Exons/genetics ; Female ; Humans ; Meningocele/etiology ; Mother-Child Relations ; Remission, Spontaneous ; Sequence Analysis, DNA
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Da-Costa L, O’Donohue MF, van- Dooijeweert B, Albrecht K, Unal S, Ramenghi U, et al. Molecular approaches to diagnose Diamond-Blackfan anemia: the Euro DBA experience. Eur J Hum Genet. 2018;61:664–73.
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Garelli E, Quarello P, Giorgio E, Carando A, Menegatti E, Mancini C, et al. Spontaneous remission in a Diamond-Blackfan anaemia patient due to a revertant uniparental disomy ablating a de novo RPS19 mutation. Br J Haematol. 2019;185:994–8. (PMID: 10.1111/bjh.15688)
Draptchinskaia N, Gustavsson P, Andersson B, Pettersson M, Willig TN, Dianzani I, et al. The gene encoding ribosomal protein S19 is mutated in Diamond-Blackfan anaemia. Nat Genet. 1999;21:169–75. (PMID: 10.1038/5951)
Gazda HT, Sheen MR, Vlachos A, Choesmel V, O’Donohue MF, Schneider H, et al. Ribosomal protein L5 and L11 mutations are associated with cleft palate and abnormal thumbs in Diamond-Blackfan anemia patients. Am J Hum Genet. 2008;83:769–80. (PMID: 10.1016/j.ajhg.2008.11.004)
Farrar JE, Dahl N. Untangling the phenotypic heterogeneity of Diamond Blackfan anemia. Semin Hematol. 2011;48:124–35. (PMID: 10.1053/j.seminhematol.2011.02.003)
Smetanina NS, Mersiyanova IV, Kurnikova MA, Ovsyannikova GS, Hachatryan LA, Bobrynina VO, et al. Clinical and genomic heterogeneity of Diamond Blackfan anemia in the Russian Federation. Pediatr Blood Cancer. 2015;62:1597–600. (PMID: 10.1002/pbc.25534)
Choesmel V, Bacqueville D, Rouquette J, Noaillac-Depeyre J, Fribourg S, Cretien A, et al. Impaired ribosome biogenesis in Diamond-Blackfan anemia. Blood. 2007;109:1275–83. (PMID: 10.1182/blood-2006-07-038372)
Wang R, Yoshida K, Toki T, Sawada T, Uechi T, Okuno Y, et al. Loss of function mutations in RPL27 and RPS27 identified by whole-exome sequencing in Diamond-Blackfan anaemia. Br J Haematol. 2015;168:854–64. (PMID: 10.1111/bjh.13229)
Ichimura T, Yoshida K, Okuno Y, Yujiri T, Nagai K, Nishi M, et al. Diagnostic challenge of Diamond-Blackfan anemia in mothers and children by whole-exome sequencing. Int J Hematol. 2017;105:515–20. (PMID: 10.1007/s12185-016-2151-7)
Vaz-Drago R, Custódio N, Carmo-Fonseca M. Deep intronic mutations and human disease. Hum Genet. 2017;136(9):1093–111. (PMID: 10.1007/s00439-017-1809-4)
Farrar JE, Vlachos A, Atsidaftos E, Carlson-Donohoe H, Markello TC, Arceci RJ, et al. Ribosomal protein gene deletions in Diamond-Blackfan anemia. Blood. 2011;118:6943–51. (PMID: 10.1182/blood-2011-08-375170)
Jongmans MCJ, Diets IJ, Quarello P, Garelli E, Kuiper RP, Pfundt R. Somatic reversion events point towards RPL4 as a novel disease gene in a condition resembling Diamond-Blackfan anemia. Haematologica. 2018;103:607–9. (PMID: 10.3324/haematol.2018.200683)
Watkins-Chow DE, Cooke J, Pidsley R, Edwards A, Slotkin R, Leeds KE, et al. Mutation of the diamond-blackfan anemia gene Rps7 in mouse results in morphological and neuroanatomical phenotypes. PLoS Genet. 2013;9:1003094. (PMID: 10.1371/journal.pgen.1003094)
Grant Information:: 2015-02424 Swedish Research Council
Contributed Indexing:: Keywords: Diamond-Blackfan Anemia (DBA); In vitro splicing; Meningocele; RPS7 gene variant; Spontaneous remission
Substance Nomenclature:: 0 (Ribosomal Proteins)
0 (ribosomal protein S7)
Entry Date(s):: Date Created: 20200811 Date Completed: 20201125 Latest Revision: 20220531
Update Code:: 20240105
DOI:: 10.1007/s12185-020-02950-6
PMID:: 32772263
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Diamond-Blackfan Anemia (DBA) is a congenital pure red cell aplasia caused by heterozygous variants in ribosomal protein genes. The hematological features associated with DBA are highly variable and non-hematological abnormalities are common. We report herein on an affected mother and her daughter presenting with transfusion-dependent anemia. The mother showed mild physical abnormalities and entered spontaneous remission at age 13 years. Her daughter was born with occipital meningocele. Exome sequencing of DNA from the mother revealed a heterozygous novel splice site variant (NM_001011.4:c.508-3T > G) in the Ribosomal Protein S7 gene (RPS7) inherited by the daughter. Functional analysis of the RPS7 variant expressed from a mini-gene construct revealed that the exon 7 acceptor splice site was replaced by a cryptic splice resulting in a transcript missing 64 bp of exon 7 (p.Val170Serfs*8). Our study confirms a pathogenic effect of a novel RPS7 variant in DBA associated with spontaneous remission in the mother and meningocele in her daughter, thus adding to the genotype-phenotype correlations in DBA.

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