A new murine Rpl5 (uL18) mutation provides a unique model of variably penetrant Diamond-Blackfan anemia.
Journal
Blood advances
ISSN: 2473-9537
Titre abrégé: Blood Adv
Pays: United States
ID NLM: 101698425
Informations de publication
Date de publication:
26 10 2021
26 10 2021
Historique:
received:
04
03
2021
accepted:
04
05
2021
pubmed:
1
9
2021
medline:
3
11
2021
entrez:
31
8
2021
Statut:
ppublish
Résumé
Ribosome dysfunction is implicated in multiple abnormal developmental and disease states in humans. Heterozygous germline mutations in genes encoding ribosomal proteins are found in most individuals with Diamond-Blackfan anemia (DBA), whereas somatic mutations have been implicated in a variety of cancers and other disorders. Ribosomal protein-deficient animal models show variable phenotypes and penetrance, similar to human patients with DBA. In this study, we characterized a novel ENU mouse mutant (Skax23m1Jus) with growth and skeletal defects, cardiac malformations, and increased mortality. After genetic mapping and whole-exome sequencing, we identified an intronic Rpl5 mutation, which segregated with all affected mice. This mutation was associated with decreased ribosome generation, consistent with Rpl5 haploinsufficiency. Rpl5Skax23-Jus/+ animals had a profound delay in erythroid maturation and increased mortality at embryonic day (E) 12.5, which improved by E14.5. Surviving mutant animals had macrocytic anemia at birth, as well as evidence of ventricular septal defect (VSD). Surviving adult and aged mice exhibited no hematopoietic defect or VSD. We propose that this novel Rpl5Skax23-Jus/+ mutant mouse will be useful in studying the factors influencing the variable penetrance that is observed in DBA.
Identifiants
pubmed: 34464976
pii: S2473-9529(21)00462-6
doi: 10.1182/bloodadvances.2021004658
pmc: PMC8945612
doi:
Substances chimiques
Ribosomal Proteins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4167-4178Subventions
Organisme : NHLBI NIH HHS
ID : T32 HL007622
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA046592
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA115503
Pays : United States
Organisme : NHLBI NIH HHS
ID : P01 HL146372
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL157062
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL148333
Pays : United States
Organisme : NICHD NIH HHS
ID : U01 HD039372
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA009357
Pays : United States
Informations de copyright
© 2021 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.
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