{"doi":"10.26508/lsa.202201856","title":"SBDS<sup>R126T</sup>rescues survival of<i>sbds</i><sup><i>−/−</i></sup>zebrafish in a dose-dependent manner independently of Tp53","abstract":"Defects in ribosomal biogenesis profoundly affect organismal development and cellular function, and these ribosomopathies produce a variety of phenotypes. One ribosomopathy, Shwachman–Diamond syndrome (SDS) is characterized by neutropenia, pancreatic exocrine insufficiency, and skeletal anomalies. SDS results from biallelic mutations in SBDS , which encodes a ribosome assembly factor. Some individuals express a missense mutation, SBDS R126T , along with the common K62X mutation. We reported that the sbds -null zebrafish phenocopies much of SDS. We further showed activation of Tp53-dependent pathways before the fish died during the larval stage. Here, we expressed SBDS R126T as a transgene in the sbds −/− background. We showed that one copy of the SBDS R126T transgene permitted the establishment of maternal zygotic sbds -null fish which produced defective embryos with cdkn1a up-regulation, a Tp53 target involved in cell cycle arrest. None survived beyond 3 dpf. However, two copies of the transgene resulted in normal development and lifespan. Surprisingly, neutropenia persisted. The surviving fish displayed suppression of female sex differentiation, a stress response in zebrafish. To evaluate the role of Tp53 in the pathogenesis of sbds −/− fish phenotype, we bred the fish with a DNA binding deficient allele, tp53 M214K . Expression of the loss-of-function tp53 M214K did not rescue neutropenia or survival in sbds -null zebrafish. Increased expression of cdkn1a was abrogated in the tp53 M214K/M214K ;sbds −/− fish. We conclude that the amount of SBDS R126T protein is important for development, inactivation of Tp53 fails to rescue neutropenia or survival in the sbds -null background, and cdkn1a up-regulation was dependent on WT tp53 . We hypothesize that additional pathways are involved in the pathophysiology of SDS.","journal":"Life Science Alliance","year":2023,"id":379106,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9561,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":403910,"name":"Arish N Shah","orcid":"0000-0002-4036-9772","position":1,"is_corresponding":false},{"id":1143561,"name":"Morgan Staton","orcid":"0009-0005-4919-8040","position":2,"is_corresponding":false},{"id":403912,"name":"Matthew Snyderman","orcid":"0009-0009-0672-7263","position":3,"is_corresponding":false},{"id":386807,"name":"Adya Sapra","orcid":null,"position":4,"is_corresponding":false},{"id":281178,"name":"Eliezer Calo","orcid":"0000-0002-3006-2742","position":5,"is_corresponding":false},{"id":386074,"name":"Seth J. Corey","orcid":"0000-0002-3575-6401","position":6,"is_corresponding":false},{"id":403909,"name":"Usua Oyarbide","orcid":"0000-0003-4082-7945","position":0,"is_corresponding":true}],"reference_count":27,"raw_metadata":null,"created_at":"2026-07-19T01:16:52.622552Z","pmid":"37816584","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}