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Mutations in signal recognition particle SRP54 cause syndromic neutropenia with Shwachman-Diamond–like features

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Author Carapito Raphael, Konantz Martina, Paillard Catherine, Miao Zhichao, Pichot Angélique, Leduc Magalie S., Yang Yaping, Bergstrom Katie L., Mahoney Donald H., Shardy Deborah L., Alsaleh Ghada, Naegely Lydie, Kolmer Aline, Paul Nicodème, Hanauer Antoine, Rolli Véronique, Müller Joëlle S., Alghisi Elisa, Sauteur Loïc, Macquin Cécile, Morlon Aurore, Sancho Consuelo Sebastia, Amati-Bonneau Patrizia, Procaccio Vincent, et al. ,
Project Role and molecular targets of the transcription factor EVI1 in lymphoblastic leukemia and blood stem cell development
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Original article (peer-reviewed)

Journal Journal of Clinical Investigation
Volume (Issue) 127(11)
Page(s) 4090 - 4103
Title of proceedings Journal of Clinical Investigation
DOI 10.1172/jci92876

Open Access

Type of Open Access Publisher (Gold Open Access)


Shwachman-Diamond syndrome (SDS) (OMIM #260400) is a rare inherited bone marrow failure syndrome (IBMFS) that is primarily characterized by neutropenia and exocrine pancreatic insufficiency. Seventy-five to ninety percent of patients have compound heterozygous loss-of-function mutations in the Shwachman-Bodian-Diamond syndrome (sbds) gene. Using trio whole-exome sequencing (WES) in an sbds-negative SDS family and candidate gene sequencing in additional SBDS-negative SDS cases or molecularly undiagnosed IBMFS cases, we identified 3 independent patients, each of whom carried a de novo missense variant in srp54 (encoding signal recognition particle 54 kDa). These 3 patients shared congenital neutropenia linked with various other SDS phenotypes. 3D protein modeling revealed that the 3 variants affect highly conserved amino acids within the GTPase domain of the protein that are critical for GTP and receptor binding. Indeed, we observed that the GTPase activity of the mutated proteins was impaired. The level of SRP54 mRNA in the bone marrow was 3.6-fold lower in patients with SRP54-mutations than in healthy controls. Profound reductions in neutrophil counts and chemotaxis as well as a diminished exocrine pancreas size in a SRP54-knockdown zebrafish model faithfully recapitulated the human phenotype. In conclusion, autosomal dominant mutations in SRP54, a key member of the cotranslation protein-targeting pathway, lead to syndromic neutropenia with a Shwachman-Diamond–like phenotype.