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

Carapito, Raphael and Konantz, Martina and Paillard, Catherine and Miao, Zhichao and Pichot, Angélique and Leduc, Magalie S. and Yang, Yaping and Bergstrom, Katie L. and Mahoney, Donald H. and Shardy, Deborah L. and Alsaleh, Ghada and Naegely, Lydie and Kolmer, Aline and Paul, Nicodème and Hanauer, Antoine and Rolli, Véronique and Müller, Joëlle S. and Alghisi, Elisa and Sauteur, Loïc and Macquin, Cécile and Morlon, Aurore and Sancho, Consuelo Sebastia and Amati-Bonneau, Patrizia and Procaccio, Vincent and Mosca-Boidron, Anne-Laure and Marle, Nathalie and Osmani, Naël and Lefebvre, Olivier and Goetz, Jacky G. and Unal, Sule and Akarsu, Nurten A. and Radosavljevic, Mirjana and Chenard, Marie-Pierre and Rialland, Fanny and Grain, Audrey and Béné, Marie-Christine and Eveillard, Marion and Vincent, Marie and Guy, Julien and Faivre, Laurence and Thauvin-Robinet, Christel and Thevenon, Julien and Myers, Kasiani and Fleming, Mark D. and Shimamura, Akiko and Bottollier-Lemallaz, Elodie and Westhof, Eric and Lengerke, Claudia and Isidor, Bertrand and Bahram, Seiamak. (2017) Mutations in signal recognition particle SRP54 cause syndromic neutropenia with Shwachman-Diamond-like features. The Journal of Clinical Investigation, 127 (11). pp. 4090-4103.

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Official URL: https://edoc.unibas.ch/80792/

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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.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin
UniBasel Contributors:Konantz, Martina
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Society for Clinical Investigation
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:09 Jun 2021 14:04
Deposited On:09 Jun 2021 14:04

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