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