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

作者：Carapito Raphael^*; Konantz Martina; Paillard Catherine; Miao Zhichao; Pichot Angelique; Leduc Magalie S; Yang Yaping; Bergstrom Katie L; Mahoney Donald H; Shardy Deborah L; Alsaleh Ghada; Naegely Lydie; Kolmer Aline; Paul Nicodeme; Hanauer Antoine; Rolli Veronique; Mueller Joelle S; Alghisi Elisa; Sauteur Loic; Macquin Cecile; Morlon Aurore; Sancho Consuelo Sebastia; Amati Bonneau Patrizia; Procaccio Vincent; Mosca Boidron Anne Laure; Marle Nathalie; Osmani Nael

来源：Journal of Clinical Investigation, 2017, 127(11): 4090-4103.

DOI：10.1172/JCI92876

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.

• 出版日期2017-11-1