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


ABSTRACT: 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.

SUBMITTER: Carapito R 

PROVIDER: S-EPMC5663364 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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

Carapito Raphael R   Konantz Martina M   Paillard Catherine C   Miao Zhichao Z   Pichot Angélique A   Leduc Magalie S MS   Yang Yaping Y   Bergstrom Katie L KL   Mahoney Donald H DH   Shardy Deborah L DL   Alsaleh Ghada G   Naegely Lydie L   Kolmer Aline A   Paul Nicodème N   Hanauer Antoine A   Rolli Véronique V   Müller Joëlle S JS   Alghisi Elisa E   Sauteur Loïc L   Macquin Cécile C   Morlon Aurore A   Sancho Consuelo Sebastia CS   Amati-Bonneau Patrizia P   Procaccio Vincent V   Mosca-Boidron Anne-Laure AL   Marle Nathalie N   Osmani Naël N   Lefebvre Olivier O   Goetz Jacky G JG   Unal Sule S   Akarsu Nurten A NA   Radosavljevic Mirjana M   Chenard Marie-Pierre MP   Rialland Fanny F   Grain Audrey A   Béné Marie-Christine MC   Eveillard Marion M   Vincent Marie M   Guy Julien J   Faivre Laurence L   Thauvin-Robinet Christel C   Thevenon Julien J   Myers Kasiani K   Fleming Mark D MD   Shimamura Akiko A   Bottollier-Lemallaz Elodie E   Westhof Eric E   Lengerke Claudia C   Isidor Bertrand B   Bahram Seiamak S  

The Journal of clinical investigation 20171003 11


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 undi  ...[more]

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