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

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

  • J Clin Invest. 2017 Nov 1;127(11):4090-4103. doi: 10.1172/JCI92876.
Raphael Carapito 1 2 3,  Martina Konantz 4,  Catherine Paillard 1 2 5,  Zhichao Miao 6,  Angélique Pichot 1 2,  Magalie S Leduc 7 8,  Yaping Yang 7,  Katie L Bergstrom 9,  Donald H Mahoney 9,  Deborah L Shardy 9,  Ghada Alsaleh 1 2,  Lydie Naegely 1 2,  Aline Kolmer 1 2,  Nicodème Paul 1 2,  Antoine Hanauer 1 2,  Véronique Rolli 1 2 3,  Joëlle S Müller 4,  Elisa Alghisi 4,  Loïc Sauteur 4,  Cécile Macquin 1 2,  Aurore Morlon 10,  Consuelo Sebastia Sancho 11,  Patrizia Amati-Bonneau 12 13,  Vincent Procaccio 12 13,  Anne-Laure Mosca-Boidron 14,  Nathalie Marle 14,  Naël Osmani 1,  Olivier Lefebvre 1,  Jacky G Goetz 1,  Sule Unal 15,  Nurten A Akarsu 16,  Mirjana Radosavljevic 1 2 3,  Marie-Pierre Chenard 17,  Fanny Rialland 18,  Audrey Grain 18,  Marie-Christine Béné 19,  Marion Eveillard 19,  Marie Vincent 20,  Julien Guy 21,  Laurence Faivre 22,  Christel Thauvin-Robinet 22,  Julien Thevenon 22,  Kasiani Myers 23,  Mark D Fleming 24,  Akiko Shimamura 25,  Elodie Bottollier-Lemallaz 26,  Eric Westhof 6,  Claudia Lengerke 4 27,  Bertrand Isidor 20 28,  Seiamak Bahram 1 2 3
Affiliations

Affiliations

  • 1 Laboratoire d'ImmunoRhumatologie Moléculaire, Plateforme GENOMAX, INSERM UMR - S1109, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France.
  • 2 LabEx TRANSPLANTEX, Faculté de Médecine, Université de Strasbourg, Strasbourg, France.
  • 3 Service d'Immunologie Biologique, Plateau Technique de Biologie, Pôle de Biologie, Nouvel Hôpital Civil, Strasbourg, France.
  • 4 Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland.
  • 5 Service d'Onco-hématologie Pédiatrique, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
  • 6 Architecture et Réactivité de l'ARN, CNRS UPR 9002, LabEx NetRNA, Institut de Biologie Moléculaire et Cellulaire, Université de Strasbourg, Strasbourg, France.
  • 7 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
  • 8 Baylor Genetics, Holcombe, Houston, Texas, USA.
  • 9 Department of Pediatrics, Hematology-Oncology Section, Texas Children's Hematology and Cancer Centers, Baylor College of Medicine, Houston, Texas, USA.
  • 10 BIOMICA SAS, Strasbourg, France.
  • 11 Service de Radiologie Pédiatrique, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
  • 12 CNRS UMR 6015, INSERM UMR - S1083, MitoVasc Institute, Angers University, Angers, France.
  • 13 Department of Biochemistry and Genetics, Angers Hospital, Angers, France.
  • 14 Laboratoire de Cytogénétique, Pôle de Biologie, Centre Hospitalier Universitaire (CHU) de Dijon, Dijon, France.
  • 15 Division of Pediatric Hematology, Hacettepe University Medical Faculty, Sihhiye, Ankara, Turkey.
  • 16 Gene Mapping Laboratory, Department of Medical Genetics, Hacettepe University Medical Faculty, Sihhiye, Ankara, Turkey.
  • 17 Département de Pathologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
  • 18 Service d'Oncologie et Hématologie Pédiatrique, Hôpital Femmes-enfants-adolescents, CHU de Nantes, Nantes, France.
  • 19 Service d'Hématologie Biologique, CHU de Nantes, Nantes, France.
  • 20 Service de Génétique Médicale, Hôpital Femmes-enfants-adolescents, CHU de Nantes, Nantes, France.
  • 21 Service d'Hématologie Biologique, Pôle Biologie, CHU de Dijon, Dijon, France.
  • 22 Service de Génétique, Hôpital d'enfants, CHU de Dijon, Dijon, France.
  • 23 Division of Blood and Marrow Transplantation and Immune Deficiency, The Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
  • 24 Department of Pathology, Boston Children's Hospital, and.
  • 25 Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, Massachusetts, USA.
  • 26 Service d'Hématologie et Oncologie Pédiatrique, Hôpital d'enfants, CHU de Dijon, Dijon, France.
  • 27 Division of Hematology, University Hospital Basel, University of Basel, Basel, Switzerland.
  • 28 Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, INSERM UMR - S957, Faculté de Médecine, Nantes, France.
PMID: 28972538 DOI: 10.1172/JCI92876
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.

Figures