PUBLICATION
Mutations in signal recognition particle SRP54 cause syndromic neutropenia with Shwachman-Diamond-like features
- Authors
- Carapito, R., Konantz, M., Paillard, C., Miao, Z., Pichot, A., Leduc, M.S., Yang, Y., Bergstrom, K.L., Mahoney, D.H., Shardy, D.L., Alsaleh, G., Naegely, L., Kolmer, A., Paul, N., Hanauer, A., Rolli, V., Müller, J.S., Alghisi, E., Sauteur, L., Macquin, C., Morlon, A., Sancho, C.S., Amati-Bonneau, P., Procaccio, V., Mosca-Boidron, A.L., Marle, N., Osmani, N., Lefebvre, O., Goetz, J.G., Unal, S., Akarsu, N.A., Radosavljevic, M., Chenard, M.P., Rialland, F., Grain, A., Béné, M.C., Eveillard, M., Vincent, M., Guy, J., Faivre, L., Thauvin-Robinet, C., Thevenon, J., Myers, K., Fleming, M.D., Shimamura, A., Bottollier-Lemallaz, E., Westhof, E., Lengerke, C., Isidor, B., Bahram, S.
- ID
- ZDB-PUB-171004-3
- Date
- 2017
- Source
- The Journal of Clinical Investigation 127(11): 4090-4103 (Journal)
- Registered Authors
- Alghisi, Elisa, Konantz, Martina, Lengerke, Claudia, Morlon, Aurore, Müller, Joëlle, Sauteur, Loïc
- Keywords
- none
- MeSH Terms
-
- Animals
- Bone Marrow Diseases/genetics*
- Child
- DNA Mutational Analysis
- Exocrine Pancreatic Insufficiency/genetics*
- Female
- Genetic Association Studies
- Humans
- Infant
- Lipomatosis/genetics*
- Male
- Models, Molecular
- Neutropenia/congenital*
- Neutropenia/genetics
- Pancreas, Exocrine/metabolism
- Phenotype
- Protein Domains
- Signal Recognition Particle/chemistry
- Signal Recognition Particle/genetics*
- Zebrafish
- PubMed
- 28972538 Full text @ Journal of Clin. Invest.
Citation
Carapito, R., Konantz, M., Paillard, C., Miao, Z., Pichot, A., Leduc, M.S., Yang, Y., Bergstrom, K.L., Mahoney, D.H., Shardy, D.L., Alsaleh, G., Naegely, L., Kolmer, A., Paul, N., Hanauer, A., Rolli, V., Müller, J.S., Alghisi, E., Sauteur, L., Macquin, C., Morlon, A., Sancho, C.S., Amati-Bonneau, P., Procaccio, V., Mosca-Boidron, A.L., Marle, N., Osmani, N., Lefebvre, O., Goetz, J.G., Unal, S., Akarsu, N.A., Radosavljevic, M., Chenard, M.P., Rialland, F., Grain, A., Béné, M.C., Eveillard, M., Vincent, M., Guy, J., Faivre, L., Thauvin-Robinet, C., Thevenon, J., Myers, K., Fleming, M.D., Shimamura, A., Bottollier-Lemallaz, E., Westhof, E., Lengerke, C., Isidor, B., Bahram, S. (2017) Mutations in signal recognition particle SRP54 cause syndromic neutropenia with Shwachman-Diamond-like features. The Journal of Clinical Investigation. 127(11):4090-4103.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping