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Mutations in the SRP54 gene cause severe congenital neutropenia as well as Shwachman-Diamond-like syndrome.

ABSTRACT: Congenital neutropenias (CNs) are rare heterogeneous genetic disorders, with about 25% of patients without known genetic defects. Using whole-exome sequencing, we identified a heterozygous mutation in the SRP54 gene, encoding the signal recognition particle (SRP) 54 GTPase protein, in 3 sporadic cases and 1 autosomal dominant family. We subsequently sequenced the SRP54 gene in 66 probands from the French CN registry. In total, we identified 23 mutated cases (16 sporadic, 7 familial) with 7 distinct germ line SRP54 mutations including a recurrent in-frame deletion (Thr117del) in 14 cases. In nearly all patients, neutropenia was chronic and profound with promyelocytic maturation arrest, occurring within the first months of life, and required long-term granulocyte colony-stimulating factor therapy with a poor response. Neutropenia was sometimes associated with a severe neurodevelopmental delay (n = 5) and/or an exocrine pancreatic insufficiency requiring enzyme supplementation (n = 3). The SRP54 protein is a key component of the ribonucleoprotein complex that mediates the co-translational targeting of secretory and membrane proteins to the endoplasmic reticulum (ER). We showed that SRP54 was specifically upregulated during the in vitro granulocytic differentiation, and that SRP54 mutations or knockdown led to a drastically reduced proliferation of granulocytic cells associated with an enhanced P53-dependent apoptosis. Bone marrow examination of SRP54-mutated patients revealed a major dysgranulopoiesis and features of cellular ER stress and autophagy that were confirmed using SRP54-mutated primary cells and SRP54 knockdown cells. In conclusion, we characterized a pathological pathway, which represents the second most common cause of CN with maturation arrest in the French CN registry.

SUBMITTER: Bellanne-Chantelot C

PROVIDER: S-EPMC6536700 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Mutations in the SRP54 gene cause severe congenital neutropenia as well as Shwachman-Diamond-like syndrome.

Bellanné-Chantelot Christine C Schmaltz-Panneau Barbara B Marty Caroline C Fenneteau Odile O Callebaut Isabelle I Clauin Séverine S Docet Aurélie A Damaj Gandhi-Laurent GL Leblanc Thierry T Pellier Isabelle I Stoven Cécile C Souquere Sylvie S Antony-Debré Iléana I Beaupain Blandine B Aladjidi Nathalie N Barlogis Vincent V Bauduer Frédéric F Bensaid Philippe P Boespflug-Tanguy Odile O Berger Claire C Bertrand Yves Y Carausu Liana L Fieschi Claire C Galambrun Claire C Schmidt Aline A Journel Hubert H Mazingue Françoise F Nelken Brigitte B Quah Thuan Chong TC Oksenhendler Eric E Ouachée Marie M Pasquet Marlène M Saada Véronique V Suarez Felipe F Pierron Gérard G Vainchenker William W Plo Isabelle I Donadieu Jean J

Blood 20180618 12

Congenital neutropenias (CNs) are rare heterogeneous genetic disorders, with about 25% of patients without known genetic defects. Using whole-exome sequencing, we identified a heterozygous mutation in the SRP54 gene, encoding the signal recognition particle (SRP) 54 GTPase protein, in 3 sporadic cases and 1 autosomal dominant family. We subsequently sequenced the SRP54 gene in 66 probands from the French CN registry. In total, we identified 23 mutated cases (16 sporadic, 7 familial ...[more]

PMID: 29914977

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Project description:BackgroundShwachman-Diamond syndrome (SDS) is a rare inherited bone marrow failure syndrome associated with cytopenia and the development of hematologic malignancies. Solid tumor occurrence is rare and, historically, these patients have had poor outcomes due to chemotherapy-induced myelosuppression and increased susceptibility to infections. We report the administration of cytotoxic systemic therapy with granulocyte colony-stimulating factor (G-CSF) in a patient with SDS and metastatic breast cancer. We describe the risk-benefit profile of utilizing G-CSF in managing this patient to improve her therapeutic outcome and review the prior literature.Case descriptionA 41-year-old Caucasian female with SDS developed stage IV triple-positive [estrogen positive, progesterone positive, and human epidermal growth factor receptor 2 (HER2) positive] invasive ductal carcinoma of the left breast with liver metastases. She had lifelong thrombocytopenia with other hematologic parameters within normal limits, no tumor protein 53 (TP53) mutation, and no history of marrow dysplasia. Based on her underlying SDS, paclitaxel was favored over docetaxel due to the reduced risk of myelosuppression and weekly dosing schedule. Her regimen included weekly paclitaxel with trastuzumab and pertuzumab every 21 days. She experienced chemotherapy-induced neutropenia with an absolute neutrophil count of less than 1,500 leading to the utilization of G-CSF support. She received chemotherapy with twice-weekly G-CSF and did not experience severe infections. After nine cycles of therapy, she had no evidence of metastatic disease on imaging. The patient has an ongoing complete response at 18 months since treatment initiation.ConclusionsThis case report describes the treatment of a patient with SDS and metastatic breast cancer with cytotoxic chemotherapy and G-CSF. G-CSF facilitated ongoing chemotherapy administration and reduced the risk of infection leading to an optimal therapeutic outcome. There should be careful consideration of early G-CSF use in patients with SDS to optimize continuous chemotherapy dosing.

Dataset Information

Mutations in the SRP54 gene cause severe congenital neutropenia as well as Shwachman-Diamond-like syndrome.

Publications

Mutations in the <i>SRP54</i> gene cause severe congenital neutropenia as well as Shwachman-Diamond-like syndrome.

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