Inherited biallelic CSF3R mutations in severe congenital neutropenia

A Triot; PM Jarvinen; JI Arostegui; D Murugan; N Kohistani; JLD Diaz; T Racek; J Puchalka; EM Gertz; AA Schaffer; D Kotlarz; D Pfeifer; CDD Rubio; MA Ozdemir; T Patiroglu; M Karakukcu; JSD Codina; J Yague; Ivo Touw; E Unal; C Klein

doi:10.1182/blood-2013-11-535419

Inherited biallelic CSF3R mutations in severe congenital neutropenia

A Triot, PM Jarvinen, JI Arostegui, D Murugan, N Kohistani, JLD Diaz, T Racek, J Puchalka, EM Gertz, AA Schaffer, D Kotlarz, D Pfeifer, CDD Rubio, MA Ozdemir, T Patiroglu, M Karakukcu, JSD Codina, J Yague, Ivo Touw, E UnalC Klein

Hematology

Research output: Contribution to journal › Article › Academic › peer-review

71 Citations (Scopus)

Abstract

Severe congenital neutropenia (SCN) is characterized by low numbers of peripheral neutrophil granulocytes and a predisposition to life-threatening bacterial infections. We describe a novel genetic SCN type in 2 unrelated families associated with recessively inherited loss-of-function mutations in CSF3R, encoding the granulocyte colony-stimulating factor (G-CSF) receptor. Family A, with 3 affected children, carried a homozygous missense mutation (NM_000760.3:c.922C>T, NP_000751.1:p.Arg308Cys), which resulted in perturbed N-glycosylation and aberrant localization to the cell surface. Family B, with 1 affected infant, carried compound heterozygous deletions provoking frame shifts and premature stop codons(NM_000760.3:c.948_963del, NP_000751.1: p. Gly316fsTer322 and NM_000760.3:c.1245del, NP_000751.1:p.Gly415fsTer432). Despite peripheral SCN, all patients had morphologic evidence of full myeloid cell maturation in bone marrow. None of the patients responded to treatment with recombinant human G-CSF. Our study highlights the genetic and morphologic SCN variability and provides evidence both for functional importance and redundancy of G-CSF receptor-mediated signaling in human granulopoiesis.

Original language	Undefined/Unknown
Pages (from-to)	3811-3817
Number of pages	7
Journal	Blood
Volume	123
Issue number	24
DOIs	https://doi.org/10.1182/blood-2013-11-535419
Publication status	Published - 2014

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EMC MM-02-41-03

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10.1182/blood-2013-11-535419

Cite this

Triot, A., Jarvinen, PM., Arostegui, JI., Murugan, D., Kohistani, N., Diaz, JLD., Racek, T., Puchalka, J., Gertz, EM., Schaffer, AA., Kotlarz, D., Pfeifer, D., Rubio, CDD., Ozdemir, MA., Patiroglu, T., Karakukcu, M., Codina, JSD., Yague, J., Touw, I., ... Klein, C. (2014). Inherited biallelic CSF3R mutations in severe congenital neutropenia. Blood, 123(24), 3811-3817. https://doi.org/10.1182/blood-2013-11-535419

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title = "Inherited biallelic CSF3R mutations in severe congenital neutropenia",

abstract = "Severe congenital neutropenia (SCN) is characterized by low numbers of peripheral neutrophil granulocytes and a predisposition to life-threatening bacterial infections. We describe a novel genetic SCN type in 2 unrelated families associated with recessively inherited loss-of-function mutations in CSF3R, encoding the granulocyte colony-stimulating factor (G-CSF) receptor. Family A, with 3 affected children, carried a homozygous missense mutation (NM_000760.3:c.922C>T, NP_000751.1:p.Arg308Cys), which resulted in perturbed N-glycosylation and aberrant localization to the cell surface. Family B, with 1 affected infant, carried compound heterozygous deletions provoking frame shifts and premature stop codons(NM_000760.3:c.948_963del, NP_000751.1: p. Gly316fsTer322 and NM_000760.3:c.1245del, NP_000751.1:p.Gly415fsTer432). Despite peripheral SCN, all patients had morphologic evidence of full myeloid cell maturation in bone marrow. None of the patients responded to treatment with recombinant human G-CSF. Our study highlights the genetic and morphologic SCN variability and provides evidence both for functional importance and redundancy of G-CSF receptor-mediated signaling in human granulopoiesis.",

author = "A Triot and PM Jarvinen and JI Arostegui and D Murugan and N Kohistani and JLD Diaz and T Racek and J Puchalka and EM Gertz and AA Schaffer and D Kotlarz and D Pfeifer and CDD Rubio and MA Ozdemir and T Patiroglu and M Karakukcu and JSD Codina and J Yague and Ivo Touw and E Unal and C Klein",

year = "2014",

doi = "10.1182/blood-2013-11-535419",

language = "Undefined/Unknown",

volume = "123",

pages = "3811--3817",

journal = "Blood",

issn = "0006-4971",

publisher = "Elsevier",

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Triot, A, Jarvinen, PM, Arostegui, JI, Murugan, D, Kohistani, N, Diaz, JLD, Racek, T, Puchalka, J, Gertz, EM, Schaffer, AA, Kotlarz, D, Pfeifer, D, Rubio, CDD, Ozdemir, MA, Patiroglu, T, Karakukcu, M, Codina, JSD, Yague, J, Touw, I, Unal, E & Klein, C 2014, 'Inherited biallelic CSF3R mutations in severe congenital neutropenia', Blood, vol. 123, no. 24, pp. 3811-3817. https://doi.org/10.1182/blood-2013-11-535419

TY - JOUR

T1 - Inherited biallelic CSF3R mutations in severe congenital neutropenia

AU - Triot, A

AU - Jarvinen, PM

AU - Arostegui, JI

AU - Murugan, D

AU - Kohistani, N

AU - Diaz, JLD

AU - Racek, T

AU - Puchalka, J

AU - Gertz, EM

AU - Schaffer, AA

AU - Kotlarz, D

AU - Pfeifer, D

AU - Rubio, CDD

AU - Ozdemir, MA

AU - Patiroglu, T

AU - Karakukcu, M

AU - Codina, JSD

AU - Yague, J

AU - Touw, Ivo

AU - Unal, E

AU - Klein, C

PY - 2014

Y1 - 2014

N2 - Severe congenital neutropenia (SCN) is characterized by low numbers of peripheral neutrophil granulocytes and a predisposition to life-threatening bacterial infections. We describe a novel genetic SCN type in 2 unrelated families associated with recessively inherited loss-of-function mutations in CSF3R, encoding the granulocyte colony-stimulating factor (G-CSF) receptor. Family A, with 3 affected children, carried a homozygous missense mutation (NM_000760.3:c.922C>T, NP_000751.1:p.Arg308Cys), which resulted in perturbed N-glycosylation and aberrant localization to the cell surface. Family B, with 1 affected infant, carried compound heterozygous deletions provoking frame shifts and premature stop codons(NM_000760.3:c.948_963del, NP_000751.1: p. Gly316fsTer322 and NM_000760.3:c.1245del, NP_000751.1:p.Gly415fsTer432). Despite peripheral SCN, all patients had morphologic evidence of full myeloid cell maturation in bone marrow. None of the patients responded to treatment with recombinant human G-CSF. Our study highlights the genetic and morphologic SCN variability and provides evidence both for functional importance and redundancy of G-CSF receptor-mediated signaling in human granulopoiesis.

AB - Severe congenital neutropenia (SCN) is characterized by low numbers of peripheral neutrophil granulocytes and a predisposition to life-threatening bacterial infections. We describe a novel genetic SCN type in 2 unrelated families associated with recessively inherited loss-of-function mutations in CSF3R, encoding the granulocyte colony-stimulating factor (G-CSF) receptor. Family A, with 3 affected children, carried a homozygous missense mutation (NM_000760.3:c.922C>T, NP_000751.1:p.Arg308Cys), which resulted in perturbed N-glycosylation and aberrant localization to the cell surface. Family B, with 1 affected infant, carried compound heterozygous deletions provoking frame shifts and premature stop codons(NM_000760.3:c.948_963del, NP_000751.1: p. Gly316fsTer322 and NM_000760.3:c.1245del, NP_000751.1:p.Gly415fsTer432). Despite peripheral SCN, all patients had morphologic evidence of full myeloid cell maturation in bone marrow. None of the patients responded to treatment with recombinant human G-CSF. Our study highlights the genetic and morphologic SCN variability and provides evidence both for functional importance and redundancy of G-CSF receptor-mediated signaling in human granulopoiesis.

U2 - 10.1182/blood-2013-11-535419

DO - 10.1182/blood-2013-11-535419

M3 - Article

C2 - 24753537

SN - 0006-4971

VL - 123

SP - 3811

EP - 3817

JO - Blood

JF - Blood

IS - 24

ER -