Original Article
A Syndrome with Congenital Neutropenia and Mutations in G6PC3
N Engl J Med 2009; 360:32-43January 1, 2009
- Abstract
Background
The main features of severe congenital neutropenia are the onset of severe bacterial infections early in life, a paucity of mature neutrophils, and an increased risk of leukemia. In many patients, the genetic causes of severe congenital neutropenia are unknown.
Methods
We performed genomewide genotyping and linkage analysis on two consanguineous pedigrees with a total of five children affected with severe congenital neutropenia. Candidate genes from the linkage interval were sequenced. Functional assays and reconstitution experiments were carried out.
Results
All index patients were susceptible to bacterial infections and had very few mature neutrophils in the bone marrow; structural heart defects, urogenital abnormalities, and venous angiectasia on the trunk and extremities were additional features. Linkage analysis of the two index families yielded a combined multipoint lod score of 5.74 on a linkage interval on chromosome 17q21. Sequencing of G6PC3, the candidate gene encoding glucose-6-phosphatase, catalytic subunit 3, revealed a homozygous missense mutation in exon 6 that abolished the enzymatic activity of glucose-6-phosphatase in all affected children in the two families. The patients' neutrophils and fibroblasts had increased susceptibility to apoptosis. The myeloid cells showed evidence of increased endoplasmic reticulum stress and increased activity of glycogen synthase kinase 3β (GSK-3β). We identified seven additional, unrelated patients who had severe congenital neutropenia with syndromic features and distinct biallelic mutations in G6PC3.
Conclusions
Defective function of glucose-6-phosphatase, catalytic subunit 3, underlies a severe congenital neutropenia syndrome associated with cardiac and urogenital malformations.
Media in This Article
Figure 1
Clinical and Hematologic Phenotype.Figure 2
Haplotypes on Chromosome 17q, Mutation Analysis of G6PC3, and Assessment of Enzymatic Activity of G6PC3 with the R253H Mutation.Article Activity
- Article
Severe congenital neutropenia was described more than 50 years ago by Kostmann,1,2 and subsequently the disorder was found to consist of a heterogeneous group of diseases.3,4 In these syndromes, the neutropenia is associated with life-threatening bacterial infections early in life. Most patients respond to treatment with recombinant human granulocyte colony-stimulating factor (rhG-CSF), which increases neutrophil counts and decreases the frequency and severity of infections.5 Nonetheless, patients may remain at risk for both infectious complications and the development of clonal disorders of hematopoiesis, such as myelodysplastic syndrome and acute myeloid leukemia.6
Considerable progress has been made in identifying the molecular defects that cause congenital neutropenia.7,8 Many patients with severe congenital or cyclic neutropenia have a heterozygous mutation in ELA2, the gene encoding neutrophil elastase.9-11 We recently identified homozygous mutations in HAX1, the gene encoding HCLS1-associated protein X1, in a subgroup of patients with autosomal recessive severe congenital neutropenia.12 In addition, mutations in WAS, the gene encoding the Wiskott–Aldrich syndrome protein,13,14 and in GFI1, the gene encoding the growth factor independent 1 transcription-repressor protein,15 have been associated with a phenotype resembling Kostmann's syndrome. In many patients with congenital neutropenia, however, the underlying molecular cause remains unknown. Despite insights into the role of apoptosis in congenital neutropenia,12,16,17 the mechanisms of neutropenia and the risk of leukemia in patients with severe congenital neutropenia are incompletely understood. We report a syndrome consisting of severe congenital neutropenia, other congenital abnormalities, and biallelic mutations in G6PC3, the gene encoding glucose-6-phosphatase, catalytic subunit 3.
Methods
Patients and Controls
We took blood and bone marrow samples from patients and healthy volunteers with their written informed consent. The study was approved by the institutional review board of Hannover Medical School.
Analytical Methods
We genotyped microsatellite markers in a whole-genome scan for a family with severe congenital neutropenia, with a pedigree identified as SCN-I. The equipment and protocols for genotyping have been described previously.12 The genetic-linkage analysis was performed with the use of a combination of quantitative and qualitative syllogisms. The quantitative decisions were made with the use of lod scores and optimal recombination fractions computed with Superlink software.18,19 For calculation of lod scores, we modeled neutropenia as a fully penetrant autosomal recessive disease with no phenocopies and a disease-allele frequency of 0.001. The Marshfield map20 was used to select usefully positioned markers for fine mapping. For details, see the Supplementary Appendix, available with the full text of this article at NEJM.org.
Exons and flanking intron–exon boundaries from candidate genes were amplified by polymerase chain reaction (PCR) and analyzed with the use of an ABI PRISM 3130 DNA Sequencer and DNA Sequencing Analysis software, version 3.4 (Applied Biosystems), and Sequencer, version 3.4.1 (Gene Codes Corporation). See the Supplementary Appendix for primer sequences and details of the restriction-length-polymorphism analysis of the frequency of the R253H mutation in healthy controls.
Promyelocytes were sorted by fluorescence-activated cell sorting, as described previously,17 with minor modifications. Analysis of the expression of the G6PC3 and HSPA5/BiP/Grp78 genes was performed with the use of a Roche LightCycler 2.0 (see the Supplementary Appendix).
The complete open reading frames of wild-type and mutant G6PC3 were amplified by PCR and cloned in pYES-cup1 (modified from pYES-NT [Invitrogen]), as described by Ashikov et al.,21 and expressed in Saccharomyces cerevisiae. Centrifugation at 100,000×g produced a microsomal fraction that was assayed for hydrolysis of glucose-6-phosphate to glucose by the addition of 14C-glucose-6-phosphate (MP Biomedicals). Released 14C-glucose was separated from glucose-6-phosphate by anion exchange and measured in the eluate by liquid scintillation.
Whole-cell lysates from primary granulocytes were separated by sodium dodecyl sulfate–polyacrylamide-gel electrophoresis (SDS-PAGE), blotted, and stained with antibodies against phospho-Mcl-1 (Ser159/Thr163), total glycogen synthase kinase 3β (GSK-3β), phospho-GSK-3β (Ser9) (all from Cell Signaling Technology/New England Biolabs), Bip/Grp78 (BD Biosciences), and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (Santa Cruz Biotechnology) (see the Supplementary Appendix).
Bone marrow samples from patients and healthy control subjects were subjected to hypotonic lysis. Fixation and electron microscopy were performed as described previously.22
Human G6PC3 complementary DNA (cDNA) was cloned into a bicistronic retroviral vector (MMP)23 containing murine cd24 as a marker gene. RD114-pseudotyped retroviral particles were generated by tripartite transfection of MMP-based vectors together with the envelope plasmid and the packaging plasmid mPD.old.gag/pol into a human embryonic kidney-cell line (HEK293T). Transduction of CD34+ cells and myeloid differentiation were performed as described previously.12
Apoptosis in peripheral-blood neutrophils or in cells that were differentiated into myeloid cells in vitro was induced with the use of tumor necrosis factor α (TNF-α) (50 ng per milliliter), thapsigargin (10 μM), or tunicamycin (5 μg per milliliter) (all from Sigma) and assessed by staining with annexin V (Invitrogen) and propidium iodide (Sigma). In fibroblasts, apoptosis was induced with the use of 5 mM dithiothreitol (Roche). Caspase 3/7 activation was assessed as described previously12 (see the Supplementary Appendix).
Results
Clinical Findings
Table 1Table 1
Clinical and Molecular Findings in Patients with G6PC3 Deficiency. lists the main features of the five patients we studied. Patients 1 and 2, who were siblings born to consanguineous parents of Aramean descent, presented with neonatal sepsis. Their extended pedigree is denoted SCN-I (see Fig. 1 in the Supplementary Appendix). Their workup in the first year of life found severe neutropenia with a paucity of mature neutrophils in the peripheral blood and bone marrow. Bone marrow smears contained few granulocytes beyond the stage of promyelocytes or myelocytes (Figure 1A and 1BFigure 1Clinical and Hematologic Phenotype., and Table 1 in the Supplementary Appendix). Erythrocyte counts were normal. Platelet counts in Patient 1 ranged from 73,000 to 425,000 per cubic millimeter, whereas Patient 2 had normal platelet counts. Both patients had unusually prominent subcutaneous veins, venous angiectasia, or both (Figure 1C); Patient 1 had a type 2 atrial septal defect (Figure 1D), and Patient 2 had cor triatriatum and hepatosplenomegaly. Genealogic investigations revealed that the SCN-I pedigree could be extended to include two additional sibships, each with one child affected by severe congenital neutropenia and type 2 atrial septal defect (Patients 3 and 4 in Fig. 1 in the Supplementary Appendix). We also identified a child with severe congenital neutropenia in a second consanguineous pedigree (SCN-II) from the same ethnic background (Patient 5 in Fig. 1 in the Supplementary Appendix). All patients received rhG-CSF, which resulted in an increase in neutrophil counts.Genetic Studies
Mutations in both ELA2 10 and HAX1 12 were excluded in all five index patients. Linkage analysis provided statistical evidence that the gene of interest in SCN-I is located on chromosome 17q21 between D17S1299 (36.2 Mb, 62.0 cM) and D17S1290 (53.7 Mb, 82.0 cM) (Figure 2AFigure 2
Haplotypes on Chromosome 17q, Mutation Analysis of G6PC3, and Assessment of Enzymatic Activity of G6PC3 with the R253H Mutation., and the Supplementary Appendix). We carried out a series of fine mapping steps in SCN-I and SCN-II and were able to genotype an additional 13 microsatellite markers between D17S1299 and D17S1290 in SCN-I and 11 of these 13 microsatellite markers in SCN-II. Table 2 in the Supplementary Appendix shows the single-marker lod scores. On the assumption that the same gene is mutated in all five affected children, the maximal linkage interval spanned from D17S1789 (39.1 Mb, 63.1 cM) to D17S791 (42.2 Mb, 64.2 cM). With the use of D17S932, D17S950, and D17S806, the peak multipoint lod score in SCN-I alone was 4.98, and the peak two-pedigree multipoint lod score was 5.74.Several candidate genes were identified in the SCN-I linkage interval (see Table 3 in the Supplementary Appendix). Of these, G6PC3, which encodes glucose-6-phosphatase, catalytic subunit 3, and is located in the narrowest possible linkage interval, was a plausible candidate, because abnormal glucose metabolism has been implicated in the neutropenia of type Ib glycogen storage disease.24 DNA sequencing revealed a homozygous missense mutation in exon 6 of the G6PC3 gene (c.G758A, p.R253H) (Figure 2B). This mutation was found in all four affected children in SCN-I and in the one affected child in SCN-II. All parents were heterozygous for the mutation, a finding consistent with autosomal recessive inheritance of a germ-line missense mutation. According to restriction-site analysis, the R253H allele of the G6PC3 gene was not found in 192 healthy central European persons. An in silico sequence analysis using the program Sorting Intolerant from Tolerant (SIFT)25 calculated that the probability that this mutation is benign is 0.01. Analysis with the program PolyPhen26 predicted that the R253H change probably interferes with the function of glucose-6-phosphatase. The wild-type protein is conserved in mammals, amphibians, bony fish, and insects.
Functional Studies
Enzymatic Activity of G6PC3 with the R253H Mutation
Wild-type G6PC3 and G6PC3 with the R253H mutation were expressed in S. cerevisiae. Microsomes were isolated from yeast transfected with wild-type G6PC3 or G6PC3 with the R253H mutation and assayed for phosphatase activity. Wild-type G6PC3 hydrolyzed glucose-6-phosphate and the universal substrate p-nitrophenylphosphate (pNPP), as demonstrated by radioactive (Figure 2C) and spectrometric (Fig. 3 in the Supplementary Appendix) assays, respectively. In contrast, the level of enzymatic activity of G6PC3 with the R253H mutation did not exceed the level of phosphatase activity in yeast transfected with an empty vector.
Apoptosis
Like neutrophils from patients with mutations in ELA2 10 or HAX1, 12 peripheral-blood neutrophils from our patients had an increased rate of spontaneous apoptosis. Apoptosis of neutrophils was markedly accelerated after induction with TNF-α (Figure 3AFigure 3
Increased Susceptibility to Apoptosis in Myeloid Cells and Fibroblast Cell Lines.) or tunicamycin (data not shown), as assessed by annexin V staining and a test for activation of caspase 3/7, respectively (see Fig. 4 in the Supplementary Appendix). Since G6PC3 is ubiquitously expressed and since the phenotype of our patients was not restricted to the hematopoietic system, we tested nonhematopoietic cells for susceptibility to apoptosis. Skin fibroblasts from patients with a deficiency of G6PC3 had an increased susceptibility to apoptosis after dithiothreitol-induced stress to the endoplasmic reticulum (Figure 3B).To provide further evidence that this form of severe congenital neutropenia is caused by mutations in G6PC3, CD34+ hematopoietic stem cells from two patients were isolated and transduced with retroviral constructs containing either the wild-type G6PC3 cDNA sequence and murine cd24 as a reporter gene (MMP-G6PC3-mcd24) or the reporter gene only (MMP-mcd24). After in vitro differentiation in the presence of rhG-CSF and recombinant human granulocyte–macrophage colony-stimulating factor (rhGM-CSF), cells were exposed to tunicamycin to induce apoptosis and analyzed by flow cytometry by gating on mcd24-positive cells. In control-transduced cells from a patient, exposure to tunicamycin induced a high degree of apoptosis (30.0% of annexin V–positive cells and 4.6% of annexin V and propidium iodide–double-positive cells underwent apoptosis). By contrast, in G6PC3-transduced cells, the percentage of cells undergoing induced apoptosis was lower (17.9% of annexin V–positive cells and 1.9% of double-positive cells) (Figure 3C, and Fig. 5 in the Supplementary Appendix). We tested the function of neutrophils in G6PC3-deficient neutrophils. Both phagosomal lysis of Escherichia coli and the oxidative burst were similar to those in neutrophils from healthy control subjects (Fig. 6 in the Supplementary Appendix).
Endoplasmic Reticulum Stress
Endoplasmic reticulum stress and the unfolded-protein response have been linked to the pathophysiology of aberrant organogenesis,27 including structural heart defects28 and congenital neutropenia caused by mutations in ELA2.17,29 Transmission electron microscopy of bone marrow cells from four patients with G6PC3 deficiency showed an enlarged rough endoplasmic reticulum in myeloid progenitor cells as compared with the rough endoplasmic reticulum in corresponding cells from a healthy subject (Figure 4A and 4BFigure 4
Pathophysiologic Consequences of G6PC3 Deficiency., and Fig. 7 in the Supplementary Appendix). This finding is consistent with increased endoplasmic reticulum stress. BiP messenger RNA (mRNA), a member of the chaperone family and another marker of endoplasmic reticulum stress, was measured by quantitative real-time PCR in bone marrow promyelocytes that had been isolated by flow cytometry. The level of BiP mRNA was increased in promyelocytes from the two patients we tested as compared with that in promyelocytes from healthy subjects (Figure 4C).GSK-3β
A signaling circuit linking glucose, GSK-3β, and Mcl-1 has been previously established30,31 in which GSK-3β controls glycogen metabolism, Wnt signaling, and apoptosis.32 Mcl-1, an antiapoptotic member of the Bcl-2 family, is involved in the maintenance of neutrophil viability.33 GSK-3β phosphorylates Mcl-1, thus facilitating its degradation in the proteasome.30 We performed Western blot studies to estimate the levels of GSK-3β, BiP, and Mcl-1 proteins in neutrophils exposed to tunicamycin, an agent that induces endoplasmic reticulum stress. Neutrophils from the two patients we examined had increased levels of BiP (Figure 4E), an increase in the enzymatically active dephosphorylated form of GSK-3β (Figure 4D, and Fig. 8 in the Supplementary Appendix), and increased phosphorylation of Mcl-1 (Figure 4E). To investigate whether intracellular glucose deprivation causes dephosphorylation of GSK-3β, we inhibited glucose metabolism in neutrophils from two healthy subjects with the use of 2-deoxyglucose. Treatment with 2-deoxyglucose induced dephosphorylation of GSK-3β (Figure 4F) and increased apoptosis of neutrophils (Figure 4G), whereas CD3-positive T lymphocytes were resistant to the effects of 2-deoxyglucose (Figure 4G).
G6PC3 Mutations in Other Patients
We assessed the frequency and variety of G6PC3 mutations in a cohort of patients with genetically unclassified severe congenital neutropenia. Of 104 such patients, 7 had distinct biallelic mutations in G6PC3 (Table 1). The mutations include nonsense mutations (Y47X and Y48X) that would abolish the function of the protein if the truncated mRNA was translated. The two other missense mutations were predicted to be deleterious to the protein by SIFT22 analysis, with probabilities of being benign of 0.03 for L185P, 0.00 for G262R, and 0.00 for G260R. None of these additional patients with G6PC3 mutations had mutations in ELA2 or HAX1, with the exception of a monoallelic genetic variant in HAX1 (p.Val172Ile) in Patient 10. Monoallelic mutations in HAX1 have never been associated with congenital neutropenia. Therefore, these three genetic defects represent distinct variants of severe congenital neutropenia. None of the patients with G6PC3 deficiency had hypoglycemia or lactic acidosis (see Table 4 in the Supplementary Appendix), as is seen in glycogen storage disorders.
A clinical review of all 12 patients with G6PC3 deficiency found variation in clinical features. Of the 12 patients, 8 had various cardiac malformations and 10 had a phenotype of unusually prominent subcutaneous veins, venous angiectasia, or both (Figure 1, and Fig. 2 in the Supplementary Appendix). Five patients had urogenital malformations, including cryptorchidism and urachal fistula (the urachus is a channel between the bladder of the fetus and the allantois). Two patients had inner-ear hearing loss, and two had delayed growth but no dysmorphic features (Table 1).
Discussion
We have described a congenital neutropenia syndrome with biallelic mutations in G6PC3. Like patients with mutations in HAX1 12 or ELA2, 16 patients with G6PC3 deficiency lacked mature neutrophils in the bone marrow and had increased susceptibility to apoptosis in peripheral neutrophils. Of 12 patients, 8 had structural heart defects (e.g., type 2 atrial septal defect, cor triatriatum, or pulmonary stenosis) and 5 had urogenital defects (e.g., cryptorchidism or urachal fistula). In most patients, an atypical, increased visibility of the superficial veins, angiectasia, or both was prominent. The spectrum of developmental aberrations may depend on factors other than the mutant G6PC3. Perhaps increased susceptibility to apoptosis also affects cardiac or urogenital development in patients with G6PC3 deficiency. There is clinical variation in other neutropenia syndromes, such as Cohen syndrome and cartilage-hair hypoplasia, even though the two syndromes are genetically homogeneous.8 All patients in our cohort had a response to treatment with rhG-CSF, and to date no patient has had a clonal hematopoietic disorder.
Three human genes mediating glucose-6-phosphatase activity have been discovered: G6PC1, G6PC2, and G6PC3. G6PC1, the classic glucose-6-phosphatase in the liver, kidney, and small intestine, catalyzes the hydrolysis of glucose-6-phosphate, an essential step in the gluconeogenic and glycogenolytic pathways. Patients without G6PC1 activity have type Ia glycogen storage disease.34 G6PC2 is expressed only in pancreatic islet cells35,36 and may be involved in glucose-dependent insulin secretion by controlling free glucose levels.37 Statistically significant associations between noncoding polymorphisms in or near G6PC2 and the level of glucose after an overnight fast have been shown.38,39 In contrast to G6PC1 and G6PC2, G6PC3 is ubiquitously expressed.40,41 Glucose-6-phosphate is transported to the endoplasmic reticulum by a glucose-6-phosphate transporter (G6PT).42 The stoichiometry and topologic relationships between the catalytic subunits of glucose-6-phosphatase and G6PT are unclear, but they do have a functional link.42-44 The complex formed between G6PT and G6PC1 (and perhaps also the complex between G6PT and G6PC2) appears to maintain normoglycemia. Our data show that G6PC3 is needed to maintain neutrophil viability and suggest an important role for glucose in the homeostasis of human neutrophils.
Cheung et al. recently described the phenotype of g6pc3-deficient mice that was generated by gene targeting.45 These mice had neutropenia and neutrophil dysfunction; another group had previously shown that murine g6pc3 deficiency results in lowered plasma cholesterol and elevated glucagon levels.46 We could not identify any consistent aberration in neutrophil function or any metabolic aberrations in patients with G6PC3 deficiency. The underlying mechanism of increased apoptosis of neutrophils in the absence of G6PC3 involves increased endoplasmic reticulum stress, which is usually seen in cases of deficient protein folding in the endoplasmic reticulum. In an attempt to counteract potentially toxic effects that can ensue from abnormally folded proteins, cells initiate a rescue program that, if ineffective, leads to apoptosis.47 We have provided evidence that GSK-3β, a key enzyme that regulates cellular differentiation and apoptosis,32 is implicated in this pathway. In the absence of intracellular glucose, GSK-3β is activated and thus can phosphorylate the antiapoptotic molecule Mcl-1, thereby mediating its degradation.30,31 Neutrophils from patients with G6PC3 deficiency have higher levels of nonphosphorylated GSK-3β and phosphorylated Mcl-1 than do neutrophils from unaffected people, a finding suggesting that a decrease in antiapoptotic Mcl-1 accounts for increased apoptosis in G6PC3-deficient neutrophils. These alterations may be in part responsible for the phenotype of G6PC3 deficiency.
Although we cannot rule out the possibility that additional mechanisms could contribute to the increase in apoptosis in G6PC3-deficient neutrophils, our data suggest that G6PC3 acts by a pathway involving GSK-3β to maintain the viability of neutrophils. Evidence of increased endoplasmic reticulum stress has previously been reported in patients with mutations in ELA2, 17,29 and premature apoptosis of neutrophils is known to cause the phenotype of congenital neutropenia.12,16,17 Thus, G6PC3 deficiency is another example of how increased apoptosis of neutrophil granulocytes can cause congenital neutropenia.
Five arguments support our claim that G6PC3 deficiency causes neutropenia. Distinct biallelic G6PC3 mutations were found in two pedigrees and seven singleton patients with congenital neutropenia; sequence analysis predicted that all four missense mutations are likely to affect the function of G6PC3; expression of wild-type G6PC3 and G6PC3 with the R253H mutation in yeast showed that the R253H mutation abrogates enzymatic activity; g6pc3 −/− knockout mice have neutropenia and increased myeloid-cell apoptosis; and the susceptibility to apoptosis in G6PC3-deficient myeloid cells was reduced by retroviral transfer of the wild-type G6PC3 gene.
Supported by grants from the Deutsche Forschungsgemeinschaft (DFG KliFo 110-2, to Dr. Klein), the Junior Research Group “Glycomics” (to Dr. Gerardy-Schahn), the Bundesministerium für Bildung und Forschung Bone Marrow Failure Syndromes (to Drs. Welte and Klein), and the European Union (MEXT-CT-2006-042316, to Dr. Grimbacher); and by the Intramural Research Program of the National Institutes of Health, National Library of Medicine (for Dr. Schäffer). Dr. Boztug is a recipient of an Else Kröner Memorial Fellowship. Drs. Klein and Gerardy-Schahn are members of REBIRTH, a Deutsche Forschungsgemeinschaft Cluster of Excellence.
Dr. Welte reports owning equity in Amgen and receiving royalties on a patent for rhG-CSF. No other potential conflict of interest relevant to this article was reported.
Drs. Appaswamy and Ashikov contributed equally to this article.
This article (10.1056/NEJMoa0805051) was updated on April 27, 2011, at NEJM.org.
We thank the patients and their families for supporting our study; all colleagues referring and registering patients at the Severe Chronic Neutropenia International Registry; François-Loïc Cosset for the kind gift of the RD114 plasmid; Edelgard Odenwald for analysis of bone marrow smears; Thomas Jack for his help with echocardiography; Jessica Pfannstiel, Maren Sievers, Marie Böhm, Marly Dalton, Martina Wackerhahn, Tanja Reinke, and Gwendoline Leroy for technical assistance; and Dr. Jean Donadieu at the Pediatric Hematology Oncology Service, Hôpital Trousseau, Paris, and Dr. Roula Farah at the Department of Pediatrics, Saint Georges Hospital, Balamand University, Beirut, Lebanon, for excellent collaboration.
Source Information
From Hannover Medical School, Hannover, Germany (K.B., G.A., A.A., J.D., M.G., G.B., J.L.-G., F.N., A.-K.G., H.B., R.G.-S., C.Z., K.W., C. Klein); the National Center for Biotechnology Information, National Institutes of Health, Bethesda, MD (A.A.S.); the University Medical Center Freiburg, Freiburg, Germany (U.S.); St. Anna Children's Hospital, Vienna (M.M.); Children's Hospital, University of Heidelberg, Heidelberg, Germany (J.G.); the University of Freiburg, Freiburg, Germany (C. Kratz); Aghia Sophia Children's Hospital, University of Athens, Athens (T.P.); Centre Hospitalier Universitaire Angers, Angers, France (I.P.); Assistance Publique–Hôpitaux de Paris, Hôpital de la Pitié–Salpétrière, Paris (C.B.-C.); the Immunology, Asthma, and Allergy Research Institute, Tehran University of Medical Sciences, Tehran, Iran (N.R.); Children's Hospital Amsterdamer Straße, Cologne, Germany (K.M.); Saint Georges University Hospital, Beirut, Lebanon (N.I.-H.); and Royal Free Hospital and University College London, London (B.G.).
Address reprint requests to Dr. Klein at the Department of Pediatric Hematology and Oncology, Medical School Hannover, Carl-Neuberg-Straße 1, Hannover D-30625, Germany, or at klein.christoph@mh-hannover.de.
- References
References
1
Kostmann R . Hereditär reticulos -- en ny systemsjukdom. Svenska Laekartidningen 1950;47:2861-28682
Kostmann R . Infantile genetic agranulocytosis; agranulocytosis infantilis hereditaria. Acta Paediatr 1956;45:Suppl:1-78
CrossRef | Medline3
Welte K ,Zeidler C ,Dale DC . Severe congenital neutropenia. Semin Hematol 2006;43:189-195
CrossRef | Web of Science | Medline4
Boztug K ,Welte K ,Zeidler C ,Klein C . Congenital neutropenia syndromes. Immunol Allergy Clin North Am 2008;28:259-275
CrossRef | Web of Science | Medline5
Bonilla MA ,Gillio AP ,Ruggeiro M , et al. Effects of recombinant human granulocyte colony-stimulating factor on neutropenia in patients with congenital agranulocytosis. N Engl J Med 1989;320:1574-1580
Full Text | Web of Science | Medline6
Rosenberg PS ,Alter BP ,Bolyard AA , et al. The incidence of leukemia and mortality from sepsis in patients with severe congenital neutropenia receiving long-term G-CSF therapy. Blood 2006;107:4628-4635
CrossRef | Web of Science | Medline7
Boxer LA ,Newburger PE . A molecular classification of congenital neutropenia syndromes. Pediatr Blood Cancer 2007;49:609-614
CrossRef | Web of Science | Medline8
Schaffer AA ,Klein C . Genetic heterogeneity in severe congenital neutropenia: how many aberrant pathways can kill a neutrophil? Curr Opin Allergy Clin Immunol 2007;7:481-494
CrossRef | Web of Science | Medline9
Horwitz M ,Benson KF ,Person RE ,Aprikyan AG ,Dale DC . Mutations in ELA2, encoding neutrophil elastase, define a 21-day biological clock in cyclic haematopoiesis. Nat Genet 1999;23:433-436
CrossRef | Web of Science | Medline10
Dale DC ,Person RE ,Bolyard AA , et al. Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia. Blood 2000;96:2317-2322
Web of Science | Medline11
Horwitz MS ,Duan Z ,Korkmaz B ,Lee HH ,Mealiffe ME ,Salipante SJ . Neutrophil elastase in cyclic and severe congenital neutropenia. Blood 2007;109:1817-1824
CrossRef | Web of Science | Medline12
Klein C ,Grudzien M ,Appaswamy G , et al. HAX1 deficiency causes autosomal recessive severe congenital neutropenia (Kostmann disease). Nat Genet 2007;39:86-92
CrossRef | Web of Science | Medline13
Devriendt K ,Kim AS ,Mathijs G , et al. Constitutively activating mutation in WASP causes X-linked severe congenital neutropenia. Nat Genet 2001;27:313-317
CrossRef | Web of Science | Medline14
Ancliff PJ ,Blundell MP ,Cory GO , et al. Two novel activating mutations in the Wiskott-Aldrich syndrome protein result in congenital neutropenia. Blood 2006;108:2182-2189
CrossRef | Web of Science | Medline15
Person RE ,Li F-Q ,Duan Z , et al. Mutations in proto-oncogene GFI1 cause human neutropenia and target ELA2. Nat Genet 2003;34:308-312
CrossRef | Web of Science | Medline16
Carlsson G ,Aprikyan AA ,Tehranchi R , et al. Kostmann syndrome: severe congenital neutropenia associated with defective expression of Bcl-2, constitutive mitochondrial release of cytochrome c, and excessive apoptosis of myeloid progenitor cells. Blood 2004;103:3355-3361
CrossRef | Web of Science | Medline17
Grenda DS ,Murakami M ,Ghatak J , et al. Mutations of the ELA2 gene found in patients with severe congenital neutropenia induce the unfolded protein response and cellular apoptosis. Blood 2007;110:4179-4187
CrossRef | Web of Science | Medline18
Fishelson M ,Geiger D . Exact genetic linkage computations for general pedigrees. Bioinformatics 2002;18:Suppl 1:S189-S198
CrossRef | Medline19
Fishelson M ,Geiger D . Optimizing exact genetic linkage computations. J Comput Biol 2004;11:263-275
CrossRef | Web of Science | Medline20
Broman KW ,Murray JC ,Sheffield VC ,White RL ,Weber JL . Comprehensive human genetic maps: individual and sex-specific variation in recombination. Am J Hum Genet 1998;63:861-869
CrossRef | Web of Science | Medline21
Ashikov A ,Routier F ,Fuhlrott J , et al. The human solute carrier gene SLC35B4 encodes a bifunctional nucleotide sugar transporter with specificity for UDP-xylose and UDP-N-acetylglucosamine. J Biol Chem 2005;280:27230-27235
CrossRef | Web of Science | Medline22
Bohn G ,Allroth A ,Brandes G , et al. A novel human primary immunodeficiency syndrome caused by deficiency of the endosomal adaptor protein p14. Nat Med 2007;13:38-45
CrossRef | Web of Science | Medline23
Klein C ,Bueler H ,Mulligan RC . Comparative analysis of genetically modified dendritic cells and tumor cells as therapeutic cancer vaccines. J Exp Med 2000;191:1699-1708
CrossRef | Web of Science | Medline24
Beaudet AL ,Anderson DC ,Michels VV ,Arion WJ ,Lange AJ . Neutropenia and impaired neutrophil migration in type IB glycogen storage disease. J Pediatr 1980;97:906-910
CrossRef | Web of Science | Medline25
Ng PC ,Henikoff S . Accounting for human polymorphisms predicted to affect function. Genome Res 2002;12:436-446
CrossRef | Web of Science | Medline26
Ramensky V ,Bork P ,Sunyaev S . Human non-synonymous SNPs: server and survey. Nucleic Acids Res 2002;30:3894-3900
CrossRef | Web of Science | Medline27
Lin JH ,Walter P ,Yen TS . Endoplasmic reticulum stress in disease pathogenesis. Annu Rev Pathol 2008;3:399-425
CrossRef | Web of Science | Medline28
Glembotski CC . The role of the unfolded protein response in the heart. J Mol Cell Cardiol 2008;44:453-459
CrossRef | Web of Science | Medline29
Kollner I ,Sodeik B ,Schreek S , et al. Mutations in neutrophil elastase causing congenital neutropenia lead to cytoplasmic protein accumulation and induction of the unfolded protein response. Blood 2006;108:493-500
CrossRef | Web of Science | Medline30
Maurer U ,Charvet C ,Wagman AS ,Dejardin E ,Green DR . Glycogen synthase kinase-3 regulates mitochondrial outer membrane permeabilization and apoptosis by destabilization of MCL-1. Mol Cell 2006;21:749-760
CrossRef | Web of Science | Medline31
Zhao Y ,Altman BJ ,Coloff JL , et al. Glycogen synthase kinase 3α and 3β mediate a glucose-sensitive antiapoptotic signaling pathway to stabilize Mcl-1. Mol Cell Biol 2007;27:4328-4339
CrossRef | Web of Science | Medline32
Cohen P ,Frame S . The renaissance of GSK3. Nat Rev Mol Cell Biol 2001;2:769-776
CrossRef | Web of Science | Medline33
Dzhagalov I ,St John A ,He YW . The antiapoptotic protein Mcl-1 is essential for the survival of neutrophils but not macrophages. Blood 2007;109:1620-1626
CrossRef | Web of Science | Medline34
Lei K-J ,Shelly LL ,Pan C-J ,Sidbury JB ,Chou JY . Mutations in the glucose-6-phosphatase gene that cause glycogen storage disease type 1a. Science 1993;262:580-583
CrossRef | Web of Science | Medline35
Martin CC ,Bischof LJ ,Bergman B , et al. Cloning and characterization of the human and rat islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) genes. J Biol Chem 2001;276:25197-25207
CrossRef | Web of Science | Medline36
Arden SD ,Zahn T ,Steegers S , et al. Molecular cloning of a pancreatic islet-specific glucose-6-phosphatase catalytic subunit-related protein. Diabetes 1999;48:531-542
CrossRef | Web of Science | Medline37
Petrolonis AJ ,Yang Q ,Tummino PJ , et al. Enzymatic characterization of the pancreatic islet-specific glucose-6-phosphatase-related protein (IGRP). J Biol Chem 2004;279:13976-13983
CrossRef | Web of Science | Medline38
Bouatia-Naji N ,Rocheleau G ,Van Lommel L , et al. A polymorphism within the G6PC2 gene is associated with fasting plasma glucose levels. Science 2008;320:1085-1088
CrossRef | Web of Science | Medline39
Chen W-M ,Erdos MR ,Jackson AU , et al. Variations in the G6PC2/ABCB11 genomic region are associated with fasting glucose levels. J Clin Invest 2008;118:2620-2628
Web of Science | Medline40
Martin CC ,Oeser JK ,Svitek CA ,Hunter SI ,Hutton JC ,O'Brien RM . Identification and characterization of a human cDNA and gene encoding a ubiquitously expressed glucose-6-phosphatase catalytic subunit-related protein. J Mol Endocrinol 2002;29:205-222
CrossRef | Web of Science | Medline41
Guionie O ,Clottes E ,Stafford K ,Burchell A . Identification and characterisation of a new human glucose-6-phosphatase isoform. FEBS Lett 2003;551:159-164
CrossRef | Web of Science | Medline42
van Schaftingen E ,Gerin I . The glucose-6-phosphatase system. Biochem J 2002;362:513-532
CrossRef | Web of Science | Medline43
Lei K-J ,Chen H ,Pan C-J , et al. Glucose-6-phosphatase dependent substrate transport in the glycogen storage disease type-1a mouse. Nat Genet 1996;13:203-209
CrossRef | Web of Science | Medline44
Melis D ,Fulceri R ,Parenti G , et al. Genotype/phenotype correlation in glycogen storage disease type 1b: a multicentre study and review of the literature. Eur J Pediatr 2005;164:501-508
CrossRef | Web of Science | Medline45
Cheung YY ,Kim SY ,Yiu WH , et al. Impaired neutrophil activity and increased susceptibility to bacterial infection in mice lacking glucose-6-phosphatase-β. J Clin Invest 2007;117:784-793
CrossRef | Web of Science | Medline46
Wang Y ,Oeser JK ,Yang C , et al. Deletion of the gene encoding the ubiquitously expressed glucose-6-phosphatase catalytic subunit-related protein (UGRP)/glucose-6-phosphatase catalytic subunit-β results in lowered plasma cholesterol and elevated glucagon. J Biol Chem 2006;281:39982-39989
CrossRef | Web of Science | Medline47
Ron D ,Walter P . Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 2007;8:519-529
CrossRef | Web of Science | Medline
- Citing Articles (52)
Citing Articles
1
Shefali Parikh, Monica Bessler. (2012) Recent insights into inherited bone marrow failure syndromes. Current Opinion in Pediatrics 24:1, 23-32
CrossRef2
Michail S. Lionakis. (2011) Genetic Susceptibility to Fungal Infections in Humans. Current Fungal Infection Reports
CrossRef3
M. Milá, A. Rufach, J.L. Dapena, J.I. Arostegui, I. Elorza, A. Llort, J. Sánchez de Toledo, C. Díaz de Heredia. (2011) Neutropenia congénita grave: análisis de las características clínicas, estudios diagnósticos, tratamiento y seguimiento a largo plazo. Anales de Pediatría 75:6, 396-400
CrossRef4
Kaan Boztug, Philip S. Rosenberg, Marie Dorda, Siddharth Banka, Thomas Moulton, Julie Curtin, Nima Rezaei, John Corns, Jeffrey W. Innis, Zekai Avci, Hung Chi Tran, Isabelle Pellier, Paolo Pierani, Rachel Fruge, Nima Parvaneh, Setareh Mamishi, Rajen Mody, Phil Darbyshire, Jayashree Motwani, Jennie Murray, George R. Buchanan, William G. Newman, Blanche P. Alter, Laurence A. Boxer, Jean Donadieu, Karl Welte, Christoph Klein. (2011) Extended Spectrum of Human Glucose-6-Phosphatase Catalytic Subunit 3 Deficiency: Novel Genotypes and Phenotypic Variability in Severe Congenital Neutropenia. The Journal of Pediatrics
CrossRef5
J. Merlijn Berg, Taco W. Kuijpers. (2011) Educational paper. European Journal of Pediatrics 170:11, 1369-1376
CrossRef6
Nima Rezaei, Payam Mohammadinejad, Asghar Aghamohammadi. (2011) The demographics of primary immunodeficiency diseases across the unique ethnic groups in Iran, and approaches to diagnosis and treatment. Annals of the New York Academy of Sciences 1238:1, 24-32
CrossRef7
Joey E Lai-Cheong, John A McGrath. (2011) Next-Generation Diagnostics for Inherited Skin Disorders. Journal of Investigative Dermatology 131:10, 1971-1973
CrossRef8
Andrew R Cullinane, Thierry Vilboux, Kevin O'Brien, James A Curry, Dawn M Maynard, Hannah Carlson-Donohoe, Carla Ciccone, Thomas C Markello, Meral Gunay-Aygun, Marjan Huizing, William A Gahl. (2011) Homozygosity Mapping and Whole-Exome Sequencing to Detect SLC45A2 and G6PC3 Mutations in a Single Patient with Oculocutaneous Albinism and Neutropenia. Journal of Investigative Dermatology 131:10, 2017-2025
CrossRef9
Gepke Visser, Wilco Jager, Liesbeth P. Verhagen, G. Peter A. Smit, Frits A. Wijburg, Berent J. Prakken, Paul J. Coffer, Miranda Buitenhuis. (2011) Survival, but not maturation, is affected in neutrophil progenitors from GSD-1b patients. Journal of Inherited Metabolic Disease
CrossRef10
Cathryn J. Poulton, Rachel Schot, Sima Kheradmand Kia, Marta Jones, Frans W. Verheijen, Hanka Venselaar, Marie-Claire Y. de Wit, Esther de Graaff, Aida M. Bertoli-Avella, Grazia M.S. Mancini. (2011) Microcephaly with Simplified Gyration, Epilepsy, and Infantile Diabetes Linked to Inappropriate Apoptosis of Neural Progenitors. The American Journal of Human Genetics 89:2, 265-276
CrossRef11
Francesca Fioredda, Michaela Calvillo, Sonia Bonanomi, Tiziana Coliva, Fabio Tucci, Piero Farruggia, Marta Pillon, Baldassarre Martire, Roberta Ghilardi, Ugo Ramenghi, Daniela Renga, Giuseppe Menna, Angelica Barone, Marina Lanciotti, Carlo Dufour. (2011) Congenital and acquired neutropenia consensus guidelines on diagnosis from the Neutropenia Committee of the Marrow Failure Syndrome Group of the AIEOP (Associazione Italiana Emato-Oncologia Pediatrica). Pediatric Blood & Cancer 57:1, 10-17
CrossRef12
Kimberley Ann Bennett, Laura Forsyth, Ann Burchell. (2011) Functional analysis of the 5′ flanking region of the human G6PC3 gene: Regulation of promoter activity by glucose, pyruvate, AMP kinase and the pentose phosphate pathway. Molecular Genetics and Metabolism 103:3, 254-261
CrossRef13
B. Hayee, A. Antonopoulos, E. J. Murphy, F. Z. Rahman, G. Sewell, B. N. Smith, S. McCartney, M. Furman, G. Hall, S. L. Bloom, S. M. Haslam, H. R. Morris, K. Boztug, C. Klein, B. Winchester, E. Pick, D. C. Linch, R. E. Gale, A. M. Smith, A. Dell, A. W. Segal. (2011) G6PC3 mutations are associated with a major defect of glycosylation: a novel mechanism for neutrophil dysfunction. Glycobiology 21:7, 914-924
CrossRef14
Alix E. Seif. (2011) Pediatric leukemia predisposition syndromes: clues to understanding leukemogenesis. Cancer Genetics 204:5, 227-244
CrossRef15
Christoph Klein. (2011) Genetic Defects in Severe Congenital Neutropenia: Emerging Insights into Life and Death of Human Neutrophil Granulocytes. Annual Review of Immunology 29:1, 399-413
CrossRef16
H. S. Jun, Y. M. Lee, K. D. Song, B. C. Mansfield, J. Y. Chou. (2011) G-CSF improves murine G6PC3-deficient neutrophil function by modulating apoptosis and energy homeostasis. Blood 117:14, 3881-3892
CrossRef17
K Walkovich, L A Boxer. (2011) Congenital neutropenia in a newborn. Journal of Perinatology 31, S22-S23
CrossRef18
S. Nanua, M. Murakami, J. Xia, D. S. Grenda, J. Woloszynek, M. Strand, D. C. Link. (2011) Activation of the unfolded protein response is associated with impaired granulopoiesis in transgenic mice expressing mutant Elane. Blood 117:13, 3539-3547
CrossRef19
Kaan Boztug, Christoph Klein. (2011) Genetic etiologies of severe congenital neutropenia. Current Opinion in Pediatrics 23:1, 21-26
CrossRef20
Roseline Froissart, Monique Piraud, Alix Boudjemline, Christine Vianey-Saban, François Petit, Aurélie Hubert-Buron, Pascale Eberschweiler, Vincent Gajdos, Philippe Labrune. (2011) Glucose-6-phosphatase deficiency. Orphanet Journal of Rare Diseases 6:1, 27
CrossRef21
Jean Donadieu, Odile Fenneteau, Blandine Beaupain, Nizar Mahlaoui, Christine Chantelot. (2011) Congenital neutropenia: diagnosis, molecular bases and patient management. Orphanet Journal of Rare Diseases 6:1, 26
CrossRef22
Siddharth Banka, Elena Chervinsky, William G Newman, Yanick J Crow, Shay Yeganeh, Joanne Yacobovich, Dian Donnai, Stavit Shalev. (2011) Further delineation of the phenotype of severe congenital neutropenia type 4 due to mutations in G6PC3. European Journal of Human Genetics 19:1, 18-22
CrossRef23
G Bouma, AJ Thrasher. 2011. Disorders of phagocyte function. , 263-272.
CrossRef24
Kaan Boztug, Xiao-Qi Ding, Hans Hartmann, Lena Ziesenitz, Alejandro A. Schäffer, Jana Diestelhorst, Dietmar Pfeifer, Giridharan Appaswamy, Sonja Kehbel, Thorsten Simon, Abdullah Al Jefri, Heinrich Lanfermann, Christoph Klein. (2010) HAX1 mutations causing severe congenital neuropenia and neurological disease lead to cerebral microstructural abnormalities documented by quantitative MRI. American Journal of Medical Genetics Part A 152A:12, 3157-3163
CrossRef25
Janice Y. Chou, Hyun Sik Jun, Brian C. Mansfield. (2010) Glycogen storage disease type I and G6Pase-β deficiency: etiology and therapy. Nature Reviews Endocrinology 6:12, 676-688
CrossRef26
Gerben Bouma, Phil J. Ancliff, Adrian J. Thrasher, Siobhan O. Burns. (2010) Recent advances in the understanding of genetic defects of neutrophil number and function. British Journal of Haematology 151:4, 312-326
CrossRef27
Roos J Leguit, Jan G Van Den Tweel. (2010) The pathology of bone marrow failure. Histopathology 57:5, 655-670
CrossRef28
D. H. McDermott, S. S. De Ravin, H. S. Jun, Q. Liu, D. A. L. Priel, P. Noel, C. M. Takemoto, T. Ojode, S. M. Paul, K. P. Dunsmore, D. Hilligoss, M. Marquesen, J. Ulrick, D. B. Kuhns, J. Y. Chou, H. L. Malech, P. M. Murphy. (2010) Severe congenital neutropenia resulting from G6PC3 deficiency with increased neutrophil CXCR4 expression and myelokathexis. Blood 116:15, 2793-2802
CrossRef29
H. S. Jun, Y. M. Lee, Y. Y. Cheung, D. H. McDermott, P. M. Murphy, S. S. De Ravin, B. C. Mansfield, J. Y. Chou. (2010) Lack of glucose recycling between endoplasmic reticulum and cytoplasm underlies cellular dysfunction in glucose-6-phosphatase- -deficient neutrophils in a congenital neutropenia syndrome. Blood 116:15, 2783-2792
CrossRef30
Siddharth Banka, William G. Newman, R. Koksal Özgül, Ali Dursun. (2010) Mutations in the G6PC3 gene cause Dursun syndrome. American Journal of Medical Genetics Part A 152A:10, 2609-2611
CrossRef31
L. S. Westerberg, P. Meelu, M. Baptista, M. A. Eston, D. A. Adamovich, V. Cotta-de-Almeida, B. Seed, M. K. Rosen, P. Vandenberghe, A. J. Thrasher, C. Klein, F. W. Alt, S. B. Snapper. (2010) Activating WASP mutations associated with X-linked neutropenia result in enhanced actin polymerization, altered cytoskeletal responses, and genomic instability in lymphocytes. Journal of Experimental Medicine 207:6, 1145-1152
CrossRef32
Caner Aytekin, Manuela Germeshausen, Nilden Tuygun, Gonul Tanir, Figen Dogu, Aydan Ikinciogullari. (2010) Eponym. European Journal of Pediatrics 169:6, 657-660
CrossRef33
Muhammad Faiyaz-Ul-Haque, Abdullah Al-Jefri, Fouad Al-Dayel, Jalaluddin A. K. M. Bhuiyan, Hala A. Abalkhail, Randa Al-Nounou, Ahmed Al-Abdullatif, Monogaran S. Pulicat, Ameera Gaafar, Ayodele A. Alaiya, Iskra Peltekova, Syed H. E. Zaidi. (2010) A novel HAX1 gene mutation in severe congenital neutropenia (SCN) associated with neurological manifestations. European Journal of Pediatrics 169:6, 661-666
CrossRef34
Akiko Shimamura, Blanche P. Alter. (2010) Pathophysiology and management of inherited bone marrow failure syndromes. Blood Reviews 24:3, 101-122
CrossRef35
Uberto Pozzoli, Matteo Fumagalli, Rachele Cagliani, Giacomo P. Comi, Nereo Bresolin, Mario Clerici, Manuela Sironi. (2010) The role of protozoa-driven selection in shaping human genetic variability. Trends in Genetics 26:3, 95-99
CrossRef36
Christoph Klein, Karl Welte. (2010) Genetic Insights into Congenital Neutropenia. Clinical Reviews in Allergy & Immunology 38:1, 68-74
CrossRef37
David C Dale. (2010) Recent progress in understanding the congenital neutropenias. Current Opinion in Hematology 17:1, 1-2
CrossRef38
Janice Y Chou, Hyun S Jun, Brian C Mansfield. (2010) Neutropenia in type Ib glycogen storage disease. Current Opinion in Hematology 17:1, 36-42
CrossRef39
S. Keerthikumar, S. Bhadra, K. Kandasamy, R. Raju, Y.L. Ramachandra, C. Bhattacharyya, K. Imai, O. Ohara, S. Mohan, A. Pandey. (2009) Prediction of Candidate Primary Immunodeficiency Disease Genes Using a Support Vector Machine Learning Approach. DNA Research 16:6, 345-351
CrossRef40
Mureo Kasahara, Reiko Horikawa, Seisuke Sakamoto, Takanobu Shigeta, Hideaki Tanaka, Akinari Fukuda, Kiyomi Abe, Keisuke Yoshii, Yasuhiro Naiki, Rika Kosaki, Atsuko Nakagawa. (2009) Living donor liver transplantation for glycogen storage disease type Ib. Liver Transplantation 15:12, 1867-1871
CrossRef41
Jun Xia, Audrey A. Bolyard, Elin Rodger, Steve Stein, Andrew A. Aprikyan, David C. Dale, Daniel C. Link. (2009) Prevalence of mutations in ELANE , GFI1 , HAX1 , SBDS , WAS and G6PC3 in patients with severe congenital neutropenia. British Journal of Haematology 147:4, 535-542
CrossRef42
Kaan Boztug, Christoph Klein. (2009) Novel genetic etiologies of severe congenital neutropenia. Current Opinion in Immunology 21:5, 472-480
CrossRef43
Luigi D Notarangelo, Jean-Laurent Casanova. (2009) Primary immunodeficiencies: increasing market share. Current Opinion in Immunology 21:5, 461-465
CrossRef44
Elvis Terci Valera, María Sol Brassesco, Manuela Germeshausen, Vanessa da Silva Silveira, Rosane Gomes de Paula Queiroz, Pérsio Roxo, Carlos Alberto Scrideli, Ullissis Pádua de Menezes, Virgínia Ferriani, Luiz Gonzaga Tone. (2009) Acute lymphoblastic leukemia following severe congenital neutropenia or de novo ALL?. Leukemia Research 33:9, e139-e142
CrossRef45
K. Boztug, F.H. Hauck, U. Wintergerst, C. Klein. (2009) Quantitative und qualitative Defekte neutrophiler Granulozyten. Monatsschrift Kinderheilkunde 157:9, 861-869
CrossRef46
J. I. Arostegui, J. S. de Toledo, M. Pascal, C. Garcia, J. Yague, C. Diaz de Heredia. (2009) A novel G6PC3 homozygous 1-bp deletion as a cause of severe congenital neutropenia. Blood 114:8, 1718-1719
CrossRef47
ITAI PESSACH, JOLAN WALTER, LUIGI D. NOTARANGELO. (2009) Recent Advances in Primary Immunodeficiencies: Identification of Novel Genetic Defects and Unanticipated Phenotypes. Pediatric Research 65:Supplement, 3R-12R
CrossRef48
Karl Welte, Cornelia Zeidler. (2009) Severe Congenital Neutropenia. Hematology/Oncology Clinics of North America 23:2, 307-320
CrossRef49
(2009) Research Highlights. Nature Genetics 41:2, 147-147
CrossRef50
Dale, David C., Link, Daniel C., . (2009) The Many Causes of Severe Congenital Neutropenia. New England Journal of Medicine 360:1, 3-5
Full Text51
C. Klein. (2009) Congenital neutropenia. Hematology 2009:1, 344-350
CrossRef52
Nima Rezaei, Kasra Moazzami, Asghar Aghamohammadi, Christoph Klein. (2009) Neutropenia and Primary Immunodeficiency Diseases. International Reviews of Immunology 28:5, 335-366
CrossRef
