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PLENARY PAPER
From the Divisions of Hematology and Medical Genetics,
Department of Medicine and the Markey Molecular Medicine Center,
University of Washington School of Medicine, Seattle, WA; St Barnabas
Medical Center, West Orange, NJ; University of Michigan, Ann Arbor, MI;
University of Ballarat, Ballarat, Australia; and Medizinische
Hochschule, Hannover, Germany.
Congenital neutropenia and cyclic neutropenia are disorders
of neutrophil production predisposing patients to recurrent bacterial infections. Recently the locus for autosomal dominant cyclic
neutropenia was mapped to chromosome 19p13.3, and this disease is
now attributable to mutations of the gene encoding neutrophil elastase
(the ELA2 gene). The authors hypothesized that congenital
neutropenia is also due to mutations of neutrophil elastase.
Patients with congenital neutropenia, cyclic neutropenia, or
Shwachman-Diamond syndrome were referred to the Severe Chronic
Neutropenia International Registry. Referring physicians provided
hematologic and clinical data. Mutational analysis was performed by
sequencing polymerase chain reaction (PCR)-amplified genomic DNA for
each of the 5 exons of the neutrophil ELA2 gene and 20 bases of the flanking regions. RNA from bone marrow mononuclear cells
was used to determine if the affected patients expressed both the
normal and the abnormal transcript. Twenty-two of 25 patients with
congenital neutropenia had 18 different heterozygous mutations. Four of
4 patients with cyclic neutropenia and 0 of 3 patients with
Shwachman-Diamond syndrome had mutations. For 5 patients with
congenital neutropenia having mutations predicted to alter RNA splicing
or transcript structure, reverse transcriptase-PCR showed
expression of both normal and abnormal transcripts. In cyclic
neutropenia, the mutations appeared to cluster near the active site of
the molecule, whereas the opposite face was predominantly affected by
the mutations found in congenital neutropenia. This study indicates
that mutations of the gene encoding neutrophil elastase are probably
the most common cause for severe congenital neutropenia as well as the cause for sporadic and autosomal dominant cyclic neutropenia.
(Blood. 2000;96:2317-2322) Cyclic and congenital neutropenia are severe
disorders of neutrophil production that cause lifelong problems with
recurrent infections. Cyclic neutropenia was first recognized as a
distinct entity in 1910 because of the extremely regular recurrence of neutropenia, fever, and mouth ulcers in a 19-month-old
boy.1 Its autosomal dominant pattern of inheritance was
first suggested by de Berardinis and Reiman in 19492 and
confirmed by Morley and colleagues3 in a study of 5 families in 1967. Characteristically in cyclic neutropenia, the blood
neutrophil counts oscillate with a 21-day periodicity with extremely
low circulating neutrophils at the nadir of the cycle and peak counts that are less than 2000/µL. The diagnosis of cyclic neutropenia depends on serial measurements of absolute neutrophil counts over a
period of several weeks.4
Congenital neutropenia is a less well-defined entity and is generally
regarded as a heterogeneous disorder. In 1954, Kostmann described
autosomal recessive congenital neutropenia in a large Swedish
family.5 Subsequently many other cases of severe
congenital neutropenia have been described,6 usually
sporadic cases as well as cases with autosomal dominant
inheritance.7 Currently, the diagnosis of severe
congenital neutropenia is made if the onset is recognized at birth or
soon thereafter, blood neutrophil counts are less than 200/µL, the
hematocrit or hemoglobin and platelet levels are normal or near normal,
and the marrow shows a selective defect in neutrophil formation with
many promyelocytes but relatively few myelocytes, metamyelocytes, and
neutrophils or "promyelocytic maturation arrest."
We recently reported positional cloning studies that map the locus for
autosomal dominant cyclic neutropenia to chromosome 19p13.3, the locus
for several serine proteases.8 Mutational analysis in 13 families and a sporadic case of cyclic neutropenia showed 7 different
mutations of the gene for neutrophil elastase (ELA2), a
serine protease synthesized chiefly at the promyelocytic stage in
neutrophil development. The same mutations were found in several
families and clustered around the active site of this enzyme. Because
patients with congenital neutropenia have many hematologic features
that are similar to patients with cyclic neutropenia, we hypothesized
that they might result from mutations in the same gene. We found that
most patients with congenital neutropenia also have neutrophil elastase
mutations, results suggesting that mutations of the gene encoding
neutrophil elastase cause both cyclic and severe congenital neutropenia.
Patients
Blood counts and DNA analyses
Reverse transcriptase-PCR (RT-PCR) Total RNA was isolated from fresh Ficoll-Hypaque-separated bone marrow mononuclear cells using a RNeasy kit (Qiagen, Valencia, CA). RT-PCR used Qiagen Omniscript RT with subsequent PCR and direct DNA sequencing. The primers amplified a 728-bp complementary DNA (cDNA) fragment between exons 2 and 5, which was subsequently digested with the restriction enzyme Taq I (New England Biolabs, Bethesda, MD) to produce a 411-bp fragment of interest in normal controls.Statistical analysis Differences between means were compared with the Student t test using Prism Graph Pad Software (San Diego, CA).Protein structure modeling Coordinates of neutrophil elastase were obtained from the Protein Data Bank9 and mutations were made using the program of Jones and colleagues.10 Homology modeling was carried out with tools available in the suite of programs in the "Molecular Operating Environment" available from the Chemical Computing Group, Montreal, Quebec, (http://www.chemcomp.com) with the assistance of E. Adman at the University of Washington.
Clinical characteristics Hematologic data for 25 unrelated patients with congenital neutropenia are summarized in Table 1. The blood neutrophil counts were severely reduced (mean, 112 ± 21/µL) and monocyte counts increased (mean, 1489 ± 227/µL). Platelet counts were increased and hematocrit values mildly decreased in most patients. Marrow examinations showed scarce or absent neutrophils, bands, and metamyelocytes, with a typical pattern of "maturation arrest" of the neutrophil series; exceptions may be attributable to infection at the time of marrow sampling, which may transiently increase neutrophil production in these patients. In 3 patients with a diagnosis of congenital neutropenia who had long series of frequent blood counts (Table 1, patients 9, 20, and 22), there were periods with regular oscillations in blood neutrophil levels and other periods when oscillations were not apparent (Figure 1).
Two groups of neutropenic patients were studied for comparison
with the patients with congenital neutropenia (Table
2). The 4 patients with cyclic
neutropenia were sporadic cases with typical 21-day cycles of fever,
mouth ulcers, and severe neutropenia. The 3 children with
Shwachman-Diamond syndrome had neutropenia that was less severe than
for the patients with congenital neutropenia.
Mutations of the neutrophil ELA2 gene Twenty-two of 25 patients diagnosed as having congenital neutropenia were found to have neutrophil elastase mutations. Eighteen different heterozygous mutations were detected (Table 1). Four unrelated patients had the identical mutations in exon 4 (patients 7-10). Two other unrelated patients had the same mutation in exon 3 (patients 4 and 5). Five mutations occurred in families with 2 or more affected members 3 fathers and 3 daughters, (patients 5, 7, and
12), a mother and a son (patient 9), and a mother (patient 10)
with 2 affected sons with different fathers, suggesting autosomal dominant inheritance. The identical mutation has been found in the
affected parent and child (or children) for all 5 of these families.
Hematologic comparisons of the relatively large group of patients with
mutations (22 patients) with the smaller group without mutations (3 patients) showed that the neutrophil counts were somewhat lower and the
monocyte counts higher in patients with the mutant neutrophil
ELA2 gene, but the differences were not statistically
significant. Seven of these mutations were predicted to alter RNA
splicing or transcript structure. RT-PCR analysis using cells from the
5 available marrow samples demonstrated the predicted effect in each of
these individuals (Figure 2).
The diversity in the mutations in congenital neutropenia was
substantially greater than in patients with cyclic neutropenia. The
mutations in the 4 sporadic cases of cyclic neutropenia shown in Table
2 and the 13 families with autosomal dominant cyclic neutropenia were
predominantly in intron 4, creating splice donor mutations, or base
substitutions near the junction of exon 4 and exon 5.8 One
of the patients with congenital neutropenia (patient 22) with a
mutation in intron 4 was at one time thought to have cyclic neutropenia
based on a period of regularly recurring symptoms. The other child with
a similar mutation (patient 21) was diagnosed in the first year of life
as having congenital neutropenia without a long series of counts and
then started on treatment. Based on examination of the tertiary
structure of neutrophil elastase, the mutations in cyclic neutropenia
appeared to cluster around the active site of the enzyme, whereas the
mutations in congenital neutropenia were predominantly on the
molecule's opposite face (Figure 3),
suggesting a correlation between the genotype and the phenotype.
With the diversity of mutations in congenital neutropenia, there was no clear correlation of the sites of the mutations and the patient's blood neutrophil counts or clinical courses. Patients 2, 5, and 20 from the group with mutations (3 of 21, or 14%) have developed acute myeloid leukemia (AML), a recognized complication in about 10% of patients with congenital neutropenia.11 The neutropenic father of another patient (patient 12) has myelodysplasia. One of the 4 patients (25%) without a mutation (patient 24) has developed AML. Schematic representation of neutrophil elastase structure with
the positions of missense and deletion mutations is shown in Figure
4. Preliminary structural analysis
suggests that all of the substitutions led to conformational changes.
Substitution of glycine 185 with positively charged arginine in the
immediate proximity to the active site, the C42S missense mutation, and the deletion of 8 amino acid fragments (
None of the patients with Shwachman-Diamond syndrome had mutations. Additionally, only one coding sequence change in the gene for neutrophil elastase was observed in 230 control chromosomes from normal individuals, and this change is presumed to represent a polymorphism, because of its appearance also in a family with cyclic neutropenia in which a mutation found in other pedigrees segregates with disease.
This report describes the occurrence of mutations of the gene encoding neutrophil elastase in 22 patients with severe congenital neutropenia and extends our previous observation of mutations of this gene in cyclic neutropenia.8 Previous research has suggested that the pathophysiology of congenital neutropenia may relate to mutations of the granulocyte colony-stimulating factor (G-CSF) receptor, based on finding the mutation before any evidence suggests the patient has myelodysplasia or evolving AML.12 However, in almost all patients, G-CSF receptor mutations have been reported as acquired abnormalities detected in the process of evolution to AML.13 Current prevalence data suggest that a minority of patients manifest this mutation,14,15 and it now seems much more likely that mutations of the gene for neutrophil elastase lead to compromised myeloid differentiation and create the risk for development of AML. The familial cases reported here and the finding that heterozygous mutations are so consistently found in affected individuals suggest that both cyclic and most cases of congenital neutropenia have an autosomal dominant inheritance or are the result of a new dominant-acting germline mutation. The results also suggest that these are closely related disorders with overlapping molecular and clinical phenotypes. Visually and mathematically discernable oscillations in neutrophil counts are at times features of cases called "congenital neutropenia."16 Similarly, affected family members with autosomal dominant cyclic neutropenia may be neutropenic without showing oscillations of their neutrophil counts.17 Oscillations in both of these disorders are usually accentuated by treatment with G-CSF.18,19 The findings reported here suggest a primary role for mutations of neutrophil elastase in causing most, but not all, cases of severe congenital neutropenia. This protease is normally synthesized and packaged in promyelocytes at an early stage in neutrophil development.20 Neutrophil elastase has many recognized and possible substrates, including coagulation proteins, growth factors, and intracellular signaling molecules.21 It is normally synthesized in the developing neutrophil as a proenzyme but stored in the primary granules in its active form, ready with full enzymatic activity when released from the granules, normally at sites of inflammation.22,23 The pathogenic role of mutant elastase in causing neutropenia may be directly linked to the poor survival characteristics of early myeloid precursor cells in congenital and cyclic neutropenia.24,25 Accelerated apoptosis of promyelocytes and their progeny in vivo may explain the classic marrow finding of "promyelocytic arrest" in these conditions, but the specific protein-protein interactions causing these cellular abnormalities and causes for congenital neutropenia in patients without elastase mutations are yet to be discovered. The structural analysis presented here suggests that improper folding and destabilization of neutrophil elastase may be the critical effects of these mutations. Oscillations in the hematopoietic system and the phenomenon of cyclic neutropenia have attracted the attention of clinicians and mathematicians for many years.26 Although numerous mechanisms have been proposed, the data in this report fit best with the hypothesis that oscillations of peripheral neutrophil counts will occur when there is reduced survival of early hematopoietic precursor cells and an intact feedback control system governing blood cell levels.27 This model assumes that neutrophil production is normally efficient, as indicated in careful quantitative studies.28 When precursor cell survival is poor, that is, the apoptotic rate is high, production of cells is very inefficient, and the output of cells is low. This state matches the high rate of apoptosis observed in severe congenital neutropenia and in patients with Shwachman-Diamond syndrome.29 Treatment with G-CSF can improve but does not completely reverse this defect in cell survival, probably through its antiapoptotic effect on myeloid cells.24,25 In cyclic neutropenia, the defect in cell survival is less severe, presumably because the mutant elastase less severely shortens precursor survival. In some individuals identified through family studies, either the cell survival may be better or the strength of the feedback loop weaker, resulting in no or substantially blunted oscillations. Because neither heterozygous nor homozygous neutrophil elastase knockout mice are neutropenic,30 it is quite likely the mutations in congenital and cyclic neutropenia lead to a gain of function or aberrant function of the enzyme. Congenital and cyclic neutropenia are rare disorders, but the mechanisms governing the regulation and deployment of neutrophils are of broad importance. Treatment with G-CSF has greatly reduced the problems of recurrent and severe infections for patients with severe chronic neutropenia31; better understanding of the genetic and molecular mechanisms of these disorders should lead to even better therapies.
We are grateful for the participation of the many physicians worldwide who contribute data to the Severe Chronic Neutropenia International Registry. We appreciate the assistance of Tammy Cottle and staff at the Severe Chronic Neutropenia International Registry, Carol Fier at Amgen, Inc, and Elin Rodger for her technical assistance.
Submitted April 4, 2000; accepted June 7, 2000.
Supported by grants from Amgen, Inc, Thousand Oaks, CA; the National Institutes of Health (NIH) DK RO1 18951 and AI20065; the Markey Trust and the Doris Duke Charitable Foundation (T98006); the Leukemia Society of America; the American Cancer Society; the Leukemia Research Foundation; the National Leukemia Research Association; and UW Center grant number P30 ES07033 from the National Institute of Environmental Health Sciences, NIH.
Paid for in part by Amgen, Thousand Oaks, CA. D.C.D., M.A.B., L.A.B., G.K., and K.W. are consultants to Amgen, and D.C.D. and K.W. receive research support from Amgen. Amgen paid part or all of the salaries of R.E.P., A.A.B., A.G.A., and C.Z. while they were engaged in this study.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: David C. Dale, Severe Chronic Neutropenia International Registry, Department of Medicine, University of Washington School of Medicine, Box 356422, Seattle, WA, 98195-6422; e-mail: dcdale{at}u.washington.edu.
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I Richard The genetic and molecular bases of monogenic disorders affecting proteolytic systems J. Med. Genet., July 1, 2005; 42(7): 529 - 539. [Abstract] [Full Text] [PDF]
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M. Horwitz Neutrophil elastase unleashed Blood, May 1, 2005; 105(9): 3392 - 3393. [Full Text] [PDF]
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P. Massullo, L. J. Druhan, B. A. Bunnell, M. G. Hunter, J. M. Robinson, C. B. Marsh, and B. R. Avalos Aberrant subcellular targeting of the G185R neutrophil elastase mutant associated with severe congenital neutropenia induces premature apoptosis of differentiating promyelocytes Blood, May 1, 2005; 105(9): 3397 - 3404. [Abstract] [Full Text] [PDF]
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L. J. Druhan, J. Ai, P. Massullo, T. Kindwall-Keller, M. A. Ranalli, and B. R. Avalos Novel mechanism of G-CSF refractoriness in patients with severe congenital neutropenia Blood, January 15, 2005; 105(2): 584 - 591. [Abstract] [Full Text] [PDF]
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 B. P. Alter Bone Marrow Failure: A Child Is Not Just a Small Adult (But an Adult Can Have a Childhood Disease) Hematology, January 1, 2005; 2005(1): 96 - 103. [Abstract] [Full Text] [PDF]
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 A. Maheshwari and R. D. Christensen Neutropenia in the Neonatal Intensive Care Unit NeoReviews, October 1, 2004; 5(10): e431 - e443. [Full Text] [PDF]
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D. C. Dale Neutrophil elastase and neutropenia Blood, June 1, 2004; 103(11): 3993 - 3994. [Full Text] [PDF]
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C. Bellanne-Chantelot, S. Clauin, T. Leblanc, B. Cassinat, F. Rodrigues-Lima, S. Beaufils, C. Vaury, M. Barkaoui, O. Fenneteau, M. Maier-Redelsperger, et al. Mutations in the ELA2 gene correlate with more severe expression of neutropenia: a study of 81 patients from the French Neutropenia Register Blood, June 1, 2004; 103(11): 4119 - 4125. [Abstract] [Full Text] [PDF]
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 M. S. Lim and K. S.J. Elenitoba-Johnson The Molecular Pathology of Primary Immunodeficiencies J. Mol. Diagn., May 1, 2004; 6(2): 59 - 83. [Full Text] [PDF]
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G. Carlsson, A. A. G. Aprikyan, R. Tehranchi, D. C. Dale, A. Porwit, E. Hellstrom-Lindberg, J. Palmblad, J.-I. Henter, and B. Fadeel 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, May 1, 2004; 103(9): 3355 - 3361. [Abstract] [Full Text] [PDF]
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F.-Q. Li, R. E. Person, K.-I. Takemaru, K. Williams, K. Meade-White, A. H. Ozsahin, T. Gungor, R. T. Moon, and M. Horwitz Lymphoid Enhancer Factor-1 Links Two Hereditary Leukemia Syndromes through Core-binding Factor {alpha} Regulation of ELA2 J. Biol. Chem., January 23, 2004; 279(4): 2873 - 2884. [Abstract] [Full Text] [PDF]
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Z. Duan, F.-Q. Li, J. Wechsler, K. Meade-White, K. Williams, K. F. Benson, and M. Horwitz A Novel Notch Protein, N2N, Targeted by Neutrophil Elastase and Implicated in Hereditary Neutropenia Mol. Cell. Biol., January 1, 2004; 24(1): 58 - 70. [Abstract] [Full Text] [PDF]
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N. Berliner, M. Horwitz, and T. P. Loughran Jr. Congenital and Acquired Neutropenia Hematology, January 1, 2004; 2004(1): 63 - 79. [Abstract] [Full Text] [PDF]
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O. Yanay, S. C. Barry, L. J. Katen, M. Brzezinski, L. Y. Flint, J. Christensen, D. Liggitt, D. C. Dale, and W. R. A. Osborne Treatment of canine cyclic neutropenia by lentivirus-mediated G-CSF delivery Blood, September 15, 2003; 102(6): 2046 - 2052. [Abstract] [Full Text] [PDF]
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 Z. Duan and M. Horwitz Targets of the transcriptional repressor oncoprotein Gfi-1 PNAS, May 13, 2003; 100(10): 5932 - 5937. [Abstract] [Full Text] [PDF]
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H. A. Papadaki, M. Horwitz, S. A. Coulocheri, R. A. Person, K. F. Benson, and G. D. Eliopoulos Low levels of serum elastase are not associated with mutations in ELA-2 elastase encoding gene in chronic idiopathic neutropenia Blood, April 1, 2003; 101(7): 2898 - 2898. [Full Text] [PDF]
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H. A. Papadaki, A. G. Eliopoulos, T. Kosteas, C. Gemetzi, A. Damianaki, H. Koutala, J. Bux, and G. D. Eliopoulos Impaired granulocytopoiesis in patients with chronic idiopathic neutropenia is associated with increased apoptosis of bone marrow myeloid progenitor cells Blood, April 1, 2003; 101(7): 2591 - 2600. [Abstract] [Full Text] [PDF]
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F. El Ouriaghli, H. Fujiwara, J. J. Melenhorst, G. Sconocchia, N. Hensel, and A. J. Barrett Neutrophil elastase enzymatically antagonizes the in vitro action of G-CSF: implications for the regulation of granulopoiesis Blood, March 1, 2003; 101(5): 1752 - 1758. [Abstract] [Full Text] [PDF]
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H. Kawaguchi, M. Kobayashi, K. Nakamura, N. Konishi, S.-i. Miyagawa, T. Sato, H. Toyoda, Y. Komada, S. Kojima, Y. Todoroki, et al. Dysregulation of transcriptions in primary granule constituents during myeloid proliferation and differentiation in patients with severe congenital neutropenia J. Leukoc. Biol., February 1, 2003; 73(2): 225 - 234. [Abstract] [Full Text] [PDF]
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 L. A. Boxer Neutrophil Abnormalities Pediatr. Rev., February 1, 2003; 24(2): 52 - 62. [Full Text] [PDF]
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D. S. Grenda, S. E. Johnson, J. R. Mayer, M. L. McLemore, K. F. Benson, M. Horwitz, and D. C. Link Mice expressing a neutrophil elastase mutation derived from patients with severe congenital neutropenia have normal granulopoiesis Blood, October 16, 2002; 100(9): 3221 - 3228. [Abstract] [Full Text] [PDF]
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P. J. Ancliff, R. E. Gale, M. J. Watts, R. Liesner, I. M. Hann, S. Strobel, and D. C. Linch Paternal mosaicism proves the pathogenic nature of mutations in neutrophil elastase in severe congenital neutropenia Blood, June 28, 2002; 100(2): 707 - 709. [Abstract] [Full Text] [PDF]
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A. Valenzuela-Fernandez, T. Planchenault, F. Baleux, I. Staropoli, K. Le-Barillec, D. Leduc, T. Delaunay, F. Lazarini, J.-L. Virelizier, M. Chignard, et al. Leukocyte Elastase Negatively Regulates Stromal Cell-derived Factor-1 (SDF-1)/CXCR4 Binding and Functions by Amino-terminal Processing of SDF-1 and CXCR4 J. Biol. Chem., May 3, 2002; 277(18): 15677 - 15689. [Abstract] [Full Text] [PDF]
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P. J. Ancliff, R. E. Gale, R. Liesner, I. M. Hann, and D. C. Linch Mutations in the ELA2 gene encoding neutrophil elastase are present in most patients with sporadic severe congenital neutropenia but only in some patients with the familial form of the disease Blood, November 1, 2001; 98(9): 2645 - 2650. [Abstract] [Full Text] [PDF]
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C. M. Bennett, J. P. Kanki, J. Rhodes, T. X. Liu, B. H. Paw, M. W. Kieran, D. M. Langenau, A. Delahaye-Brown, L. I. Zon, M. D. Fleming, et al. Myelopoiesis in the zebrafish, Danio rerio Blood, August 1, 2001; 98(3): 643 - 651. [Abstract] [Full Text] [PDF]
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M. H. A. Hermans, I. P. Touw, D. C. Dale, and A. Aprikyan Significance of neutrophil elastase mutations versus G-CSF receptor mutations for leukemic progression of congenital neutropenia Blood, April 1, 2001; 97(7): 2185 - 2186. [Full Text] [PDF]
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S. Jeha, K. W. Chan, A. G. Aprikyan, W. K. Hoots, S. Culbert, H. Zietz, D. C. Dale, and M. Albitar Spontaneous remission of granulocyte colony-stimulating factor-associated leukemia in a child with severe congenital neutropenia Blood, November 15, 2000; 96(10): 3647 - 3649. [Abstract] [Full Text] [PDF]
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F.-Q. Li and M. Horwitz Characterization of Mutant Neutrophil Elastase in Severe Congenital Neutropenia J. Biol. Chem., April 20, 2001; 276(17): 14230 - 14241. [Abstract] [Full Text] [PDF]
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| Copyright © 2000 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
Top
Abstract
Introduction
145-152) all probably alter
biologic function. The 5 truncation and frame shift mutations in
patients 15 through 19 remove the C-terminal portion of the molecule
probably resulting in destabilization of the protein structure near the
active site.
