RBCC Red Blood Cell Collection

ELANE (ELA2) [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Neutrophil elastase; 3.4.21.37 (Bone marrow serine protease; Elastase-2; Human leukocyte elastase; HLE; Medullasin; PMN elastase; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P08246
ID ELNE_HUMAN Reviewed; 267 AA.
AC P08246; P09649; Q6B0D9; Q6LDP5;
DT 01-AUG-1988, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-AUG-1988, sequence version 1.
DT 22-JAN-2014, entry version 155.
DE RecName: Full=Neutrophil elastase;
DE EC=3.4.21.37;
DE AltName: Full=Bone marrow serine protease;
DE AltName: Full=Elastase-2;
DE AltName: Full=Human leukocyte elastase;
DE Short=HLE;
DE AltName: Full=Medullasin;
DE AltName: Full=PMN elastase;
DE Flags: Precursor;
GN Name=ELANE; Synonyms=ELA2;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=3479752; DOI=10.1093/nar/15.22.9601;
RA Nakamura H., Okano K., Aoki Y., Shimizu H., Naruto M.;
RT "Nucleotide sequence of human bone marrow serine protease (medullasin)
RT gene.";
RL Nucleic Acids Res. 15:9601-9601(1987).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=2902087;
RA Takahashi H., Nukiwa T., Yoshimura K., Quick C.D., States D.J.,
RA Holmes M.D., Whang-Peng J., Knutsen T., Crystal R.G.;
RT "Structure of the human neutrophil elastase gene.";
RL J. Biol. Chem. 263:14739-14747(1988).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=2775493;
RA Farley D., Travis J., Salvesen G.;
RT "The human neutrophil elastase gene. Analysis of the nucleotide
RT sequence reveals three distinct classes of repetitive DNA.";
RL Biol. Chem. Hoppe-Seyler 370:737-744(1989).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=2322278; DOI=10.1016/0006-291X(90)90668-D;
RA Okano K., Aoki Y., Shimizu H., Naruto M.;
RT "Functional expression of human leukocyte elastase (HLE)/medullasin in
RT eukaryotic cells.";
RL Biochem. Biophys. Res. Commun. 167:1326-1332(1990).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS ILE-219; LEU-257 AND
RP LEU-262.
RG NIEHS SNPs program;
RL Submitted (APR-2004) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Lung;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 30-267.
RX PubMed=2822677;
RA Okano K., Aoki Y., Sakurai T., Kajitani M., Kanai S., Shimazu T.,
RA Shimizu H., Naruto M.;
RT "Molecular cloning of complementary DNA for human medullasin: an
RT inflammatory serine protease in bone marrow cells.";
RL J. Biochem. 102:13-16(1987).
RN [8]
RP PROTEIN SEQUENCE OF 30-247.
RX PubMed=3550808; DOI=10.1073/pnas.84.8.2228;
RA Sinha S., Watorek W., Karr S., Giles J., Bode W., Travis J.;
RT "Primary structure of human neutrophil elastase.";
RL Proc. Natl. Acad. Sci. U.S.A. 84:2228-2232(1987).
RN [9]
RP PRELIMINARY PROTEIN SEQUENCE OF 30-103.
RA Travis J., Giles P.J., Porcelli L., Reilly C.F., Baugh R., Powers J.;
RL (In) Protein degradation in health and disease,
RL Ciba Foundation Symposium, pp.75:51-68, Excerpta Medica,
RL Amsterdam and Oxford (1980).
RN [10]
RP PROTEIN SEQUENCE OF 30-49.
RX PubMed=2501794; DOI=10.1073/pnas.86.14.5610;
RA Gabay J.E., Scott R.W., Campanelli D., Griffith J., Wilde C.,
RA Marra M.N., Seeger M., Nathan C.F.;
RT "Antibiotic proteins of human polymorphonuclear leukocytes.";
RL Proc. Natl. Acad. Sci. U.S.A. 86:5610-5614(1989).
RN [11]
RP PROTEIN SEQUENCE OF 30-49.
RC TISSUE=Neutrophil;
RX PubMed=7897245; DOI=10.1016/0022-1759(94)00295-8;
RA Gaskin G., Kendal H., Coulthart A., Turner N., Pusey C.D.;
RT "Use of proteinase 3 purified by reverse phase HPLC to detect
RT autoantibodies in systemic vasculitis.";
RL J. Immunol. Methods 180:25-33(1995).
RN [12]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 75-267.
RX PubMed=3422232;
RA Takahashi H., Nukiwa T., Basset P., Cystal R.G.;
RT "Myelomonocytic cell lineage expression of the neutrophil elastase
RT gene.";
RL J. Biol. Chem. 263:2543-2547(1988).
RN [13]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 123-267.
RX PubMed=2462434;
RA Farley D., Salvesen G.S., Travis J.;
RT "Molecular cloning of human neutrophil elastase.";
RL Biol. Chem. Hoppe-Seyler 369:3-7(1988).
RN [14]
RP PROTEIN SEQUENCE OF 262-267.
RX PubMed=1859409; DOI=10.1016/0006-291X(91)90135-T;
RA Aoki Y., Hase T.;
RT "The primary structure and elastinolytic activity of medullasin (a
RT serine protease of bone marrow).";
RL Biochem. Biophys. Res. Commun. 178:501-506(1991).
RN [15]
RP FUNCTION.
RX PubMed=15140022; DOI=10.1111/j.0906-6705.2004.00145.x;
RA Tralau T., Meyer-Hoffert U., Schroder J.M., Wiedow O.;
RT "Human leukocyte elastase and cathepsin G are specific inhibitors of
RT C5a-dependent neutrophil enzyme release and chemotaxis.";
RL Exp. Dermatol. 13:316-325(2004).
RN [16]
RP INTERACTION WITH NOTCH2NL, AND CHARACTERIZATION OF VARIANT CH GLN-191.
RX PubMed=14673143; DOI=10.1128/MCB.24.1.58-70.2004;
RA Duan Z., Li F.-Q., Wechsler J., Meade-White K., Williams K.,
RA Benson K.F., Horwitz M.;
RT "A novel notch protein, N2N, targeted by neutrophil elastase and
RT implicated in hereditary neutropenia.";
RL Mol. Cell. Biol. 24:58-70(2004).
RN [17]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-88 AND ASN-173, AND MASS
RP SPECTROMETRY.
RC TISSUE=Liver;
RX PubMed=19159218; DOI=10.1021/pr8008012;
RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.;
RT "Glycoproteomics analysis of human liver tissue by combination of
RT multiple enzyme digestion and hydrazide chemistry.";
RL J. Proteome Res. 8:651-661(2009).
RN [18]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [19]
RP X-RAY CRYSTALLOGRAPHY (1.84 ANGSTROMS).
RX PubMed=2911584; DOI=10.1073/pnas.86.1.7;
RA Navia M.A., McKeever B.M., Springer J.P., Lin T.-Y., Williams H.R.,
RA Fluder E.M., Dorn C.P., Hoogsteen K.;
RT "Structure of human neutrophil elastase in complex with a peptide
RT chloromethyl ketone inhibitor at 1.84-A resolution.";
RL Proc. Natl. Acad. Sci. U.S.A. 86:7-11(1989).
RN [20]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS).
RX PubMed=3391280; DOI=10.1016/0014-5793(88)80118-2;
RA Wei A.-Z., Mayr I., Bode W.;
RT "The refined 2.3-A crystal structure of human leukocyte elastase in a
RT complex with a valine chloromethyl ketone inhibitor.";
RL FEBS Lett. 234:367-373(1988).
RN [21]
RP X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS).
RX PubMed=3640709;
RA Bode W., Wei A.-Z., Huber R., Meyer E., Travis J., Neumann S.;
RT "X-ray crystal structure of the complex of human leukocyte elastase
RT (PMN elastase) and the third domain of the turkey ovomucoid
RT inhibitor.";
RL EMBO J. 5:2453-2458(1986).
RN [22]
RP VARIANTS CH VAL-32; PHE-177 AND GLN-191.
RX PubMed=10581030; DOI=10.1038/70544;
RA Horwitz M., Benson K.F., Person R.E., Aprikyan A.G., Dale D.C.;
RT "Mutations in ELA2, encoding neutrophil elastase, define a 21-day
RT biological clock in cyclic haematopoiesis.";
RL Nat. Genet. 23:433-436(1999).
RN [23]
RP VARIANTS GFI1 THR-57; THR-60; SER-71; MET-101; LEU-126; LEU-139;
RP VAL-210 AND ARG-214.
RX PubMed=11001877;
RA Dale D.C., Person R.E., Bolyard A.A., Aprikyan A.G., Bos C.,
RA Bonilla M.A., Boxer L.A., Kannourakis G., Zeidler C., Welte K.,
RA Benson K.F., Horwitz M.;
RT "Mutations in the gene encoding neutrophil elastase in congenital and
RT cyclic neutropenia.";
RL Blood 96:2317-2322(2000).
RN [24]
RP VARIANTS GFI1 TYR-55; GLU-85; PRO-GLN-LEU-123 INS; LEU-126; SER-151;
RP 190-VAL--PHE-199 DEL AND ARG-205.
RX PubMed=11675333; DOI=10.1182/blood.V98.9.2645;
RA Ancliff P.J., Gale R.E., Liesner R., Hann I.M., Linch D.C.;
RT "Mutations in the ELA2 gene encoding neutrophil elastase are present
RT in most patients with sporadic severe congenital neutropenia but only
RT in some patients with the familial form of the disease.";
RL Blood 98:2645-2650(2001).
RN [25]
RP VARIANT GFI1 ARG-71.
RX PubMed=12091371; DOI=10.1182/blood-2002-01-0060;
RA Ancliff P.J., Gale R.E., Watts M.J., Liesner R., Hann I.M.,
RA Strobel S., Linch D.C.;
RT "Paternal mosaicism proves the pathogenic nature of mutations in
RT neutrophil elastase in severe congenital neutropenia.";
RL Blood 100:707-709(2002).
RN [26]
RP VARIANTS GFI1 LEU-98 AND LEU-101, AND CHARACTERIZATION OF VARIANTS
RP GFI1 LEU-98 AND LEU-101.
RX PubMed=17436313; DOI=10.1002/humu.20529;
RA Salipante S.J., Benson K.F., Luty J., Hadavi V., Kariminejad R.,
RA Kariminejad M.H., Rezaei N., Horwitz M.S.;
RT "Double de novo mutations of ELA2 in cyclic and severe congenital
RT neutropenia.";
RL Hum. Mutat. 28:874-881(2007).
RN [27]
RP VARIANTS SCN1 VAL-25 AND THR-166.
RX PubMed=20220065; DOI=10.3324/haematol.2009.017665;
RA Germeshausen M., Zeidler C., Stuhrmann M., Lanciotti M., Ballmaier M.,
RA Welte K.;
RT "Digenic mutations in severe congenital neutropenia.";
RL Haematologica 95:1207-1210(2010).
CC -!- FUNCTION: Modifies the functions of natural killer cells,
CC monocytes and granulocytes. Inhibits C5a-dependent neutrophil
CC enzyme release and chemotaxis.
CC -!- CATALYTIC ACTIVITY: Hydrolysis of proteins, including elastin.
CC Preferential cleavage: Val-|-Xaa > Ala-|-Xaa.
CC -!- SUBUNIT: Interacts with NOTCH2NL.
CC -!- INTERACTION:
CC Q07563:Col17a1 (xeno); NbExp=2; IntAct=EBI-986345, EBI-6251005;
CC -!- TISSUE SPECIFICITY: Bone marrow cells.
CC -!- DISEASE: Cyclic haematopoiesis (CH) [MIM:162800]: Autosomal
CC dominant disease in which blood-cell production from the bone
CC marrow oscillates with 21-day periodicity. Circulating neutrophils
CC vary between almost normal numbers and zero. During intervals of
CC neutropenia, affected individuals are at risk for opportunistic
CC infection. Monocytes, platelets, lymphocytes and reticulocytes
CC also cycle with the same frequency. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- DISEASE: Neutropenia, severe congenital 1, autosomal dominant
CC (SCN1) [MIM:202700]: A disorder of hematopoiesis characterized by
CC maturation arrest of granulopoiesis at the level of promyelocytes
CC with peripheral blood absolute neutrophil counts below 0.5 x
CC 10(9)/l and early onset of severe bacterial infections. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- SIMILARITY: Belongs to the peptidase S1 family. Elastase
CC subfamily.
CC -!- SIMILARITY: Contains 1 peptidase S1 domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=CAA29300.1; Type=Erroneous initiation;
CC -!- WEB RESOURCE: Name=ELA2base; Note=ELA2 mutation db;
CC URL="http://bioinf.uta.fi/ELA2base/";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/ELA2";
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/ela2/";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Elastase entry;
CC URL="http://en.wikipedia.org/wiki/Elastase";
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DR EMBL; Y00477; CAA68537.1; -; Genomic_DNA.
DR EMBL; M20203; AAA36359.1; -; Genomic_DNA.
DR EMBL; M20199; AAA36359.1; JOINED; Genomic_DNA.
DR EMBL; M20200; AAA36359.1; JOINED; Genomic_DNA.
DR EMBL; M20201; AAA36359.1; JOINED; Genomic_DNA.
DR EMBL; M34379; AAA36173.1; -; mRNA.
DR EMBL; AY596461; AAS89303.1; -; Genomic_DNA.
DR EMBL; BC074816; AAH74816.1; -; mRNA.
DR EMBL; BC074817; AAH74817.1; -; mRNA.
DR EMBL; D00187; BAA00128.1; -; mRNA.
DR EMBL; X05875; CAA29299.1; -; mRNA.
DR EMBL; X05875; CAA29300.1; ALT_INIT; mRNA.
DR EMBL; J03545; AAA52378.1; -; mRNA.
DR EMBL; M27783; AAA35792.1; -; mRNA.
DR PIR; A31976; ELHUL.
DR RefSeq; NP_001963.1; NM_001972.2.
DR RefSeq; XP_005259574.1; XM_005259517.1.
DR UniGene; Hs.99863; -.
DR PDB; 1B0F; X-ray; 3.00 A; A=30-247.
DR PDB; 1H1B; X-ray; 2.00 A; A/B=30-247.
DR PDB; 1HNE; X-ray; 1.84 A; E=30-247.
DR PDB; 1PPF; X-ray; 1.80 A; E=30-247.
DR PDB; 1PPG; X-ray; 2.30 A; E=30-247.
DR PDB; 2RG3; X-ray; 1.80 A; A=30-247.
DR PDB; 2Z7F; X-ray; 1.70 A; E=30-247.
DR PDB; 3Q76; X-ray; 1.86 A; A/B=30-247.
DR PDB; 3Q77; X-ray; 2.00 A; A=30-247.
DR PDBsum; 1B0F; -.
DR PDBsum; 1H1B; -.
DR PDBsum; 1HNE; -.
DR PDBsum; 1PPF; -.
DR PDBsum; 1PPG; -.
DR PDBsum; 2RG3; -.
DR PDBsum; 2Z7F; -.
DR PDBsum; 3Q76; -.
DR PDBsum; 3Q77; -.
DR ProteinModelPortal; P08246; -.
DR SMR; P08246; 30-247.
DR IntAct; P08246; 4.
DR MINT; MINT-1505052; -.
DR STRING; 9606.ENSP00000263621; -.
DR BindingDB; P08246; -.
DR ChEMBL; CHEMBL248; -.
DR DrugBank; DB00058; Alpha-1-proteinase inhibitor.
DR DrugBank; DB00099; Filgrastim.
DR DrugBank; DB00019; Pegfilgrastim.
DR GuidetoPHARMACOLOGY; 2358; -.
DR MEROPS; S01.131; -.
DR DMDM; 119292; -.
DR PaxDb; P08246; -.
DR PeptideAtlas; P08246; -.
DR PRIDE; P08246; -.
DR Ensembl; ENST00000263621; ENSP00000263621; ENSG00000197561.
DR Ensembl; ENST00000590230; ENSP00000466090; ENSG00000197561.
DR GeneID; 1991; -.
DR KEGG; hsa:1991; -.
DR UCSC; uc002lqb.3; human.
DR CTD; 1991; -.
DR GeneCards; GC19P000852; -.
DR HGNC; HGNC:3309; ELANE.
DR HPA; CAB015409; -.
DR MIM; 130130; gene.
DR MIM; 162800; phenotype.
DR MIM; 202700; phenotype.
DR neXtProt; NX_P08246; -.
DR Orphanet; 486; Autosomal dominant severe congenital neutropenia.
DR Orphanet; 2686; Cyclic neutropenia.
DR PharmGKB; PA27735; -.
DR eggNOG; COG5640; -.
DR HOGENOM; HOG000251820; -.
DR HOVERGEN; HBG013304; -.
DR InParanoid; P08246; -.
DR KO; K01327; -.
DR OMA; LRGGHFC; -.
DR OrthoDB; EOG7MKW6Q; -.
DR PhylomeDB; P08246; -.
DR BRENDA; 3.4.21.37; 2681.
DR Reactome; REACT_118779; Extracellular matrix organization.
DR Reactome; REACT_133391; Extracellular matrix organization.
DR SABIO-RK; P08246; -.
DR EvolutionaryTrace; P08246; -.
DR GeneWiki; Neutrophil_elastase; -.
DR GenomeRNAi; 1991; -.
DR NextBio; 8051; -.
DR PRO; PR:P08246; -.
DR ArrayExpress; P08246; -.
DR Bgee; P08246; -.
DR CleanEx; HS_ELA2; -.
DR Genevestigator; P08246; -.
DR GO; GO:0009986; C:cell surface; IDA:UniProtKB.
DR GO; GO:0005576; C:extracellular region; NAS:UniProtKB.
DR GO; GO:0030141; C:secretory granule; IDA:MGI.
DR GO; GO:0004175; F:endopeptidase activity; IDA:UniProtKB.
DR GO; GO:0008201; F:heparin binding; IDA:MGI.
DR GO; GO:0004252; F:serine-type endopeptidase activity; IEA:Ensembl.
DR GO; GO:0002438; P:acute inflammatory response to antigenic stimulus; IEA:Ensembl.
DR GO; GO:0006874; P:cellular calcium ion homeostasis; NAS:UniProtKB.
DR GO; GO:0030574; P:collagen catabolic process; TAS:Reactome.
DR GO; GO:0022617; P:extracellular matrix disassembly; TAS:Reactome.
DR GO; GO:0050900; P:leukocyte migration; IEA:Ensembl.
DR GO; GO:0045079; P:negative regulation of chemokine biosynthetic process; IDA:UniProtKB.
DR GO; GO:0050922; P:negative regulation of chemotaxis; NAS:UniProtKB.
DR GO; GO:0044130; P:negative regulation of growth of symbiont in host; IEA:Ensembl.
DR GO; GO:0050728; P:negative regulation of inflammatory response; NAS:UniProtKB.
DR GO; GO:0045415; P:negative regulation of interleukin-8 biosynthetic process; IDA:UniProtKB.
DR GO; GO:0070947; P:neutrophil mediated killing of fungus; IEA:Ensembl.
DR GO; GO:0006909; P:phagocytosis; IEA:Ensembl.
DR GO; GO:0050778; P:positive regulation of immune response; IEA:Ensembl.
DR GO; GO:0045416; P:positive regulation of interleukin-8 biosynthetic process; IDA:UniProtKB.
DR GO; GO:0043406; P:positive regulation of MAP kinase activity; NAS:UniProtKB.
DR GO; GO:0048661; P:positive regulation of smooth muscle cell proliferation; IDA:UniProtKB.
DR GO; GO:0030163; P:protein catabolic process; NAS:UniProtKB.
DR GO; GO:0006508; P:proteolysis; IDA:MGI.
DR GO; GO:0032496; P:response to lipopolysaccharide; IEA:Ensembl.
DR GO; GO:0009411; P:response to UV; IDA:UniProtKB.
DR GO; GO:0001878; P:response to yeast; IEA:Ensembl.
DR InterPro; IPR001254; Peptidase_S1.
DR InterPro; IPR018114; Peptidase_S1_AS.
DR InterPro; IPR001314; Peptidase_S1A.
DR InterPro; IPR009003; Trypsin-like_Pept_dom.
DR Pfam; PF00089; Trypsin; 1.
DR PRINTS; PR00722; CHYMOTRYPSIN.
DR SMART; SM00020; Tryp_SPc; 1.
DR SUPFAM; SSF50494; SSF50494; 1.
DR PROSITE; PS50240; TRYPSIN_DOM; 1.
DR PROSITE; PS00134; TRYPSIN_HIS; 1.
DR PROSITE; PS00135; TRYPSIN_SER; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Complete proteome; Direct protein sequencing;
KW Disease mutation; Disulfide bond; Glycoprotein; Hydrolase;
KW Polymorphism; Protease; Reference proteome; Serine protease; Signal;
KW Zymogen.
FT SIGNAL 1 27 Potential.
FT PROPEP 28 29
FT /FTId=PRO_0000027703.
FT CHAIN 30 267 Neutrophil elastase.
FT /FTId=PRO_0000027704.
FT DOMAIN 30 247 Peptidase S1.
FT ACT_SITE 70 70 Charge relay system.
FT ACT_SITE 117 117 Charge relay system.
FT ACT_SITE 202 202 Charge relay system.
FT CARBOHYD 88 88 N-linked (GlcNAc...).
FT CARBOHYD 124 124 N-linked (GlcNAc...).
FT CARBOHYD 173 173 N-linked (GlcNAc...).
FT DISULFID 55 71
FT DISULFID 151 208
FT DISULFID 181 187
FT DISULFID 198 223
FT VARIANT 25 25 A -> V (in SCN1).
FT /FTId=VAR_064512.
FT VARIANT 32 32 G -> V (in CH).
FT /FTId=VAR_009538.
FT VARIANT 55 55 C -> Y (in GFI1).
FT /FTId=VAR_038609.
FT VARIANT 57 57 A -> T (in GFI1).
FT /FTId=VAR_038610.
FT VARIANT 60 60 I -> T (in GFI1).
FT /FTId=VAR_038611.
FT VARIANT 71 71 C -> R (in GFI1; dbSNP:rs28931611).
FT /FTId=VAR_038612.
FT VARIANT 71 71 C -> S (in GFI1).
FT /FTId=VAR_038613.
FT VARIANT 85 85 G -> E (in GFI1).
FT /FTId=VAR_038614.
FT VARIANT 98 98 V -> L (in GFI1; located on the same
FT allele as L-101; reduces proteolytic
FT enzyme activity by slightly less than
FT half; together with L-101 shows an
FT additive effect with minimal remaining
FT enzyme activity).
FT /FTId=VAR_038615.
FT VARIANT 101 101 V -> L (in GFI1; located on the same
FT allele as L-98; reduces proteolytic
FT enzyme activity by slightly less than
FT half; together with L-98 shows an
FT additive effect with minimal remaining
FT enzyme activity).
FT /FTId=VAR_038616.
FT VARIANT 101 101 V -> M (in GFI1; dbSNP:rs28929494).
FT /FTId=VAR_038617.
FT VARIANT 123 123 L -> PQL (in GFI1).
FT /FTId=VAR_038618.
FT VARIANT 126 126 S -> L (in GFI1).
FT /FTId=VAR_038619.
FT VARIANT 139 139 P -> L (in GFI1; dbSNP:rs28929493).
FT /FTId=VAR_038620.
FT VARIANT 151 151 C -> S (in GFI1).
FT /FTId=VAR_038621.
FT VARIANT 166 166 A -> T (in SCN1; the patient also carries
FT mutation Lys-116 in G6PC3).
FT /FTId=VAR_064513.
FT VARIANT 177 177 V -> F (in CH).
FT /FTId=VAR_009539.
FT VARIANT 190 199 Missing (in GFI1).
FT /FTId=VAR_038622.
FT VARIANT 191 191 R -> Q (in CH; loss of interaction with
FT NOTCH2NL and loss of NOTCH2NL and NOTCH2
FT proteolytic cleavage).
FT /FTId=VAR_009540.
FT VARIANT 205 205 P -> R (in GFI1).
FT /FTId=VAR_038623.
FT VARIANT 210 210 G -> V (in GFI1).
FT /FTId=VAR_038624.
FT VARIANT 214 214 G -> R (in GFI1).
FT /FTId=VAR_038625.
FT VARIANT 219 219 V -> I (in dbSNP:rs17216656).
FT /FTId=VAR_019237.
FT VARIANT 257 257 P -> L (in dbSNP:rs17216663).
FT /FTId=VAR_019238.
FT VARIANT 262 262 P -> L (in dbSNP:rs17216670).
FT /FTId=VAR_019239.
FT STRAND 44 49
FT STRAND 52 61
FT STRAND 64 67
FT HELIX 69 72
FT HELIX 77 79
FT STRAND 81 85
FT STRAND 97 107
FT TURN 111 114
FT STRAND 119 125
FT STRAND 130 132
FT STRAND 150 158
FT STRAND 160 162
FT STRAND 170 177
FT STRAND 185 189
FT STRAND 191 193
FT STRAND 205 208
FT STRAND 211 222
FT STRAND 226 228
FT STRAND 230 234
FT HELIX 235 238
FT HELIX 239 246
SQ SEQUENCE 267 AA; 28518 MW; 3F7610DC33CAA4B9 CRC64;
MTLGRRLACL FLACVLPALL LGGTALASEI VGGRRARPHA WPFMVSLQLR GGHFCGATLI
APNFVMSAAH CVANVNVRAV RVVLGAHNLS RREPTRQVFA VQRIFENGYD PVNLLNDIVI
LQLNGSATIN ANVQVAQLPA QGRRLGNGVQ CLAMGWGLLG RNRGIASVLQ ELNVTVVTSL
CRRSNVCTLV RGRQAGVCFG DSGSPLVCNG LIHGIASFVR GGCASGLYPD AFAPVAQFVN
WIDSIIQRSE DNPCPHPRDP DPASRTH
//

MIM 130130
*RECORD*
*FIELD* NO
130130
*FIELD* TI
*130130 ELASTASE, NEUTROPHIL-EXPRESSED; ELANE
;;ELASTASE 2; ELA2;;
ELASTASE, NEUTROPHIL; NE;;
read moreHNE;;
ELASTASE, LEUKOCYTE;;
HLE;;
MEDULLASIN;;
PROTEASE, SERINE, BONE MARROW
*FIELD* TX

DESCRIPTION

Neutrophil elastase (EC 3.4.21.37) is a serine protease of neutrophil
and monocyte granules (Horwitz et al., 1999). Its key physiologic role
is in innate host defense, but it can also participate in tissue
remodeling and possesses secretagogue actions important to local
inflammatory responses (Chua and Laurent, 2006).

CLONING

Aoki (1978) purified a 31-kD serine protease from human bone marrow cell
mitochondria. Both granulocytes and erythroblasts were found to contain
the protease medullasin, but it was not detected in lymphocytes or
thrombocytes. It was shown to be located on the inner membrane of
mitochondria. Nakamura et al. (1987) reported the complete genomic
sequence and deduced the amino acid sequence of the medullasin
precursor. It contains 267 amino acids, including a possible leader
sequence of 29 amino acids.

Fletcher et al. (1987) cloned a cDNA encoding elastase-2 from a human
pancreatic cDNA library. Similarities to and differences from elastase-1
(130120) and the chymotrypsins (e.g., 118890) were described.

Kawashima et al. (1987) isolated cDNAs from a human pancreatic cDNA
library, which indicated that at least 2 elastase II messages are
expressed in pancreas. The 2 human elastases II have been designated IIA
and IIB. There is 90% overall homology between the amino acid sequences
of these 2 classes of elastase II, which is synthesized as a
preproenzyme of 269 amino acids.

Sinha et al. (1987) determined the complete amino acid sequence of human
neutrophil elastase. The protein consists of 218 amino acid residues,
contains 2 asparagine-linked carbohydrate side chains, and is joined
together by 2 disulfide bonds. There is only moderate homology with
porcine pancreatic elastase (43%). Okano et al. (1987) showed that the
218-amino acid sequence of human neutrophil elastase is identical to
that of medullasin.

GENE FUNCTION

Belaaouaj et al. (2000) determined the mechanism of neutrophil
elastase-mediated killing of E. coli. They found that neutrophil
elastase degraded outer membrane protein A (OmpA), localized on the
surface of gram-negative bacteria.

Weinrauch et al. (2002) identified human neutrophil elastase as a key
host defense protein in preventing the escape of Shigella from
phagocytic vacuoles in neutrophils. Neutrophil elastase degrades
Shigella virulence factors at a 1,000-fold lower concentration than that
needed to degrade other bacterial proteins. In neutrophils in which
neutrophil elastase is inactivated pharmacologically or genetically,
Shigella escapes from phagosomes, increasing bacterial survival.
Neutrophil elastase also preferentially cleaves virulence factors of
Salmonella and Yersinia. Weinrauch et al. (2002) concluded that their
findings established neutrophil elastase as the first neutrophil factor
that targets bacterial virulence proteins.

Increased leukocyte elastase activity in mice lacking secretory
leukocyte protease inhibitor (SLPI; 107285) leads to impaired wound
healing due to enhanced activity of transforming growth factor-beta
(190180) and perhaps additional mechanisms (Ashcroft et al., 2000).
Proepithelin (PEPI; 138945), also known as progranulin, an epithelial
growth factor, can be converted to epithelins (EPIs) in vivo. Zhu et al.
(2002) found that PEPI and EPIs exert opposing activities. EPIs
inhibited the growth of epithelial cells but induced them to secrete the
neutrophil attractant interleukin-8 (IL8; 146930), while PEPI blocked
neutrophil activation by tumor necrosis factor (TNF; 191160), preventing
release of oxidants and proteases. SLPI and PEPI formed complexes,
preventing elastase from converting PEPI to EPIs. Supplying PEPI
corrected the wound-healing defect in Slpi null mice. The authors
concluded that SLPI/elastase act via PEPI/EPIs to operate a switch at
the interface between innate immunity and wound healing.

The fusion protein PML (102578)-RARA (180240), which is generated by the
t(15;17)(q22;q11.2) translocation associated with acute promyelocytic
leukemia (APL; 612376), initiates APL when expressed in the early
myeloid compartment of transgenic mice. Lane and Ley (2003) found that
PML-RARA was cleaved in several positions by a neutral serine protease
in a human myeloid cell line; purification revealed that the protease
was ELA2. Immunofluorescence localization studies suggested that
cleavage of PML-RARA must have occurred within the cell, perhaps within
the nucleus. The functional importance of ELA2 for APL development was
assessed in Ela2-deficient mice. More than 90% of bone marrow
PML-RARA-cleaving activity was lost in the absence of Ela2, and
Ela2-deficient animals, but not cathepsin G (CTSG; 116830)-deficient
animals, were protected from APL development. The authors determined
that primary mouse and human APL cells also contained ELA2-dependent
PML-RARA-cleaving activity. Lane and Ley (2003) concluded that, since
ELA2 is maximally produced in promyelocytes, it may play a role in APL
pathogenesis by facilitating the leukemogenic potential of PML-RARA.

Using the LSL-Kras-G12D (191170.0005) model of mouse lung adenocarcinoma
(211980), Houghton et al. (2010) found that mutant mice who were also
Elane -/- had markedly decreased tumor burden compared to Elane +/+
mice. All LSL-Kras/Elane +/+ mice died, whereas none of the Elane -/-
mice died in the study period. In vitro studies in human and mouse
adenocarcinoma cells showed that neutrophil elastase directly induced
tumor cell proliferation at physiologic levels by gaining access to an
endosomal compartment within tumor cells, where it degraded insulin
receptor substrate-1 (IRS1; 147545). Degradation of IRS1 was associated
with increased interaction between PI3K (see 171834) and the potent
mitogen PDGFR (173410), skewing the PI3K axis toward tumor cell
proliferation. The findings identified IRS1 as a key regulator of PI3K
within malignant cells.

- Role in Human Immunodeficiency Virus-1 Infection

Bristow et al. (1995) found that human, but not murine, epithelial and
leukocyte elastase bound the fusion domain of human immunodeficiency
virus (HIV)-1 gp160 and interacted with a pentapeptide representative of
the HIV-1 fusion domain. HIV-1 infectivity was blocked during, but not
after, the initial contact between virus and cells. Bristow et al.
(1995) suggested that the elastase present on T-cell membranes
participates in permissiveness of host cells to infection.

Bristow (2001) found that decreased HIV infectivity correlated
significantly with decreased cell surface expression of HLE on monocytes
but not lymphocytes. Decreased levels of alpha-1-antitrypsin (AAT;
107400), also known as protease inhibitor (PI), correlated with
increased cell surface HLE expression and increased HIV infectivity.

Bristow et al. (2001) showed that decreased HIV viral load correlated
with decreased circulating PI. Furthermore, asymptomatic patients
manifested deficient levels of active PI. Bristow et al. (2001) noted
that deficient levels of PI lead to degenerative lung diseases and
suggested that preventing PI deficiency may prevent HIV-associated
pathophysiology.

Using subclones of monocytic cell lines, Bristow et al. (2003) showed
that HLE localized to the cell surface, but not granules, of
HIV-1-permissive clones, and to the granules, but not the cell surface,
of HIV-1-nonpermissive clones. Stimulation of nonpermissive clones with
lipopolysaccharide and LBP (151990), followed by exogenous PI, induced
cell surface HLE expression, resulting in susceptibility to HIV
infection. PI appeared to promote HIV coreceptor colocalization with
surface HLE, thus permitting HIV infectivity.

GENE STRUCTURE

Zimmer et al. (1992) demonstrated that the genes encoding azurocidin
(NAZC; 162815), proteinase-3 (PRTN3; 177020), and neutrophil elastase
each have 5 exons. All 3 genes are expressed coordinately and their
protein products are packaged together at high levels into azurophil
granules during neutrophil differentiation. Belaaouaj et al. (1997)
demonstrated that the murine homolog of human ELA2 also contains 5
exons.

MAPPING

Zimmer et al. (1992) showed that the NAZC, PRTN3, and ELA2 genes are
within an approximately 50-kb cluster on chromosome 19pter.

By interphase studies with differentially labeled probes for
fluorescence in situ hybridization, Pilat et al. (1994) demonstrated
that ELA2 is in a gene cluster on 19p13.3 with azurocidin, proteinase-3,
and granzyme M (600311).

By interspecific backcross analysis, Belaaouaj et al. (1997) mapped the
mouse Ela2 gene to chromosome 10.

MOLECULAR GENETICS

Cyclic neutropenia (162800), also known as cyclic hematopoiesis, is an
autosomal dominant disorder in which blood-cell production from the bone
marrow oscillates with 21-day periodicity. Circulating neutrophils vary
between almost normal numbers and zero. During intervals of neutropenia,
affected individuals are at risk for opportunistic infection. Monocytes,
platelets, lymphocytes, and reticulocytes also cycle with the same
frequency. Horwitz et al. (1999) used a genomewide screen and positional
cloning to map the locus to 19p13.3. They identified 7 different
single-basepair substitutions in the ELA2 gene, each on a unique
haplotype, in 13 of 13 families, as well as a new mutation in a sporadic
case (e.g., 130130.0001-130130.0005). Neutrophil elastase is a target
for protease inhibition by alpha-1-antitrypsin (AAT; 107400), and its
unopposed release destroys tissue at sites of inflammation. Horwitz et
al. (1999) hypothesized that a perturbed interaction between neutrophil
elastase and serpins or other substrates may regulate mechanisms
governing the clock-like timing of hematopoiesis.

After mutations in the ELA2 gene were identified as the basis of
autosomal dominant cyclic neutropenia, Dale et al. (2000) hypothesized
that congenital neutropenia (202700) is also due to mutation in this
gene. 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. Their studies
revealed that 22 of 25 patients with congenital neutropenia had 18
different heterozygous mutations. All 4 patients with cyclic neutropenia
and none of 3 patients with Shwachman-Diamond syndrome (260400) had
mutations of the ELA2 gene. In the congenital neutropenia patients, 5
different mutations were found in families with 2 or more affected
members. Three instances of father-daughter pairs, 1 mother-son pair,
and 1 mother with 2 affected sons by different fathers suggested
autosomal dominant inheritance.

Because all of the mutations in the ELA2 gene associated with severe
congenital neutropenia had been heterozygous, Ancliff et al. (2001)
conducted a study to determine whether mutations in ELA2 could account
for the disease phenotype in classic autosomal recessive severe
congenital neutropenia (Kostmann disease; 610738), as well as in the
sporadic and autosomal dominant types. They used direct automated
sequencing to study all 5 exons of ELA2 and their flanking introns in 18
patients (3 autosomal recessive, 5 autosomal dominant from 3 kindreds,
and 10 sporadic). No mutations were found in the autosomal recessive
families. A point mutation was identified in 1 of 3 autosomal dominant
families, and a base substitution was identified in 8 of 10 patients
with the sporadic form, although 1 of the 8 was shown to have a low
frequency polymorphism. These results suggested that mutations in ELA2
are not responsible for classic autosomal recessive Kostmann disease,
but provided further evidence for the role of ELA2 in the autosomal
dominant form of severe congenital neutropenia.

Ancliff et al. (2002) described the case of a healthy father of a
patient who was demonstrated to be mosaic for his daughter's
cys42-to-arg ELA2 mutation (130130.0009). Semiquantitative PCR showed
that approximately half of his T cells carried the mutation, in contrast
to less than 10% of neutrophils. Individual hematopoietic colonies grown
from peripheral blood were heterozygous for the mutation or were
homozygous wildtype. The results demonstrated that precursors containing
the mutation are selectively lost during myelopoiesis or fail to develop
into neutrophils. Ancliff et al. (2002) stated that this was the first
in vivo confirmation of the pathogenic nature of elastase mutations in
humans. The normal neutrophil count in the father suggested that the
mutant elastase does not have paracrine effects.

Thusberg and Vihinen (2006) reported detailed bioinformatic analyses of
32 different pathogenic missense mutations in the ELA2 gene. Using 31
different analytic methods, the authors found that different mutations
resulted in diverse deleterious effects on protein structure and
function, including changes in electrostatic surface potential, contacts
and stability, and aggregation, among other changes. There were no
obvious genotype/phenotype correlations to explain the phenotypic
expression of cyclic versus congenital neutropenia.

Salipante et al. (2007) reported 2 unrelated patients with cyclic
neutropenia and severe congenital neutropenia, respectively, who each
had 2 de novo mutations in cis in the ELA2 gene (see, e.g.,
130130.0010). In both patients, the 2 mutations were paternally derived
and likely arose during spermatogenesis. Functional expression studies
showed reduced proteolytic activity, evidence for induction of the
unfolded protein response, and disturbed subcellular localization
consistent with protein mistrafficking.

Ishikawa et al. (2008) identified heterozygous mutations in the ELA2
gene in 11 (61%) of 18 Japanese patients with severe congenital
neutropenia. Five (28%) patients had SCN3 (610738) due to mutation in
the HAX1 gene (605998).

GENOTYPE/PHENOTYPE CORRELATIONS

Grenda et al. (2007) demonstrated significant activation of the unfolded
protein response (UPR) and cellular apoptosis in cells derived from
patients with SCN1 and in human granulocyte precursors specifically
transfected with SCN1-associated ELA2 mutations, including V72M
(130130.0007), P110L (130130.0006), and G185R (130130.0011). The UPR
response was assessed by increased expression of XBP1 (194355) and HSPA5
(138120). Milder effects were observed with the cyclic
neutropenia-associated R191Q (130130.0001) mutation. There was no
evidence for protein mistrafficking within the cell. The findings
indicated that the magnitude of UPR activation and apoptosis induced by
ELA2 mutations correlated with the phenotypic severity. Grenda et al.
(2007) concluded that ELA2-related disorders result from accumulation of
misfolded mutant proteins, activation of the UPR, and cellular
apoptosis, consistent with a toxic dominant-negative cell intrinsic
effect.

Rosenberg et al. (2007) reported that 2 of 4 SCN1 patients with the
G185R mutation developed myelodysplastic syndrome/acute myeloid leukemia
(MDS/AML) by 15 years follow-up, whereas none of 7 patients with the
P110L mutation or 5 patients with the S97L (130130.0008) mutation had
developed MDS/AML.

Germeshausen et al. (2013) found 116 different ELANE mutations in 162
(41%) of 395 patients with congenital neutropenia and 26 mutations in 51
(55%) of 92 patients with cyclic neutropenia, including 69 novel
mutations. The mutations were spread throughout the gene sequence.
Cyclic neutropenia-associated mutations were predicted to be more benign
than congenital neutropenia-associated mutations, but the mutation
severity largely overlapped. The frequency of acquired CSF3R (138971)
mutations, malignant transformation, and the need for hematopoietic stem
cell transplantation were significantly higher in congenital neutropenia
patients with ELANE mutations than in ELANE mutation-negative patients.
Cellular elastase activity was reduced in neutrophils from all patients,
irrespective of the mutation status. In congenital neutropenia,
enzymatic activity was significantly lower in patients with ELANE
mutations compared with those with wildtype ELANE. Despite differences
in the spectrum of mutations, type or localization of mutation only
partially determines the clinical phenotype. Thus, there were no
apparent genotype/phenotype correlations. The report also indicated that
specific ELANE mutations have limited predictive value for
leukemogenesis; the risk for leukemia was correlated with disease
severity rather than with occurrence of an ELANE mutation.

ANIMAL MODEL

Bullous pemphigoid (BP) is an autoimmune skin disease characterized by
subepidermal blisters and autoantibodies against 2
hemidesmosome-associated proteins, BP180 (COL17A1; 113811) and BP240
(BPAG1; 113810). The immunopathologic features of BP can be reproduced
in mice by passive transfer of anti-BP180 antibodies. Lesion formation
in this animal model depends on complement activation and neutrophil
recruitment. Liu et al. (2000) investigated the role of neutrophil
elastase in antibody-induced blister formation in experimental BP.
Abnormally high levels of caseinolytic activity, consistent with NE,
were detected in extracts of lesional skin and blister fluid of mice
injected with anti-BP180 IgG. In NE-null (NE -/-) mutant mice, the
pathogenic anti-BP180 IgG failed to induce subepidermal blistering.
Wildtype mice given NE inhibitors, but not mice given cathepsin
G/chymase inhibitors, were resistant to the pathogenic activity of
anti-BP180 antibodies. Incubation of murine skin with NE induced BP-like
epidermal-dermal detachment. Finally, Liu et al. (2000) showed that NE
cleaved BP180 in vitro and in vivo. These results implicated NE directly
in the dermal-epidermal cleavage induced by anti-BP180 antibodies in the
experimental BP model.

Using mice deficient in Ctsg and/or Ela2, Reeves et al. (2002) confirmed
data originally generated by Tkalcevic et al. (2000) and Belaaouaj et
al. (1998) that Ctsg -/- mice resist Candida but not Staphylococcal
infection, whereas the reverse is true in Ela2 -/- mice. Both organisms
were more virulent in double-knockout mice. Purified neutrophils from
these mice mirrored these results in vitro in spite of exhibiting normal
phagocytosis, degranulation, oxidase activity, superoxide production,
and myeloperoxidase (MPO; 606989) activity. Reeves et al. (2002)
hypothesized that reactive oxygen species (ROS) and proteases act
together since deficiencies in either lead to comparable reductions in
killing efficiency. They determined that conditions in the phagocytic
vacuole after activation provoke the influx of enormous concentrations
of ROS compensated by a surge of K+ ions crossing the membrane in a
pH-dependent manner. The resulting rise in ionic strength induces the
release of cationic granule proteins, including Ctsg and Ela2, from the
highly charged anionic sulfated proteoglycan matrix within the granules.
Reeves et al. (2002) concluded that it is essential for the volume of
the vacuole to be restricted for the requisite hypertonicity to develop.
They proposed that disruption of the integrity of the cytoskeletal
network by microbial products could offer a mechanism of virulence by
inhibiting the activation of granule proteins.

Benson et al. (2003) stated that over 20 different mutations of
neutrophil elastase had been identified, but their consequences had been
elusive because they confer no consistent effects on enzymatic activity
(Li and Horwitz, 2001). The autosomal recessive disorder canine cyclic
hematopoiesis (Lothrop et al., 1987), also known as gray collie
syndrome, is not caused by mutations in neutrophil elastase. Benson et
al. (2003) showed that homozygous mutation of the gene encoding the dog
adaptor protein complex-3 (AP3) beta-subunit (AP3B1; 603401), directing
trans-Golgi export of transmembrane cargo proteins to lysosomes, causes
canine cyclic hematopoiesis. C-terminal processing of neutrophil
elastase exposes an AP3 interaction signal responsible for redirecting
neutrophil elastase trafficking from membranes to granules. Disruption
of either neutrophil elastase or AP3 perturbs the intracellular
trafficking of neutrophil elastase. Most mutations in ELA2 that cause
human cyclic hematopoiesis prevent membrane localization of neutrophil
elastase, whereas most mutations in ELA2 that cause severe congenital
neutropenia (SCN) lead to exclusive membrane localization.

HISTORY

The elastase secreted by leukocytes is a serine protease inhibitable by
alpha-1-protease inhibitor (107400), whereas the elastase secreted by
macrophages (MMP12; 601046) is a metalloprotease not inhibitable by
alpha-1-protease inhibitor (Rosenbloom, 1984).

*FIELD* AV
.0001
CYCLIC NEUTROPENIA
ELANE, ARG191GLN

In 3 of 13 families with cyclic neutropenia (162800), Horwitz et al.
(1999) demonstrated a G-to-A transition in the ELA2 gene at the second
position in codon 191 (numbering from the first residue after the
presignal peptide had been cleaved), resulting in an arg191-to-gln amino
acid substitution.

.0002
CYCLIC NEUTROPENIA
ELANE, LEU177PHE

In 2 of 13 families with cyclic neutropenia (162800), Horwitz et al.
(1999) found a G-to-T transversion in the ELA2 gene at the wobble
position of codon 177, resulting in replacement of the normal leucine
with a phenylalanine.

.0003
CYCLIC NEUTROPENIA
ELANE, ALA32VAL

In 1 family, Horwitz et al. (1999) demonstrated that cyclic neutropenia
(162800) was due to a C-to-T transition in the ELA2 gene resulting in an
ala32-to-val amino acid substitution.

.0004
CYCLIC NEUTROPENIA
ELANE, IVS4DS, G-A, +1

In 2 of 13 families and in a sporadic new mutation case with cyclic
neutropenia (162800), Horwitz et al. (1999) found a splice donor
mutation of intron 4 of the ELA2 gene, a transition of the invariant
guanine to an adenine at the +1 position. The parents were not affected
and did not carry the mutation, and paternity was confirmed.

.0005
CYCLIC NEUTROPENIA
ELANE, IVS4DS, G-A, +5

In 3 families with cyclic neutropenia (162800), Horwitz et al. (1999)
noted a G-to-A transition at the +5 position of intron 4 of the ELA2
gene, where guanine is present in 84% of cases.

.0006
NEUTROPENIA, SEVERE CONGENITAL, 1, AUTOSOMAL DOMINANT
ELANE, PRO110LEU

In 4 unrelated patients with congenital neutropenia (SCN1; 202700), Dale
et al. (2000) found heterozygosity for a 15862C-T transition in genomic
DNA causing a pro110-to-leu (P110L) amino acid substitution. One of the
families had an affected mother and 2 affected sons with different
fathers, supporting autosomal dominant inheritance. Another family with
the P110L mutation had an affected mother and son; another family had an
affected father and daughter.

Rosenberg et al. (2007) identified the P110L mutation in 7 of 82
unrelated patients with SCN1. None of the patients had developed MDS/AML
at 15 years follow-up.

.0007
NEUTROPENIA, SEVERE CONGENITAL, 1, AUTOSOMAL DOMINANT
ELANE, VAL72MET

In 2 unrelated families, Dale et al. (2000) found that patients with
congenital neutropenia (SCN1; 202700) were heterozygous for the same
34371G-A substitution in exon 3 of the ELA2 gene, resulting in a
val72-to-met (V72M) mutation. In 1 of the families a father and daughter
were affected.

.0008
NEUTROPENIA, SEVERE CONGENITAL, 1, AUTOSOMAL DOMINANT
ELANE, SER97LEU

Ancliff et al. (2001) commented on the variation in phenotype in
patients with the same ELA2 mutation. They reported 2 patients with a
C-to-T transition at nucleotide 4495 in exon 4 of the ELA2 gene,
resulting in a ser97-to-leu (S97L) substitution. One of the patients,
aged 5 years at the time of report, had severe neutropenia (SCN1;
202700) and remained on GCSF therapy with only a modest response. The
other patient, aged 13 years at the time of report, had severe
neutropenia and recurrent infections until he started GCSF at the age of
4 years. He responded well and needed only a small maintenance dose.
GCSF was discontinued when he was 8; he remained free of major
infections and had a neutrophil count of approximately 0.5 x 10(9)/L.
The authors stated that the difference may reflect the influence of
other inherited modifying factors.

Rosenberg et al. (2007) identified the S97L mutation in 5 of 82
unrelated patients with SCN1. None of the patients had developed MDS/AML
at 15 years follow-up.

.0009
NEUTROPENIA, SEVERE CONGENITAL, 1, AUTOSOMAL DOMINANT
ELANE, CYS42ARG

In a child with severe congenital neutropenia (SCN1; 202700), Ancliff et
al. (2001) identified heterozygosity for a 1929T-C mutation in the ELA2
gene, resulting in a cys42-to-arg (C42R) substitution. They found
mosaicism for the mutation in her healthy father. Approximately half of
the father's T cells carried the mutation, in contrast to less than 10%
of neutrophils.

.0010
NEUTROPENIA, SEVERE CONGENITAL, 1, AUTOSOMAL DOMINANT
ELANE, VAL69LEU AND VAL72LEU

In a patient with severe congenital neutropenia (SCN1; 202700),
Salipante et al. (2007) identified 2 de novo mutations in the ELA2 gene
in cis on the paternal allele. The father was unaffected, and the
mutations likely arose during spermatogenesis. The mutations, which were
9 nucleotides apart in exon 3, resulted in val69-to-leu (V69L) and
val72-to-leu (V72L) substitutions. Functional expression studies showed
that each mutation by itself reduced proteolytic enzyme activity by
slightly less than half, but together showed an additive effect with
minimal remaining enzyme activity. Nuclear localization studies showed
that the V72L mutant distributed to the cytoplasm, whereas the V69L
mutant accumulated at the cell surface. The 2 mutations together yielded
a compromise with moderate amounts in both the cytoplasm and at the cell
surface, as well as some expression in the nucleus. Salipante et al.
(2007) concluded that the mutations result in disturbed subcellular
protein trafficking. There was also some evidence for induction of the
unfolded protein response.

.0011
NEUTROPENIA, SEVERE CONGENITAL, 1, AUTOSOMAL DOMINANT
ELANE, GLY185ARG

In patients with SCN1 (202700), Dale et al. (2000) and
Bellanne-Chantelot et al. (2004) identified a heterozygous 4924G-A
transition in exon 5 of the ELA2 gene, resulting in a gly185-to-arg
(G185R) substitution.

Rosenberg et al. (2007) identified the G185R mutation in 4 of 82
unrelated patients with SCN1. Patients with the G185R mutation had a
particularly severe disease course, and 2 developed MDS/AML at 10 and 15
years, respectively.

*FIELD* RF
1. Ancliff, P. J.; Gale, R. E.; Liesner, R.; Hann, I. M.; Linch, D.
C.: 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 98:
2645-2650, 2001.

2. Ancliff, P. J.; Gale, R. E.; Watts, M. J.; Liesner, R.; Hann, I.
M.; Strobel, S.; Linch, D. C.: Paternal mosaicism proves the pathogenic
nature of mutations in neutrophil elastase in severe congenital neutropenia. Blood 100:
707-709, 2002.

3. Aoki, Y.: Crystallization and characterization of a new protease
in mitochondria of bone marrow cells. J. Biol. Chem. 253: 2026-2032,
1978.

4. Ashcroft, G. S.; Lei, K.; Jin, W.; Longenecker, G.; Kulkarni, A.
B.; Greenwell-Wild, T.; Hale-Donze, H.; McGrady, G.; Song, X.-Y.;
Wahl, S. M.: Secretory leukocyte protease inhibitor mediates non-redundant
functions necessary for normal wound healing. Nature Med. 6: 1147-1153,
2000.

5. Belaaouaj, A.; Kim, K. S.; Shapiro, S. D.: Degradation of outer
membrane protein A in Escherichia coli killing by neutrophil elastase. Science 289:
1185-1187, 2000.

6. Belaaouaj, A.; McCarthy, R.; Baumann, M.; Gao, Z.; Ley, T. J.;
Abraham, S. N.; Shapiro, S. D.: Mice lacking neutrophil elastase
reveal impaired host defense against gram negative bacterial sepsis. Nature
Med. 4: 615-618, 1998.

7. Belaaouaj, A.; Walsh, B. C.; Jenkins, N. A.; Copeland, N. G.; Shapiro,
S. D.: Characterization of the mouse neutrophil elastase gene and
localization to chromosome 10. Mammalian Genome 8: 5-8, 1997.

8. Bellanne-Chantelot, C.; Clauin, S.; Leblanc, T.; Cassinat, B.;
Rodrigues-Lima, F.; Beaufils, S.; Vaury, C.; Barkaoui, M.; Fenneteau,
O.; Maier-Redelsperger, M.; Chomienne, C.; Donadieu, J.: Mutations
in the ELA2 gene correlate with more severe expression of neutropenia:
a study of 81 patients from the French Neutropenia Register. Blood 103:
4119-4125, 2004.

9. Benson, K. F.; Li, F.-Q.; Person, R. E.; Albani, D.; Duan, Z.;
Wechsler, J.; Meade-White, K.; Williams, K.; Acland, G. M.; Niemeyer,
G.; Lothrop, C. D.; Horwitz, M.: Mutations associated with neutropenia
in dogs and humans disrupt intracellular transport of neutrophil elastase. Nature
Genet. 35: 90-96, 2003.

10. Bristow, C. L.: Slow human immunodeficiency virus (HIV) infectivity
correlated with low HIV coreceptor levels. Clin. Diag. Lab. Immun. 8:
932-936, 2001.

11. Bristow, C. L.; Fiscus, S. A.; Flood, P. M.; Arnold, R. R.: Inhibition
of HIV-1 by modification of a host membrane protease. Int. Immun. 7:
239-249, 1995.

12. Bristow, C. L.; Mercatante, D. R.; Kole, R.: HIV-1 preferentially
binds receptors copatched with cell-surface elastase. Blood 102:
4479-4486, 2003.

13. Bristow, C. L.; Patel, H.; Arnold, R. R.: Self antigen prognostic
for human immunodeficiency virus disease progression. Clin. Diag.
Lab. Immun. 8: 937-942, 2001.

14. Chua, F.; Laurent, G. J.: Neutrophil elastase: mediator of extracellular
matrix destruction and accumulation. Proc. Am. Thoracic Soc. 3:
424-427, 2006.

15. Dale, D. C.; Person, R. E.; Bolyard, A. A.; Aprikyan, A. G.; Bos,
C.; Bonilla, M. A.; Boxer, L. A.; Kannourakis, G.; Zeidler, C.; Welte,
K.; Benson, K. F.; Horwitz, M.: Mutations in the gene encoding neutrophil
elastase in congenital and cyclic neutropenia. Blood 96: 2317-2322,
2000.

16. Fletcher, T. S.; Shen, W.-F.; Largman, C.: Primary structure
of human pancreatic elastase 2 determined by sequence analysis of
the cloned mRNA. Biochemistry 26: 7256-7261, 1987.

17. Germeshausen, M.; Deerberg, S.; Peter, Y.; Reimer, C.; Kratz,
C. P.; Ballmaier, M.: The spectrum of ELANE mutations and their implications
in severe congenital and cyclic neutropenia. Hum. Mutat. 34: 905-914,
2013.

18. Grenda, D. S.; Murakami, M.; Ghatak, J.; Xia, J.; Boxer, L. A.;
Dale, D.; Dinauer, M. C.; Link, D. C.: Mutations of the ELA2 gene
found in patients with severe congenital neutropenia induce the unfolded
protein response and cellular apoptosis. Blood 110: 4179-4187, 2007.

19. Horwitz, M.; Benson, K. F.; Person, R. E.; Aprikyan, A. G.; Dale,
D. C.: Mutations in ELA2, encoding neutrophil elastase, define a
21-day biological clock in cyclic haematopoiesis. Nature Genet. 23:
433-436, 1999.

20. Houghton, A. M.; Rzymkiewicz, D. M.; Ji, H.; Gregory, A. D.; Egea,
E. E.; Metz, H. E.; Stolz, D. B.; Land, S. R.; Marconcini, L. A.;
Kliment, C. R.; Jenkins, K. M.; Beaulieu, K. A.; Mouded, M.; Frank,
S. J.; Wong, K. K.; Shapiro, S. D.: Neutrophil elastase-mediated
degradation of IRS-1 accelerates lung tumor growth. Nature Med. 16:
219-223, 2010.

21. Ishikawa, N.; Okada, S.; Miki, M.; Shirao, K.; Kihara, H.; Tsumura,
M.; Nakamura, K.; Kawaguchi, H.; Ohtsubo, M.; Yasunaga, S.; Matsubara,
K.; Sako, M.; Hara, J.; Shiohara, M.; Kojima, S.; Sato, T.; Takihara,
Y.; Kobayashi, M.: Neurodevelopmental abnormalities associated with
severe congenital neutropenia due to the R86X mutation in the HAX1
gene. J. Med. Genet. 45: 802-807, 2008.

22. Kawashima, I.; Tani, T.; Shimoda, K.; Takiguchi, Y.: Characterization
of pancreatic elastase II cDNAs: two elastase II mRNAs are expressed
in human pancreas. DNA 6: 163-172, 1987.

23. Lane, A. A.; Ley, T. J.: Neutrophil elastase cleaves PML-RAR-alpha
and is important for the development of acute promyelocytic leukemia
in mice. Cell 115: 305-318, 2003.

24. Li, F.-Q.; Horwitz, M.: Characterization of mutant neutrophil
elastase in severe congenital neutropenia. J. Biol. Chem. 276: 14230-14241,
2001.

25. Liu, Z.; Shapiro, S. D.; Zhou, X.; Twining, S. S.; Senior, R.
M.; Giudice, G. J.; Fairley, J. A.; Diaz, L. A.: A critical role
for neutrophil elastase in experimental bullous pemphigoid. J. Clin.
Invest. 105: 113-123, 2000.

26. Lothrop, C. D., Jr.; Coulson, P. A., Jr.; Nolan, H. L.; Cole,
B.; Jones, J. B.; Sanders, W. L.: Cyclic hormonogenesis in gray collie
dogs: interactions of hematopoietic and endocrine systems. Endocrinology 120:
1027-1032, 1987.

27. Nakamura, H.; Okano, K.; Aoki, Y.; Shimizu, H.; Naruto, M.: Nucleotide
sequence of human bone marrow serine protease (medullasin) gene. Nucleic
Acids Res. 15: 9601-9602, 1987.

28. Okano, K.; Aoki, Y.; Sakurai, T.; Kajitani, M.; Kanai, S.; Shimazu,
T.; Shimizu, H.; Naruto, M.: Molecular cloning of complementary DNA
for human medullasin: an inflammatory serine protease in bone marrow
cells. J. Biochem. 102: 13-16, 1987.

29. Pilat, D.; Fink, T.; Obermaier-Skrobanek, B.; Zimmer, M.; Wekerle,
H.; Lichter, P.; Jenne, D. E.: The human Met-ase gene (GZMM): structure,
sequence, and close physical linkage to the serine protease gene cluster
on 19p13.3. Genomics 24: 445-450, 1994.

30. Reeves, E. P.; Lu, H.; Jacobs, H. L.; Messina, C. G. M.; Bolsover,
S.; Gabella, G.; Potma, E. O.; Warley, A.; Roes, J.; Segal, A. W.
: Killing activity of neutrophils is mediated through activation of
proteases by K+ flux. Nature 416: 291-297, 2002.

31. Rosenberg, P. S.; Alter, B. P.; Link, D. C.; Stein, S.; Rodger,
E.; Bolyard, A. A.; Aprikyan, A. A.; Bonilla, M. A.; Dror, Y.; Kannourakis,
G.; Newburger, P. E.; Boxer, L. A.; Dale, D. C.: Neutrophil elastase
mutations and risk of leukaemia in severe congenital neutropenia. Brit.
J. Haemat. 140: 210-213, 2007.

32. Rosenbloom, J.: Elastin: relation of protein and gene structure
to disease. Lab. Invest. 51: 605-623, 1984.

33. Salipante, S. J.; Benson, K. F.; Luty, J.; Hadavi, V.; Kariminejad,
R.; Kariminejad, M. H.; Rezaei, N.; Horwitz, M. S.: Double de novo
mutations of ELA2 in cyclic and severe congenital neutropenia. Hum.
Mutat. 28: 874-881, 2007.

34. Sinha, S.; Watorek, W.; Karr, S.; Giles, J.; Bode, W.; Travis,
J.: Primary structure of human neutrophil elastase. Proc. Nat. Acad.
Sci. 84: 2228-2232, 1987.

35. Thusberg, J.; Vihinen, M.: Bioinformatic analysis of protein
structure-function relationships: case study of leukocyte elastase
(ELA2) missense mutations. Hum. Mutat. 27: 1230-1243, 2006.

36. Tkalcevic, J.; Novelli, M.; Phylactides, M.; Iredale, J. P.; Segal,
A. W.; Roes, J.: Impaired immunity and enhanced resistance to endotoxin
in the absence of neutrophil elastase and cathepsin G. Immunity 12:
201-210, 2000.

37. Weinrauch, Y.; Drujan, D.; Shapiro, S. D.; Weiss, J.; Zychlinsky,
Z.: Neutrophil elastase targets virulence factors of enterobacteria. Nature 417:
91-94, 2002.

38. Zhu, J.; Nathan, C.; Jin, W.; Sim, D.; Ashcroft, G. S.; Wahl,
S. M.; Lacomis, L.; Erdjument-Bromage, H.; Tempst, P.; Wright, C.
D.; Ding, A.: Conversion of proepithelin to epithelins: roles of
SLPI and elastase in host defense and wound repair. Cell 111: 867-878,
2002.

39. Zimmer, M.; Medcalf, R. L.; Fink, T. M.; Mattmann, C.; Lichter,
P.; Jenne, D. E.: Three human elastase-like genes coordinately expressed
in the myelomonocyte lineage are organized as a single genetic locus
on 19pter. Proc. Nat. Acad. Sci. 89: 8215-8219, 1992.

*FIELD* CN
Cassandra L. Kniffin - updated: 8/6/2013
Cassandra L. Kniffin - updated: 3/9/2010
Cassandra L. Kniffin - updated: 2/11/2009
Cassandra L. Kniffin - updated: 5/21/2008
Cassandra L. Kniffin - updated: 10/18/2007
Cassandra L. Kniffin - updated: 12/29/2006
Paul J. Converse - updated: 3/14/2005
Stylianos E. Antonarakis - updated: 11/19/2003
Victor A. McKusick - updated: 8/21/2003
Stylianos E. Antonarakis - updated: 1/16/2003
Victor A. McKusick - updated: 9/27/2002
Ada Hamosh - updated: 5/28/2002
Paul J. Converse - updated: 4/9/2002
Victor A. McKusick - updated: 12/13/2001
Ada Hamosh - updated: 8/15/2000
Victor A. McKusick - updated: 1/24/2000
Victor A. McKusick - updated: 11/30/1999
Victor A. McKusick - updated: 2/12/1997
Mark H. Paalman - edited: 8/15/1996
Alan F. Scott - updated: 8/14/1996

*FIELD* CD
Victor A. McKusick: 1/5/1988

*FIELD* ED
carol: 08/14/2013
carol: 8/13/2013
tpirozzi: 8/12/2013
ckniffin: 8/6/2013
alopez: 8/9/2012
wwang: 6/8/2011
wwang: 6/7/2011
carol: 8/13/2010
wwang: 3/15/2010
ckniffin: 3/9/2010
carol: 12/10/2009
wwang: 4/6/2009
ckniffin: 2/11/2009
mgross: 10/28/2008
wwang: 5/27/2008
ckniffin: 5/21/2008
wwang: 10/26/2007
ckniffin: 10/18/2007
alopez: 2/1/2007
wwang: 1/22/2007
ckniffin: 12/29/2006
mgross: 3/14/2005
terry: 11/4/2004
mgross: 11/19/2003
alopez: 9/2/2003
alopez: 8/22/2003
terry: 8/21/2003
tkritzer: 2/11/2003
mgross: 1/16/2003
carol: 10/1/2002
tkritzer: 9/27/2002
ckniffin: 5/29/2002
terry: 5/28/2002
alopez: 4/9/2002
carol: 4/9/2002
mcapotos: 12/17/2001
terry: 12/13/2001
terry: 11/14/2001
mcapotos: 1/22/2001
mcapotos: 1/12/2001
terry: 1/9/2001
alopez: 8/17/2000
terry: 8/15/2000
mcapotos: 1/28/2000
mcapotos: 1/24/2000
terry: 1/24/2000
alopez: 12/1/1999
terry: 11/30/1999
dkim: 9/8/1998
alopez: 5/26/1998
mark: 4/3/1997
terry: 2/12/1997
terry: 2/7/1997
mark: 8/16/1996
mark: 8/15/1996
terry: 8/15/1996
terry: 1/18/1995
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
root: 4/23/1988
marie: 3/25/1988

MIM 162800
*RECORD*
*FIELD* NO
162800
*FIELD* TI
#162800 CYCLIC NEUTROPENIA
;;CYCLIC HEMATOPOIESIS
*FIELD* TX
A number sign (#) is used with this entry because cyclic neutropenia is
read morecaused by mutation in the gene encoding neutrophil elastase (ELANE;
130130).

DESCRIPTION

Cyclic neutropenia is a rare disease characterized by regular 21-day
cyclic fluctuations in the number of blood neutrophils, monocytes,
eosinophils, lymphocytes, platelets, and reticulocytes. The recurrent
severe neutropenia causes patients to experience periodic symptoms of
fever, malaise, mucosal ulcers, and, rarely, life-threatening
infections. The disease occurs both as a congenital disorder and in an
acquired form, with essentially identical phenotypic presentations
(summary by Migliaccio et al., 1990).

CLINICAL FEATURES

Hahneman and Alt (1958) described a 29-year-old man who from an early
age had neutropenia that recurred every 21 days and was accompanied by
infection. Complete remission occurred at age 18 years. The man's
daughter was seen at the age of 2 years with similar periodic disease
recurring every 14 days. Torrioli-Riggio (1958) also reported cases.

Morley et al. (1967) described 20 cases in 5 families. Clinical
manifestations usually began in childhood and improved thereafter. The
commonest were fever, oral ulcerations, and skin infections. Neutropenia
occurred at intervals of 15 to 35 days. It was often accompanied by
monocytosis and sometimes by anemia, eosinophilia, or thrombocytopenia.
Male-to-male transmission occurred.

Peng et al. (2000) described a family in which all 4 male members, the
father and 3 sons, had hereditary cyclic neutropenia starting in
childhood with a cycle of approximately 21 days. Recurrent mucosa and
skin infections with fever had occurred frequently, but gradually
decreased in severity as they reached adulthood. Monocytosis was found
during the neutrophil nadirs in all 4 patients. Decreased sperm count
and motility were demonstrated in the 2 elder sons. Chromosome analysis
showed a pericentric inversion of the Y chromosome in all of the men.
The chromosome anomaly was inv(Y)(p11.2;q11.23).

Krance et al. (1982) reported a family in which 7 persons in 4 sibships
had cyclic neutropenia. One unaffected member of the family who was in
the process of bone marrow transplantation as treatment for acute
lymphoblastic leukemia in relapse, acquired cyclic neutropenia from her
histocompatible donor sib.

While cyclic hematopoiesis is commonly described as 'benign,' Palmer et
al. (1996) found that 4 affected children in 3 of 9 families died of
Clostridium or E. coli colitis, documenting the need for urgent
evaluation of abdominal pain. Misdiagnosis with other neutropenias was
common but can be avoided by serial blood counts in index cases.

CLINICAL MANAGEMENT

Hammond et al. (1989) found that granulocyte-colony stimulating factor
(GCSF or CSF3; 138970) is effective treatment.

Inoue et al. (1992) identified cyclic neutropenia in a 34-year-old
woman, her 3 sons, and her mother. Oscillations in the blood neutrophil
counts were rather regular, with a periodicity of 21 days. The GCSF
level in the mother's serum was persistently high, with the peak
occurring during the neutropenic phase. The patient's serum appeared to
contain an inhibitory factor. To control infections, Inoue et al. (1992)
administered recombinant human GCSF for 7 days around the early
neutropenic phase.

In a review of cyclic neutropenia, Palmer et al. (1996) found that
treatment with human CSF3 resulted in dramatic improvement of
neutropenia and morbidity.

INHERITANCE

Reports of male-to-male transmission of cyclic neutropenia in several
families indicate autosomal dominant inheritance (Palmer et al., 1996).

On the basis of studies in 9 families, Palmer et al. (1996) found no
clinical evidence of decreased penetrance or heterogeneity. However, the
pattern of expression suggested anticipation: no families appeared to
display milder phenotypes in successive generations, and the most severe
cases occurred in children in the youngest generations. The spectrum of
severity included death from necrotizing enterocolitis in 4 subjects
ranging in age from 6 to 17 years. In 3 of the 9 pedigrees, the proband
appeared to represent a new mutation.

MAPPING

Horwitz et al. (1999) used a genomewide screen and positional cloning to
map the cyclic neutropenia locus to chromosome 19p13.3.

MOLECULAR GENETICS

Horwitz et al. (1999) identified 7 different single-basepair
substitutions in the ELANE gene (e.g., 130130.0001-130130.0005),
encoding neutrophil elastase (ELA2). In each of 13 families studied, a
mutation in ELANE was found on a unique haplotype; the haplotype
carrying a new mutation in a sporadic case was also unique. Neutrophil
elastase is a target for protease inhibition by alpha-1-antitrypsin
(AAT; 107400), and its unopposed release destroys tissue at sites of
inflammation. Horwitz et al. (1999) hypothesized that a perturbed
interaction between neutrophil elastase and serpins or other substrates
may regulate mechanisms governing the clock-like timing of
hematopoiesis.

ANIMAL MODEL

Cyclic neutropenia in the collie dog is accompanied by gray fur, leads
to early death from pyogenic infections, and is an autosomal recessive
(Dale et al., 1970). Weiden et al. (1974) showed by transplantation of
gray collie bone marrow into normal dogs which had been irradiated that
the basic defect is in the stem cell. There are sufficient similarities
between the canine and human diseases (Guerry et al., 1972) to suggest
that the same may be true in man. Krance et al. (1982) confirmed this
when a patient, in the process of bone marrow transplantation as
treatment for acute lymphoblastic leukemia in relapse, acquired cyclic
neutropenia from her histocompatible donor sib. In dogs, the disease can
be transferred and cured through bone marrow transplantation (Jones et
al., 1975). The disease in collie dogs differs from the human disease in
the length of the cycle (12 rather than 21 days).

The autosomal recessive disorder canine cyclic hematopoiesis (Lothrop et
al., 1987), also known as gray collie syndrome, is not caused by
mutations in neutrophil elastase. Benson et al. (2003) showed that
homozygous mutation of the gene encoding the dog adaptor protein
complex-3 (AP3) beta-subunit (AP3B1; 603401), directing trans-Golgi
export of transmembrane cargo proteins to lysosomes, causes canine
cyclic hematopoiesis. C-terminal processing of neutrophil elastase
exposes an AP3 interaction signal responsible for redirecting neutrophil
elastase trafficking from membranes to granules. Disruption of either
neutrophil elastase or AP3 perturbs the intracellular trafficking of
neutrophil elastase.

*FIELD* SA
Dale et al. (1972); Dale et al. (1972); Meuret and Fliedner (1970);
Page and Good (1957); Wright et al. (1981)
*FIELD* RF
1. Benson, K. F.; Li, F.-Q.; Person, R. E.; Albani, D.; Duan, Z.;
Wechsler, J.; Meade-White, K.; Williams, K.; Acland, G. M.; Niemeyer,
G.; Lothrop, C. D.; Horwitz, M.: Mutations associated with neutropenia
in dogs and humans disrupt intracellular transport of neutrophil elastase. Nature
Genet. 35: 90-96, 2003.

2. Dale, D. C.; Alling, D. W.; Wolff, S. M.: Cyclic hematopoiesis:
the mechanism of cyclic neutropenia in grey collie dogs. J. Clin.
Invest. 51: 2197-2204, 1972.

3. Dale, D. C.; Kimball, H. R.; Wolff, S. M.: Studies of cyclic neutropenia
in gray collie dogs. (Abstract) Clin. Res. 18: 402 only, 1970.

4. Dale, D. C.; Ward, S. B.; Kimball, H. R.; Wolff, S. M.: Studies
of neutrophil production and turnover in grey collie dogs with cyclic
neutropenia. J. Clin. Invest. 51: 2190-2196, 1972.

5. Guerry, D. D.; Dale, D. C.; Omine, M.; Perry, S.; Wolff, S. M.
: Studies on the mechanism of human cyclic neutropenia. (Abstract) Brit.
J. Haemat. 40: 951 only, 1972.

6. Hahneman, B. M.; Alt, H. L.: Cyclic neutropenia in a father and
daughter. JAMA 168: 270-272, 1958.

7. Hammond, W. P., IV; Price, T. H.; Souza, L. M.; Dale, D. C.: Treatment
of cyclic neutropenia with granulocyte colony-stimulating factor. New
Eng. J. Med. 320: 1306-1311, 1989.

8. Horwitz, M.; Benson, K. F.; Person, R. E.; Aprikyan, A. G.; Dale,
D. C.: Mutations in ELA2, encoding neutrophil elastase, define a
21-day biological clock in cyclic haematopoiesis. Nature Genet. 23:
433-436, 1999.

9. Inoue, T.; Tani, K.; Tajiri, M.; Ishida, Y.; Seguchi, M.; Tanaka,
H.; Asano, S.; Kaneko, T.; Matsumoto, N.: A case report of familial
cyclic neutropenia. Tohoku J. Exp. Med. 167: 107-113, 1992.

10. Jones, J. B.; Yang, T. J.; Dale, J. B.; Lange, R. D.: Canine
cyclic haematopoiesis: marrow transplantation between littermates. Brit.
J. Haemat. 30: 215-223, 1975.

11. Krance, R. A.; Spruce, W. E.; Forman, S. J.; Rosen, R. B.; Hecht,
T.; Hammond, W. P.; Blume, K. G.: Human cyclic neutropenia transferred
by allogeneic bone marrow grafting. Blood 60: 1263-1266, 1982.

12. Lothrop, C. D., Jr.; Coulson, P. A., Jr.; Nolan, H. L.; Cole,
B.; Jones, J. B.; Sanders, W. L.: Cyclic hormonogenesis in gray collie
dogs: interactions of hematopoietic and endocrine systems. Endocrinology 120:
1027-1032, 1987.

13. Meuret, G.; Fliedner, T. M.: Zellkinetik der Granulopoiese und
des Neutrophilensystems bei einem Fall von zyklischer Neutropenie. Acta
Haemat. 43: 48-63, 1970.

14. Migliaccio, A. R.; Migliaccio, G.; Dale, D. C.; Hammond, W. P.
: Hematopoietic progenitors in cyclic neutropenia: effect of granulocyte
colony-stimulating factor in vivo. Blood 75: 1951-1959, 1990.

15. Morley, A. A.; Carew, J. P.; Baikie, A. G.: Familial cyclical
neutropenia. Brit. J. Haemat. 13: 719-738, 1967.

16. Page, A. R.; Good, R. A.: Studies on cyclic neutropenia. A clinical
and experimental investigation. Am. J. Dis. Child. 94: 623-661,
1957.

17. Palmer, S. E.; Stephens, K.; Dale, D. C.: Genetics, phenotype,
and natural history of autosomal dominant cyclic hematopoiesis. Am.
J. Med. Genet. 66: 413-422, 1996.

18. Peng, H.-W.; Chou, C.-F.; Liang, D.-C.: Hereditary cyclic neutropenia
in the male members of a Chinese family with inverted Y chromosome. Brit.
J. Haemat. 110: 438-440, 2000.

19. Torrioli-Riggio, G.: Considerazioni su una famiglia di granulopenici. Acta
Genet. Med. Gemellol. 7: 237-248, 1958.

20. Weiden, P. L.; Robinett, B.; Graham, T. C.; Adamson, J.; Storb,
R.: Canine cyclic neutropenia. A stem cell defect. J. Clin. Invest. 53:
950-953, 1974.

21. Wright, D. G.; Dale, D. C.; Fauci, A. S.; Wolff, S. M.: Human
cyclic neutropenia: clinical review and long-term follow-up of patients. Medicine 60:
1-13, 1981.

*FIELD* CS

Heme:
Cyclic neutropenia

Mouth:
Mucosal ulcers

Misc:
15 to 35-day cyclic fluctuations in formed elements of blood;
Recurring fever and malaise;
Occasional life-threatening infections

Inheritance:
Autosomal dominant

*FIELD* CN
Victor A. McKusick - updated: 11/29/2000
Victor A. McKusick - updated: 1/7/2000
Victor A. McKusick - updated: 11/30/1999

*FIELD* CD
Victor A. McKusick: 6/2/1986

*FIELD* ED
wwang: 06/08/2011
terry: 12/11/2009
carol: 12/10/2009
terry: 6/3/2009
mcapotos: 12/18/2000
terry: 11/29/2000
carol: 1/28/2000
terry: 1/7/2000
alopez: 12/1/1999
terry: 11/30/1999
jenny: 12/3/1996
terry: 11/22/1996
mimadm: 12/2/1994
carol: 12/1/1992
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/27/1989
carol: 6/6/1989

MIM 202700
*RECORD*
*FIELD* NO
202700
*FIELD* TI
#202700 NEUTROPENIA, SEVERE CONGENITAL, 1, AUTOSOMAL DOMINANT; SCN1
*FIELD* TX
A number sign (#) is used with this entry because severe congenital
read moreneutropenia-1 (SCN1) is caused by heterozygous mutation in the
neutrophil elastase gene (ELANE; 130130) on chromosome 19p13.

See also cyclic neutropenia (162800), which is an allelic disorder.

DESCRIPTION

Severe congenital neutropenia is a heterogeneous disorder of
hematopoiesis characterized by a maturation arrest of granulopoiesis at
the level of promyelocytes with peripheral blood absolute neutrophil
counts below 0.5 x 10(9)/l and early onset of severe bacterial
infections (Skokowa et al., 2007). About 60% of affected individuals of
European and Middle Eastern ancestry have dominant ELANE mutations,
resulting in a form of severe congenital neutropenia, which is
designated here as SCN1.

- Genetic Heterogeneity of Severe Congenital Neutropenia

Severe congenital neutropenia is a genetically heterogeneous disorder
showing autosomal dominant, autosomal recessive, and X-linked
inheritance. Autosomal dominant SCN2 (613107) is caused by mutation in
the protooncogene GFI1 (600871) on chromosome 1p22. Autosomal recessive
SCN3 (610738) is caused by mutation in the HAX1 gene (605998) on 1q21.3;
autosomal recessive SCN4 (612541) is caused by mutation in the G6PC3
gene (611045) on 17q21; and autosomal recessive SCN5 (615285) is caused
by mutation in the VPS45 gene (610035) on chromosome 1q. X-linked SCN
(SCNX; 300299) is caused by mutation in the WAS gene (300392) on Xp11.

See also adult chronic idiopathic nonimmune neutropenia (607847) and
chronic benign familial neutropenia (162700).

- Susceptibility to Myelodysplastic Syndrome/Acute Myeloid
Leukemia

SCN patients with acquired mutations in the granulocyte
colony-stimulating factor receptor (CSF3R; 138971) in hematopoietic
cells define a group with high risk for progression to myelodysplastic
syndrome and/or acute myeloid leukemia.

CLINICAL FEATURES

Gilman et al. (1970) described prolonged survival and death from acute
monocytic leukemia at age 14 years and 10 months. About three-fourths of
patients die before age 3 years. Fungal and viral infections had not
been a problem.

Freedman et al. (2000) stated that the Severe Chronic Neutropenia
International Registry (SCNIR) in Seattle had data on 696 neutropenic
patients, including 352 patients with congenital neutropenia, treated
with GCSF from 1987 to 2000. The 352 congenital patients were observed
for a mean of 6 years (range, 0.1 to 11 years) while being treated. Of
these patients, 31 developed myelodysplastic syndrome (MDS) and/or acute
myeloid leukemia (AML), for a crude rate of malignant transformation of
nearly 9%. None of the 344 patients with idiopathic or cyclic
neutropenia developed MDS/AML. Transformation was associated with
acquired marrow cytogenetic clonal changes: 18 patients developed a
partial or complete loss of chromosome 7, and 9 patients manifested
abnormalities of chromosome 21 (usually trisomy 21; 190685). For each
yearly treatment interval, the annual rate of MDS/AML development was
less than 2%. Freedman et al. (2000) concluded that although the data
did not support a cause-and-effect relationship between development of
MDS/AML and GCSF therapy or other patient demographics, they could not
exclude a direct contribution of GCSF in the pathogenesis of MDS/AML.
Improved survival of congenital neutropenia patients receiving GCSF
therapy may allow time for expression of the leukemic predisposition
that characterizes the natural history of these disorders.

In a review of immunodeficiencies caused by defects in phagocytes,
Lekstrom-Himes and Gallin (2000) discussed severe congenital
neutropenia.

CLINICAL MANAGEMENT

Bonilla et al. (1989) administered recombinant human granulocyte
colony-stimulating factor (GCSF; 138970) to 5 patients. All 5 patients
showed a response and had sustained neutrophil counts of 1,000 cells per
microliter or more for 9 to 13 months while receiving subcutaneous
maintenance therapy. Preexisting chronic infections resolved and the
number of new infectious episodes decreased. Bonilla et al. (1989)
raised the possibility that the receptors are defective and do not
respond to GCSF unless it is administered in pharmacologic doses. This
possibility appeared to be confirmed by the findings of Dong et al.
(1994) of somatic mutation in the GCSFR gene (138971).

In SCN, absolute neutrophil counts are usually less than 200 cells per
cubic millimeter, with a remainder of the blood counts relatively normal
(Dale et al., 2000). Treatment with GCSF leads to an increase in
neutrophil counts to more than 1,000 cells per cubic millimeter in 90%
of patients and results in significant improvements in survival and
quality of life (Dale et al., 1993; Bonilla et al., 1994).

Yakisan et al. (1997) noted that although r-metHuGCSF treatment of
children with severe congenital neutropenia has substantially improved
the patients' quality of life and life expectancy, bone pain and unusual
fractures have been reported in treated patients. The authors reviewed
roentgenograms in 29 of 30 patients to evaluate bone loss before and
during treatment and assessed bone mineral status in 17 of the 30
patients. Their data indicated a high incidence of bone mineral loss in
children with severe congenital neutropenia. The investigators concluded
that it is more likely that the bone loss was caused by the
pathophysiologic features of the underlying disease; however, they could
not rule out the possibility that r-metHuGCSF accelerates bone mineral
loss.

BIOCHEMICAL FEATURES

Myeloid precursor cells from patients with severe congenital neutropenia
(SCN) require pharmacologic dosages of recombinant human granulocyte
colony-stimulating factor (GCSF) to differentiate normal neutrophils.
Because JAK2 (147796), a nonreceptor tyrosine kinase, is involved in the
signaling pathway of GCSF, Rauprich et al. (1995) studied the expression
and activity of JAK2 in neutrophils from SCN patients during therapy.
The immunoprecipitated JAK2 protein showed increased tyrosine
phosphorylation in neutrophils from SCN patients as compared with that
in neutrophils from healthy controls. Rauprich et al. (1995) pointed out
that only a few patients, who subsequently develop acute myeloid
leukemia, have a point mutation in the cytoplasmic region of the GCSF
receptor, resulting in a truncation from the C terminus of the receptor
and an inability of the receptor to transduce the signal on GCSF
stimulation. Thus they suspected that various defects are responsible
for SCN. That pharmacologic doses of GCSF are required to overcome the
neutropenia suggested a defect of other specific molecules in the GCSF
signal transduction pathway. The primary defect does not appear to be in
JAK2; it may be that the phosphotyrosines on the receptor create binding
sites for STAT proteins (signal transducers and activators of
transcription; see 600555).

Skokowa et al. (2006) found significantly decreased or absent LEF1
(153245) expression in arrested promyelocytes from patients with
congenital neutropenia. LEF1 decrease resulted in defective expression
of downstream target genes, including CCND1 (168461), MYC (190080), and
BIRC5 (603352). Promyelocytes from healthy individuals showed highest
LEF1 expression. Reconstitution of LEF1 in early hematopoietic
progenitors from 2 individuals with congenital neutropenia resulted in
the differentiation of these progenitors into mature granulocytes. LEF1
directly bound to and regulated the transcription factor CEBPA (116897).
The findings indicated that LEF1 plays a role in granulopoiesis.

MOLECULAR GENETICS

After demonstrating mutations in the ELA2 gene (ELANE; 130130) in
patients with cyclic neutropenia (162800), Dale et al. (2000)
hypothesized that congenital neutropenia is also due to mutation in this
gene. They performed mutation analysis by sequencing PCR-amplified
genomic DNA for each of the 5 exons of the ELA2 gene and 20 bases of the
flanking regions. In 22 of 25 patients with congenital neutropenia, 18
different heterozygous mutations were found. All 4 patients with cyclic
neutropenia, but none of the 3 patients with Shwachman-Diamond syndrome
(260400), had mutations of ELA2. 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. In the congenital neutropenia patients, 5
different mutations were found in families with 2 or more affected
members. Three instances of father-daughter pairs, 1 mother-son pair,
and 1 mother with 2 affected sons by different fathers suggested
autosomal dominant inheritance.

Ishikawa et al. (2008) identified heterozygous mutations in the ELA2
gene in 11 (61%) of 18 Japanese patients with severe congenital
neutropenia. Five (28%) patients had SCN3 (610738) due to mutation in
the HAX1 gene.

Among 109 probands with SCN, Smith et al. (2008) found that 33 (30%) had
24 different ELA2 mutations, 2 (2%) had WAS (300392) mutations, and 4
(4%) had HAX1 mutations.

- Progression to Myelodysplastic Syndrome and Acute Myeloid
Leukemia

Dong et al. (1994) used RT-PCR to amplify cDNA for granulocyte
colony-stimulating factor receptor (CSF3R; 138971) in patients with
severe congenital neutropenia, referred to as Kostmann syndrome, and
screened for mutations by single-strand conformation polymorphism (SSCP)
analysis. In 1 patient, they identified a somatic point mutation that
resulted in the cytoplasmic truncation of the GCSF receptor protein. The
mutation was present predominantly in the granulocytic lineage. Further
functional characterization demonstrated that the truncated receptor was
unable to transduce a maturation signal. Dong et al. (1994) suggested
that the mutant receptor chain may act in a dominant-negative manner to
block granulocyte maturation. Dong et al. (1994) commented that
congenital neutropenia may be a heterogeneous group of disorders with
different basic etiologies. They also commented that cases of this
disorder that terminated in acute leukemia had been reported (Gilman et
al., 1970; Lui et al., 1978; Rosen and Kang, 1979) and that some
patients with the disorder developed leukemia or myelodysplastic
syndrome following treatment with GCSF.

Dong et al. (1995) described mutations in the GCSFR gene in
hematopoietic cells from 2 patients with acute myeloid leukemia and
histories of severe congenital neutropenia. Like the mutation in the
patient reported by Dong et al. (1994), the mutations truncated the
C-terminal cytoplasmic region of the GCSF receptor. The mutation in one
of the patients was already present in the neutropenic phase that
preceded the development of acute myeloid leukemia.

SCN patients are at increased risk of developing acute myelogenous
leukemia (AML) or myelodysplasia (MDS). In the series of Welte and Dale
(1996), 10% of the patients with SCN followed for 5 or more years
developed AML or MDS. Patients with GCSFR mutations appeared to be at
the greatest risk; Welte and Touw (1997) found that 8 of 16 patients
with SCN and GCSFR mutations developed AML or MDS. Conversely, no
patients with SCN and without a mutation of the CSF3R gene had been
reported who developed AML or MDS. This striking association led to
speculation that CSF3R mutations may contribute to leukemogenesis in
these patients.

Tidow et al. (1997) concluded that GCSFR mutations are acquired
abnormalities detected in the process of evolution to acute myelocytic
leukemia (AML). Dale et al. (2000) stated that prevalence data suggested
that a minority of patients manifest this mutation, and it seemed much
more likely that mutations of the ELA2 gene lead to compromised myeloid
differentiation and create the risk for development of AML.

Among 82 patients with SCN, Rosenberg et al. (2007) found no difference
in the risk of MDS/AML in patients with mutant ELA2 (63%) compared to
those with wildtype ELA2 (37%). The cumulative incidences at 15 years
were 36% and 25%, respectively. Two of 4 patients with the G185R
mutation (130130.0011) developed MDS/AML by 15 years follow-up, whereas
none of 7 patients with the P110L (130130.0006) mutation or 5 patients
with the S97L (130130.0008) mutation had developed MDS/AML.

ANIMAL MODEL

To test the hypothesis that CSF3R mutations may contribute to
leukemogenesis in SCN patients, McLemore et al. (1998) generated mice
carrying a targeted, 'knock-in' mutation of their Csf3r gene that
reproduced the mutation found in a patient with SCN and AML. A point
mutation (C to T at nucleotide 2403) was introduced into exon 17 of the
Csf3r gene, using homologous recombination in embryonic stem cells. The
mutation generated a premature stop codon that led to truncation of the
C-terminal 96 amino acids and reproduced the mutation found in a patient
with SCN by Dong et al. (1995). The mutant allele was expressed in a
myeloid-specific fashion at levels comparable to the wildtype allele.
Mice heterozygous or homozygous for this mutation had normal levels of
circulating neutrophils and no evidence for a block in myeloid
maturation, indicating that resting granulopoiesis was normal. However,
in response to GCSF treatment, these mice demonstrated a significantly
greater increase in the level of circulating neutrophils. This effect
appeared to be due to increased neutrophil production as the absolute
number of GCSF-responsive progenitors in the bone marrow and their
proliferation in response to GCSF was increased. Furthermore, the in
vitro survival and GCSF-dependent suppression of apoptosis of mutant
neutrophils were normal. Despite this evidence for a hyperproliferative
response to GCSF, no cases of AML were detected. These data demonstrated
that the GCSFR mutation found in patients with SCN is not sufficient to
induce either an SCN phenotype or AML in mice. McLemore et al. (1998)
suggested that the results represent strong evidence that these
mutations are not responsible for the impaired granulopoiesis present in
patients with SCN. In fact, the results of the study suggested that
expression of the mutant GCSFR on myeloid progenitors may render them
hyperresponsive to GCSF. Whether this altered GCSF-responsiveness
contributes to the development of AML and/or MDS in patients with SCN
will require further study.

At about the same time as the report by McLemore et al. (1998), Hermans
et al. (1998) reported that mice either heterozygous or homozygous for a
mutation in the Csf3r gene had no normal resting granulopoiesis and had
reduced numbers of neutrophils in their blood, indicating a block in
maturation due to the truncation of the GCSF receptor. Hermans (1998)
suggested that the increased expression of truncated GCSF receptor in
the model of McLemore et al. (1998) may have compensated for the
mutation and explained the absence of neutropenia.

HISTORY

Hedenberg (1959) found that addition of sulfur-containing amino acids to
tissue cultures led to maturation of white cells. L'Esperance et al.
(1973) showed that the disease could be reproduced in tissue culture.
Barak et al. (1971) also cultured marrow cells from a patient with this
disease.

L'Esperance et al. (1975) proposed heterogeneity of this disorder
because in soft agar cultures of bone marrow one patient showed 'loose'
colonies developing only to promyelocytes, whereas a second produced
normal neutrophil colonies. Maturation arrest occurs at the promyelocyte
stage.

Hansen et al. (1977) found association with HLA-B12 (see 142830) and
postulated linkage disequilibrium. A gene controlling neutrophil
differentiation was presumably closely linked to the HLA complex. Hansen
et al. (1977) suggested that the relationship may reflect a basic
function of the histocompatibility system, namely, coding for
cell-surface determinants fundamental to cell-cell recognition and to
control of cellular differentiation.

*FIELD* SA
Andrews et al. (1960); Bjure et al. (1962)
*FIELD* RF
1. Andrews, J. P.; McClellan, J. T.; Scott, C. H.: Lethal congenital
neutropenia with eosinophilia occurring in two siblings. Am. J. Med. 29:
358-362, 1960.

2. Barak, Y.; Paran, M.; Levin, S.; Sachs, L.: In vitro induction
of myeloid proliferation and maturation in infantile genetic agranulocytosis. Blood 38:
74-80, 1971.

3. Bjure, J.; Nilsson, L. R.; Plum, C. M.: Familial neutropenia possibly
caused by deficiency of a plasma factor. Acta Paediat. 51: 497-508,
1962.

4. Bonilla, M. A.; Dale, D.; Zeidler, C.; Last, L.; Reiter, A.; Ruggeiro,
M.; Davis, M.; Koci, B.; Hammond, W.; Gillio, A.; Welte, K.: Long-term
safety of treatment with recombinant human granulocyte colony-stimulating
factor (r-metHuG-CSF) in patients with severe congenital neutropenias. Brit.
J. Haemat. 88: 723-730, 1994.

5. Bonilla, M. A.; Gillio, A. P.; Ruggeiro, M.; Kernan, N. A.; Brochstein,
J. A.; Abboud, M.; Fumagalli, L.; Vincent, M.; Gabrilove, J. L.; Welte,
K.; Souza, L. M.; O'Reilly, R. J.: Effects of recombinant human granulocyte
colony-stimulating factor on neutropenia in patients with congenital
agranulocytosis. New Eng. J. Med. 320: 1574-1580, 1989.

6. Dale, D. C.; Bonilla, M. A.; Davis, M. W.; Nakanishi, A. M.; Hammond,
W. P.; Kurtzberg, J.; Wang, W.; Jakubowski, A.; Winton, E.; Lalezari,
P.; Robinson, W.; Glaspy, J. A.; Emerson, S.; Gabrilove, J.; Vincent,
M.; Boxer, L. A.: A randomized controlled phase III trial of recombinant
human granulocyte colony-stimulating factor (filgrastim) for treatment
of severe chronic neutropenia. Blood 81: 2496-2502, 1993.

7. Dale, D. C.; Person, R. E.; Bolyard, A. A.; Aprikyan, A. G.; Bos,
C.; Bonilla, M. A.; Boxer, L. A.; Kannourakis, G.; Zeidler, C.; Welte,
K.; Benson, K. F.; Horwitz, M.: Mutations in the gene encoding neutrophil
elastase in congenital and cyclic neutropenia. Blood 96: 2317-2322,
2000.

8. Dong, F.; Brynes, R. K.; Tidow, N.; Welte, K.; Lowenberg, B.; Touw,
I. P.: Mutations in the gene for the granulocyte colony-stimulating-factor
receptor in patients with acute myeloid leukemia preceded by severe
congenital neutropenia. New Eng. J. Med. 333: 487-493, 1995.

9. Dong, F.; Hoefsloot, L. H.; Schelen, A. M.; Broeders, L. C. A.
M.; Meijer, Y.; Veerman, A. J. P.; Touw, I. P.; Lowenberg, B.: Identification
of a nonsense mutation in the granulocyte-colony-stimulating factor
receptor in severe congenital neutropenia. Proc. Nat. Acad. Sci. 91:
4480-4484, 1994.

10. Freedman, M. H.; Bonilla, M. A.; Fier, C.; Bolyard, A. A.; Scarlata,
D.; Boxer, L. A.; Brown, S.; Cham, B.; Kannourakis, G.; Kinsey, S.
E.; Mori, P. G.; Cottle, T.; Welte, K.; Dale, D. C.: Myelodysplasia
syndrome and acute myeloid leukemia in patients with congenital neutropenia
receiving G-CSF therapy. Blood 96: 429-436, 2000.

11. Gilman, P. A.; Jackson, D. P.; Guild, H. G.: Congenital agranulocytosis:
prolonged survival and terminal acute leukemia. Blood 36: 576-585,
1970.

12. Hansen, J. A.; Dupont, B.; L'Esperance, P. L.; Good, R. A.: Congenital
neutropenia: abnormal neutrophil differentiation associated with HLA. Immunogenetics 4:
327-332, 1977.

13. Hedenberg, F.: Infantile agranulocytosis of probably congenital
origin. Acta Paediat. 48: 77-84, 1959.

14. Hermans, M.: Personal Communication. Rotterdam, The Netherlands
11/25/1998.

15. Hermans, M. H. A.; Ward, A. C.; Antonissen, C.; Karis, A.; Lowenberg,
B.; Touw, I. P.: Perturbed granulopoiesis in mice with a targeted
mutation in the granulocyte colony-stimulating factor receptor gene
associated with severe chronic neutropenia. Blood 92: 32-39, 1998.

16. Ishikawa, N.; Okada, S.; Miki, M.; Shirao, K.; Kihara, H.; Tsumura,
M.; Nakamura, K.; Kawaguchi, H.; Ohtsubo, M.; Yasunaga, S.; Matsubara,
K.; Sako, M.; Hara, J.; Shiohara, M.; Kojima, S.; Sato, T.; Takihara,
Y.; Kobayashi, M.: Neurodevelopmental abnormalities associated with
severe congenital neutropenia due to the R86X mutation in the HAX1
gene. J. Med. Genet. 45: 802-807, 2008.

17. L'Esperance, P. L.; Brunning, R.; Deinard, A. S.; Park, B. H.;
Biggar, W. D.; Good, R. A.: Congenital neutropenia: impaired maturation
with diminished stem-cell input.In: Bergsma, D.: Immunodeficiency
in Man and Animals. New York: National Foundation-March of Dimes
(pub.) 1975. Pp. 59-65.

18. L'Esperance, P. L.; Brunning, R.; Good, R. A.: Congenital neutropenia:
in vitro growth of colonies mimicking the disease. Proc. Nat. Acad.
Sci. 70: 669-672, 1973.

19. Lekstrom-Himes, J. A.; Gallin, J. I.: Immunodeficiency diseases
caused by defects in phagocytes. New Eng. J. Med. 343: 1703-1714,
2000.

20. Lui, V.; Ragab, A. H.; Findley, H.; Frauen, B.: Infantile genetic
agranulocytosis and acute lymphocytic leukemia in two sibs. J. Pediat. 92:
1028, 1978.

21. McLemore, M. L.; Poursine-Laurent, J.; Link, D. C.: Increased
granulocyte colony-stimulating factor responsiveness but normal resting
granulopoiesis in mice carrying a targeted granulocyte colony-stimulating
factor receptor mutation derived from a patient with severe congenital
neutropenia. J. Clin. Invest. 102: 483-492, 1998.

22. Rauprich, P.; Kasper, B.; Tidow, N.; Welte, K.: The protein tyrosine
kinase JAK2 is activated in neutrophils from patients with severe
congenital neutropenia. Blood 86: 4500-4505, 1995.

23. Rosen, R. B.; Kang, S.-J.: Congenital agranulocytosis terminating
in acute myelomonocytic leukemia. J. Pediat. 94: 406-408, 1979.

24. Rosenberg, P. S.; Alter, B. P.; Link, D. C.; Stein, S.; Rodger,
E.; Bolyard, A. A.; Aprikyan, A. A.; Bonilla, M. A.; Dror, Y.; Kannourakis,
G.; Newburger, P. E.; Boxer, L. A.; Dale, D. C.: Neutrophil elastase
mutations and risk of leukaemia in severe congenital neutropenia. Brit.
J. Haemat. 140: 210-213, 2007.

25. Skokowa, J.; Cario, G.; Uenalan, M.; Schambach, A.; Germeshausen,
M.; Battmer, K.; Zeidler, C.; Lehmann, U.; Eder, M.; Baum, C.; Grosschedl,
R.; Stanulla, M.; Scherr, M.; Welte, K.: LEF-1 is crucial for neutrophil
granulocytopoiesis and its expression is severely reduced in congenital
neutropenia. Nature Med. 12: 1191-1197, 2006. Note: Erratum: Nature
Med. 12: 1329 only, 2006.

26. Skokowa, J.; Germeschausen, M.; Zeidler, C.; Welte, K.: Severe
congenital neutropenia: inheritance and pathophysiology. Curr. Opin.
Hemat. 14: 22-28, 2007. Note: Erratum: Curr. Opin. Hemat. 14: 181
only, 2007.

27. Smith, B. N.; Ancliff, P. J.; Pizzey, A.; Khwaja, A.; Linch, D.
C.; Gale, R. E.: Homozygous HAX1 mutations in severe congenital neutropenia
patients with sporadic disease: a novel mutation in two unrelated
British kindreds. Brit. J. Haemat. 144: 762-770, 2008.

28. Tidow, N.; Pilz, C.; Teichmann, B.; Muller-Brechlin, A.; Germeshausen,
M.; Kasper, B.; Rauprich, P.; Sykora, K.-W.; Welte, K.: Clinical
relevance of point mutations in the cytoplasmic domain of the granulocyte
colony-stimulating factor receptor gene in patients with severe congenital
neutropenia. Blood 89: 2369-2375, 1997.

29. Welte, K.; Dale, D.: Pathophysiology and treatment of severe
chronic neutropenia. Ann. Hemat. 72: 158-165, 1996.

30. Welte, K.; Touw, I. P.: G-CSF receptor mutations in patients
with severe chronic neutropenia: a step in leukemogenesis? (Abstract) Blood 90:
1921A only, 1997.

31. Yakisan, E.; Schirg, E.; Zeidler, C.; Bishop, N. J.; Reiter, A.;
Hirt, A.; Riehm, H.; Welte, K.: High incidence of significant bone
loss in patients with severe congenital neutropenia (Kostmann's syndrome). J.
Pediat. 131: 592-597, 1997.

*FIELD* CS

Growth:
Lethal before age 3 years

Heme:
Agranulocytosis;
Promyelocytic maturation arrest;
Monocytosis;
Eosinophilia;
Thrombocytosis

Oncology:
Acute monocytic leukemia

Lab:
Hypergammaglobulinemia

Inheritance:
Autosomal recessive

*FIELD* CN
Cassandra L. Kniffin - updated: 6/18/2009
Cassandra L. Kniffin - updated: 2/11/2009
Cassandra L. Kniffin - updated: 5/21/2008
Anne M. Stumpf - reorganized: 2/1/2007
Victor A. McKusick - updated: 1/30/2007
Cassandra L. Kniffin - updated: 10/17/2006
Victor A. McKusick - updated: 9/17/2004
Victor A. McKusick - updated: 6/3/2003
Victor A. McKusick - updated: 1/9/2001
Victor A. McKusick - updated: 1/4/2001
Ada Hamosh - updated: 11/6/2000
Victor A. McKusick - updated: 9/28/2000
Victor A. McKusick - updated: 12/4/1998
Victor A. McKusick - updated: 10/1/1998
Moyra Smith - updated: 12/18/1997

*FIELD* CD
Victor A. McKusick: 6/2/1986

*FIELD* ED
ckniffin: 07/16/2013
terry: 3/14/2013
wwang: 6/8/2011
ckniffin: 6/7/2011
wwang: 6/7/2011
mgross: 10/29/2009
wwang: 7/22/2009
ckniffin: 6/18/2009
wwang: 4/6/2009
ckniffin: 2/11/2009
wwang: 1/26/2009
ckniffin: 1/21/2009
wwang: 5/27/2008
ckniffin: 5/21/2008
wwang: 2/27/2007
wwang: 2/26/2007
alopez: 2/1/2007
terry: 1/30/2007
wwang: 12/11/2006
wwang: 10/25/2006
ckniffin: 10/17/2006
alopez: 9/17/2004
terry: 9/17/2004
terry: 6/2/2004
alopez: 7/28/2003
alopez: 6/3/2003
terry: 6/3/2003
carol: 3/20/2002
mcapotos: 12/17/2001
terry: 12/13/2001
mcapotos: 1/22/2001
mcapotos: 1/12/2001
terry: 1/9/2001
terry: 1/4/2001
carol: 11/6/2000
mcapotos: 10/17/2000
mcapotos: 10/16/2000
terry: 9/28/2000
carol: 12/8/1998
terry: 12/4/1998
terry: 11/18/1998
carol: 10/6/1998
terry: 10/1/1998
dkim: 9/11/1998
mark: 1/30/1998
alopez: 6/10/1997
terry: 5/10/1997
mark: 3/11/1996
terry: 3/4/1996
mark: 2/13/1996
mimadm: 11/12/1995
mark: 10/9/1995
carol: 1/24/1995
davew: 8/15/1994
jason: 6/13/1994
warfield: 3/7/1994