RBCC Red Blood Cell Collection

SERPING1 (C1IN, C1NH) [Confidence: low (only semi-automatic identification from reviews)]
Plasma protease C1 inhibitor; C1 Inh; C1Inh (C1 esterase inhibitor; C1-inhibiting factor; Serpin G1; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P05155
ID IC1_HUMAN Reviewed; 500 AA.
AC P05155; A6NMU0; A8KAI9; B2R6L5; Q16304; Q547W3; Q59EI5; Q7Z455;
read moreAC Q96FE0; Q9UC49; Q9UCF9;
DT 13-AUG-1987, integrated into UniProtKB/Swiss-Prot.
DT 01-FEB-1991, sequence version 2.
DT 22-JAN-2014, entry version 174.
DE RecName: Full=Plasma protease C1 inhibitor;
DE Short=C1 Inh;
DE Short=C1Inh;
DE AltName: Full=C1 esterase inhibitor;
DE AltName: Full=C1-inhibiting factor;
DE AltName: Full=Serpin G1;
DE Flags: Precursor;
GN Name=SERPING1; Synonyms=C1IN, C1NH;
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 [MRNA].
RX PubMed=3488058; DOI=10.1016/0006-291X(86)91123-X;
RA Que B.G., Petra P.H.;
RT "Isolation and analysis of a cDNA coding for human C1 inhibitor.";
RL Biochem. Biophys. Res. Commun. 137:620-625(1986).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], PARTIAL PROTEIN SEQUENCE, AND
RP GLYCOSYLATION AT ASN-25; THR-48; SER-64; ASN-69; THR-71; ASN-81;
RP THR-83; THR-88; THR-92; THR-96; ASN-238; ASN-253 AND ASN-352.
RX PubMed=3756141; DOI=10.1021/bi00363a018;
RA Bock S.C., Skriver K., Nielsen E., Thoegersen H.-C., Wiman B.,
RA Donaldson V.H., Eddy R.L., Marrinan J., Radziejewska E., Huber R.,
RA Shows T.B., Magnusson S.;
RT "Human C1 inhibitor: primary structure, cDNA cloning, and chromosomal
RT localization.";
RL Biochemistry 25:4292-4301(1986).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
RX PubMed=3267220; DOI=10.1111/j.1432-1033.1988.tb13980.x;
RA Carter P.E., Dunbar B., Fothergill J.E.;
RT "Genomic and cDNA cloning of the human C1 inhibitor. Intron-exon
RT junctions and comparison with other serpins.";
RL Eur. J. Biochem. 173:163-169(1988).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=2026152; DOI=10.1111/j.1432-1033.1991.tb15911.x;
RA Carter P.E., Duponchel C., Tosi M., Fothergill J.E.;
RT "Complete nucleotide sequence of the gene for human C1 inhibitor with
RT an unusually high density of Alu elements.";
RL Eur. J. Biochem. 197:301-308(1991).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Foreskin;
RA Heus J., Platenburg-Kootwijk E., Meershoek E., De Winter R.,
RA Knijnenburg J., Kupers L., Habex H., Renaers I., Samuel C.,
RA Bonnarens L., Hoffman S., Brouwer M., Hack E., Horbach D.,
RA Timmermans M., Nuijens J., Pieper F.;
RT "Production of recombinant human C1 inhibitor in milk of transgenic
RT rabbits for potential use in enzyme replacement therapy for hereditary
RT angioedema.";
RL Submitted (OCT-2001) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Heart, and Uterus;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT MET-480.
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT MET-480.
RC TISSUE=Brain;
RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S.,
RA Ohara O., Nagase T., Kikuno R.F.;
RL Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT MET-480.
RG SeattleSNPs variation discovery resource;
RL Submitted (JAN-2005) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16554811; DOI=10.1038/nature04632;
RA Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K.,
RA Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F.,
RA Bloom T., Bruford E., Chang J.L., Cuomo C.A., Eichler E.,
RA FitzGerald M.G., Jaffe D.B., LaButti K., Nicol R., Park H.-S.,
RA Seaman C., Sougnez C., Yang X., Zimmer A.R., Zody M.C., Birren B.W.,
RA Nusbaum C., Fujiyama A., Hattori M., Rogers J., Lander E.S.,
RA Sakaki Y.;
RT "Human chromosome 11 DNA sequence and analysis including novel gene
RT identification.";
RL Nature 440:497-500(2006).
RN [11]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [12]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT MET-480.
RC TISSUE=Brain;
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 [13]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 6-500.
RX PubMed=3393514;
RA Rauth G., Schumacher G., Buckel P., Mueller-Esterl W.;
RT "Molecular cloning of the cDNA coding for human C1 inhibitor.";
RL Protein Seq. Data Anal. 1:251-257(1988).
RN [14]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 18-188, AND VARIANT HAE
RP 84-ASP--THR-138 DEL.
RC TISSUE=Blood;
RX PubMed=12773530; DOI=10.1074/jbc.M302977200;
RA Bos I.G.A., Lubbers Y.T.P., Roem D., Abrahams J.P., Hack C.E.,
RA Eldering E.;
RT "The functional integrity of the serpin domain of C1-inhibitor depends
RT on the unique N-terminal domain, as revealed by a pathological
RT mutant.";
RL J. Biol. Chem. 278:29463-29470(2003).
RN [15]
RP PROTEIN SEQUENCE OF 23-62.
RX PubMed=6416294; DOI=10.1021/bi00290a019;
RA Harrison R.A.;
RT "Human C1 inhibitor: improved isolation and preliminary structural
RT characterization.";
RL Biochemistry 22:5001-5007(1983).
RN [16]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 33-228.
RX PubMed=2154751; DOI=10.1073/pnas.87.4.1551;
RA Stoppa-Lyonnet D., Carter P.E., Meo T., Tosi M.;
RT "Clusters of intragenic Alu repeats predispose the human C1 inhibitor
RT locus to deleterious rearrangements.";
RL Proc. Natl. Acad. Sci. U.S.A. 87:1551-1555(1990).
RN [17]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 213-500.
RX PubMed=3089875; DOI=10.1016/0378-1119(86)90230-1;
RA Tosi M., Duponchel C., Bourgarel P., Colomb M., Meo T.;
RT "Molecular cloning of human C1 inhibitor: sequence homologies with
RT alpha 1-antitrypsin and other members of the serpins superfamily.";
RL Gene 42:265-272(1986).
RN [18]
RP PROTEIN SEQUENCE OF 217-233.
RX PubMed=8618290; DOI=10.1097/00005392-199606000-00030;
RA Pillai S., Wright D., Gupta A., Zhou G., Hull G., Jiang H., Zhang H.;
RT "Molecular weights and isoelectric points of sperm antigens relevant
RT to autoimmune infertility in men.";
RL J. Urol. 155:1928-1933(1996).
RN [19]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 241-458, AND PARTIAL PROTEIN SEQUENCE.
RX PubMed=3458172; DOI=10.1073/pnas.83.10.3161;
RA Davis A.E. III, Whitehead A.S., Harrison R.A., Dauphinias A.,
RA Bruns G.A., Cicardi M., Rosen F.S.;
RT "Human inhibitor of the first component of complement, C1:
RT characterization of cDNA clones and localization of the gene to
RT chromosome 11.";
RL Proc. Natl. Acad. Sci. U.S.A. 83:3161-3165(1986).
RN [20]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 418-500, AND VARIANTS HAE
RP MET-473; ARG-481; PRO-481; ARG-489 AND SER-498.
RX PubMed=7814636; DOI=10.1172/JCI117663;
RA Verpy E., Couture-Tosi E., Eldering E., Lopez-Trascasa M., Spath P.,
RA Meo T., Tosi M.;
RT "Crucial residues in the carboxy-terminal end of C1 inhibitor revealed
RT by pathogenic mutants impaired in secretion or function.";
RL J. Clin. Invest. 95:350-359(1995).
RN [21]
RP PROTEIN SEQUENCE OF 464-481, FUNCTION, AND REACTIVE SITE FOR
RP CHYMOTRYPSIN.
RC TISSUE=Plasma;
RX PubMed=8495195;
RA Aulak K.S., Davis A.E. III, Donaldson V.H., Harrison R.A.;
RT "Chymotrypsin inhibitory activity of normal C1-inhibitor and a P1 Arg
RT to His mutant: evidence for the presence of overlapping reactive
RT centers.";
RL Protein Sci. 2:727-732(1993).
RN [22]
RP INTERACTION WITH MASP1.
RX PubMed=10946292;
RA Matsushita M., Thiel S., Jensenius J.C., Terai I., Fujita T.;
RT "Proteolytic activities of two types of mannose-binding lectin-
RT associated serine protease.";
RL J. Immunol. 165:2637-2642(2000).
RN [23]
RP INTERACTION WITH E.COLI STCE, AND PROTEOLYTIC PROCESSING BY E.COLI
RP STCE.
RX PubMed=12123444; DOI=10.1046/j.1365-2958.2002.02997.x;
RA Lathem W.W., Grys T.E., Witowski S.E., Torres A.G., Kaper J.B.,
RA Tarr P.I., Welch R.A.;
RT "StcE, a metalloprotease secreted by Escherichia coli O157:H7,
RT specifically cleaves C1 esterase inhibitor.";
RL Mol. Microbiol. 45:277-288(2002).
RN [24]
RP GLYCOSYLATION AT ASN-253.
RX PubMed=12754519; DOI=10.1038/nbt827;
RA Zhang H., Li X.-J., Martin D.B., Aebersold R.;
RT "Identification and quantification of N-linked glycoproteins using
RT hydrazide chemistry, stable isotope labeling and mass spectrometry.";
RL Nat. Biotechnol. 21:660-666(2003).
RN [25]
RP INTERACTION WITH E.COLI STCE, AND PROTEOLYTIC PROCESSING BY E.COLI
RP STCE.
RX PubMed=15096536; DOI=10.1084/jem.20030255;
RA Lathem W.W., Bergsbaken T., Welch R.A.;
RT "Potentiation of C1 esterase inhibitor by StcE, a metalloprotease
RT secreted by Escherichia coli O157:H7.";
RL J. Exp. Med. 199:1077-1087(2004).
RN [26]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-25; ASN-238; ASN-253 AND
RP ASN-352, AND MASS SPECTROMETRY.
RC TISSUE=Plasma;
RX PubMed=14760718; DOI=10.1002/pmic.200300556;
RA Bunkenborg J., Pilch B.J., Podtelejnikov A.V., Wisniewski J.R.;
RT "Screening for N-glycosylated proteins by liquid chromatography mass
RT spectrometry.";
RL Proteomics 4:454-465(2004).
RN [27]
RP GLYCOSYLATION AT ASN-25.
RX PubMed=16040958; DOI=10.1128/IAI.73.8.4478-4487.2005;
RA Liu D., Cramer C.C., Scafidi J., Davis A.E. III;
RT "N-linked glycosylation at Asn3 and the positively charged residues
RT within the amino-terminal domain of the c1 inhibitor are required for
RT interaction of the C1 Inhibitor with Salmonella enterica serovar
RT typhimurium lipopolysaccharide and lipid A.";
RL Infect. Immun. 73:4478-4487(2005).
RN [28]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-25; ASN-69; ASN-238;
RP ASN-253 AND ASN-352, AND MASS SPECTROMETRY.
RC TISSUE=Plasma;
RX PubMed=16335952; DOI=10.1021/pr0502065;
RA Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E.,
RA Moore R.J., Smith R.D.;
RT "Human plasma N-glycoproteome analysis by immunoaffinity subtraction,
RT hydrazide chemistry, and mass spectrometry.";
RL J. Proteome Res. 4:2070-2080(2005).
RN [29]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-69; ASN-81; ASN-238;
RP ASN-253 AND ASN-352, AND MASS 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 [30]
RP GLYCOSYLATION AT ASN-238; ASN-253 AND ASN-352.
RX PubMed=19139490; DOI=10.1074/mcp.M800504-MCP200;
RA Jia W., Lu Z., Fu Y., Wang H.P., Wang L.H., Chi H., Yuan Z.F.,
RA Zheng Z.B., Song L.N., Han H.H., Liang Y.M., Wang J.L., Cai Y.,
RA Zhang Y.K., Deng Y.L., Ying W.T., He S.M., Qian X.H.;
RT "A strategy for precise and large scale identification of core
RT fucosylated glycoproteins.";
RL Mol. Cell. Proteomics 8:913-923(2009).
RN [31]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-352, STRUCTURE OF
RP CARBOHYDRATES, AND MASS SPECTROMETRY.
RC TISSUE=Cerebrospinal fluid;
RX PubMed=19838169; DOI=10.1038/nmeth.1392;
RA Nilsson J., Rueetschi U., Halim A., Hesse C., Carlsohn E.,
RA Brinkmalm G., Larson G.;
RT "Enrichment of glycopeptides for glycan structure and attachment site
RT identification.";
RL Nat. Methods 6:809-811(2009).
RN [32]
RP GLYCOSYLATION AT ASN-25; THR-47 AND THR-48, STRUCTURE OF
RP CARBOHYDRATES, AND MASS SPECTROMETRY.
RX PubMed=22171320; DOI=10.1074/mcp.M111.013649;
RA Halim A., Nilsson J., Ruetschi U., Hesse C., Larson G.;
RT "Human urinary glycoproteomics; attachment site specific analysis of
RT N-and O-linked glycosylations by CID and ECD.";
RL Mol. Cell. Proteomics 0:0-0(2011).
RN [33]
RP GLYCOSYLATION AT THR-47 AND THR-48, AND MASS SPECTROMETRY.
RX PubMed=23234360; DOI=10.1021/pr300963h;
RA Halim A., Ruetschi U., Larson G., Nilsson J.;
RT "LC-MS/MS characterization of O-glycosylation sites and glycan
RT structures of human cerebrospinal fluid glycoproteins.";
RL J. Proteome Res. 12:573-584(2013).
RN [34]
RP X-RAY CRYSTALLOGRAPHY (2.35 ANGSTROMS) OF 119-500, DISULFIDE BONDS,
RP AND GLYCOSYLATION AT ASN-238.
RX PubMed=17488724; DOI=10.1074/jbc.M700841200;
RA Beinrohr L., Harmat V., Dobo J., Loerincz Z., Gal P., Zavodszky P.;
RT "C1 inhibitor serpin domain structure reveals the likely mechanism of
RT heparin potentiation and conformational disease.";
RL J. Biol. Chem. 282:21100-21109(2007).
RN [35]
RP REVIEW ON VARIANTS.
RX PubMed=7749926; DOI=10.1038/nsb0295-96;
RA Stein P.E., Carrell R.W.;
RT "What do dysfunctional serpins tell us about molecular mobility and
RT disease?";
RL Nat. Struct. Biol. 2:96-113(1995).
RN [36]
RP VARIANT HAE HIS-466.
RX PubMed=3178731;
RA Aulak K.S., Pemberton P.A., Rosen F.S., Carrell R.W., Lachmann P.J.,
RA Harrison R.A.;
RT "Dysfunctional C1-inhibitor(At), isolated from a type II hereditary-
RT angio-oedema plasma, contains a P1 'reactive centre' (Arg444-->His)
RT mutation.";
RL Biochem. J. 253:615-618(1988).
RN [37]
RP VARIANT HAE SER-466.
RX PubMed=2365061; DOI=10.1016/0014-5793(90)81494-9;
RA Aulak K.S., Cicardi M., Harrison R.A.;
RT "Identification of a new P1 residue mutation (444Arg-->Ser) in a
RT dysfunctional C1 inhibitor protein contained in a type II hereditary
RT angioedema plasma.";
RL FEBS Lett. 266:13-16(1990).
RN [38]
RP VARIANT HAE THR-458.
RX PubMed=2296585; DOI=10.1073/pnas.87.1.265;
RA Levy N.J., Ramesh N., Cicardi M., Harrison R.A., Davis A.E. III;
RT "Type II hereditary angioneurotic edema that may result from a single
RT nucleotide change in the codon for alanine-436 in the C1 inhibitor
RT gene.";
RL Proc. Natl. Acad. Sci. U.S.A. 87:265-268(1990).
RN [39]
RP VARIANT HAE LYS-273 DEL.
RX PubMed=2118657; DOI=10.1073/pnas.87.17.6786;
RA Parad R.B., Kramer J., Strunk R.C., Rosen F.S., Davis A.E. III;
RT "Dysfunctional C1 inhibitor Ta: deletion of Lys-251 results in
RT acquisition of an N-glycosylation site.";
RL Proc. Natl. Acad. Sci. U.S.A. 87:6786-6790(1990).
RN [40]
RP VARIANTS HAE GLU-456 AND VAL-458.
RA Siddique Z.M., McPhaden A.R., Whaley K.;
RT "Identification of type II hereditary angio-oedema (HAE) mutations.";
RL Clin. Exp. Immunol. 86:11-12(1991).
RN [41]
RP VARIANT HAE LEU-466.
RX PubMed=1451784; DOI=10.1016/0014-5793(92)80204-T;
RA Frange D., Aulak K.S., Cicardi M., Harrison R.A., Davis A.E. III;
RT "A dysfunctional C1 inhibitor protein with a new reactive center
RT mutation (Arg-444-->Leu).";
RL FEBS Lett. 301:34-36(1992).
RN [42]
RP VARIANTS HAE GLU-454 AND THR-458.
RX PubMed=1363816; DOI=10.1038/ng0892-354;
RA Davis A.E. III, Aulak K., Parad R.B., Stecklein H.P., Eldering E.,
RA Hack C.E., Kramer J., Strunk R.C., Bissler J., Rosen F.S.;
RT "C1 inhibitor hinge region mutations produce dysfunction by different
RT mechanisms.";
RL Nat. Genet. 1:354-358(1992).
RN [43]
RP VARIANT HAE ARG-429.
RX PubMed=8172583;
RA Davis A.E. III, Bissler J.J., Cicardi M.;
RT "Mutations in the C1 inhibitor gene that result in hereditary
RT angioneurotic edema.";
RL Behring Inst. Mitt. 93:313-320(1993).
RN [44]
RP VARIANT HAE VAL-465.
RX PubMed=7883978; DOI=10.1172/JCI117780;
RA Zahedi R., Bissler J.J., Davis A.E. III, Andreadis C., Wisnieski J.J.;
RT "Unique C1 inhibitor dysfunction in a kindred without angioedema. II.
RT Identification of an Ala443-->Val substitution and functional analysis
RT of the recombinant mutant protein.";
RL J. Clin. Invest. 95:1299-1305(1995).
RN [45]
RP VARIANT HAE PRO-467.
RX PubMed=8529136;
RA Ocejo-Vinyals J.G., Leyva-Cobian F., Fernandez-Luna J.L.;
RT "A mutation unique in serine protease inhibitors (serpins) identified
RT in a family with type II hereditary angioneurotic edema.";
RL Mol. Med. 1:700-705(1995).
RN [46]
RP VARIANTS HAE.
RX PubMed=8755917;
RA Verpy E., Biasotto M., Brai M., Misiano G., Meo T., Tosi M.;
RT "Exhaustive mutation scanning by fluorescence-assisted mismatch
RT analysis discloses new genotype-phenotype correlations in angiodema.";
RL Am. J. Hum. Genet. 59:308-319(1996).
RN [47]
RP VARIANTS HAE TYR-130; PRO-394; VAL-408; CYS-466; GLU-473; GLU-493 AND
RP ARG-498.
RX PubMed=14635117; DOI=10.1002/humu.9202;
RA Kalmar L., Bors A., Farkas H., Vas S., Fandl B., Varga L., Fuest G.,
RA Tordai A.;
RT "Mutation screening of the C1 inhibitor gene among Hungarian patients
RT with hereditary angioedema.";
RL Hum. Mutat. 22:498-498(2003).
RN [48]
RP VARIANT HAE ARG-345, AND VARIANTS ALA-56 AND MET-480.
RX PubMed=16409206; DOI=10.1111/j.1398-9995.2006.01010.x;
RA Kang H.-R., Yim E.-Y., Oh S.-Y., Chang Y.-S., Kim Y.-K., Cho S.-H.,
RA Min K.-U., Kim Y.-Y.;
RT "Normal C1 inhibitor mRNA expression level in type I hereditary
RT angioedema patients: newly found C1 inhibitor gene mutations.";
RL Allergy 61:260-264(2006).
RN [49]
RP VARIANTS HAE ALA-118; CYS-154; PHE-170; ARG-184; PRO-230; LYS-232;
RP ASN-272 DEL; ARG-299; GLN-430; THR-441; PRO-447; SER-466; CYS-466;
RP LEU-466; GLY-473 AND GLY-497, AND VARIANTS ALA-56 AND MET-480.
RX PubMed=22994404; DOI=10.1111/all.12024;
RA Xu Y.Y., Zhi Y.X., Yin J., Wang L.L., Wen L.P., Gu J.Q., Guan K.,
RA Craig T., Zhang H.Y.;
RT "Mutational spectrum and geno-phenotype correlation in Chinese
RT families with Hereditary Angioedema.";
RL Allergy 67:1430-1436(2012).
CC -!- FUNCTION: Activation of the C1 complex is under control of the C1-
CC inhibitor. It forms a proteolytically inactive stoichiometric
CC complex with the C1r or C1s proteases. May play a potentially
CC crucial role in regulating important physiological pathways
CC including complement activation, blood coagulation, fibrinolysis
CC and the generation of kinins. Very efficient inhibitor of FXIIa.
CC Inhibits chymotrypsin and kallikrein.
CC -!- SUBUNIT: Binds to E.coli stcE which allows localization of
CC SERPING1 to cell membranes thus protecting the bacteria against
CC complement-mediated lysis. Interacts with MASP1.
CC -!- SUBCELLULAR LOCATION: Secreted.
CC -!- PTM: Highly glycosylated (49%) with N- and O-glycosylation. O-
CC glycosylated with core 1 or possibly core 8 glycans. N-glycan
CC heterogeneity at Asn-25: Hex5HexNAc4 (minor), dHex1Hex5HexNAc4
CC (minor), Hex6HexNAc5 (major) and dHex1Hex6HexNAc5 (minor).
CC -!- PTM: Can be proteolytically cleaved by E.coli stcE.
CC -!- POLYMORPHISM: Chymotrypsin uses Ala-465 as its reactive site in
CC normal plasma protease C1 inhibitor, and His-466 as its reactive
CC site in the variant His-466.
CC -!- DISEASE: Hereditary angioedema (HAE) [MIM:106100]: An autosomal
CC dominant disorder characterized by episodic local swelling
CC involving subcutaneous or submucous tissue of the upper
CC respiratory and gastrointestinal tracts, face, extremities, and
CC genitalia. Hereditary angioedema due to C1 esterase inhibitor
CC deficiency is comprised of two clinically indistinguishable forms.
CC In hereditary angioedema type 1, serum levels of C1 esterase
CC inhibitor are decreased, while in type 2, the levels are normal or
CC elevated, but the protein is non-functional. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the serpin family.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAA53096.1; Type=Erroneous gene model prediction;
CC -!- WEB RESOURCE: Name=Wikipedia; Note=C1-inhibitor entry;
CC URL="http://en.wikipedia.org/wiki/C1-inhibitor";
CC -!- WEB RESOURCE: Name=SERPING1base; Note=SERPING1 mutation db;
CC URL="http://bioinf.uta.fi/SERPING1base/";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/SERPING1";
CC -!- WEB RESOURCE: Name=SeattleSNPs;
CC URL="http://pga.gs.washington.edu/data/serping1/";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
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DR EMBL; M13690; AAA35613.1; -; mRNA.
DR EMBL; M13656; AAB59387.1; -; mRNA.
DR EMBL; X07427; CAA30314.1; -; Genomic_DNA.
DR EMBL; X07428; CAA30314.1; JOINED; Genomic_DNA.
DR EMBL; X07429; CAA30314.1; JOINED; Genomic_DNA.
DR EMBL; X07430; CAA30314.1; JOINED; Genomic_DNA.
DR EMBL; X07431; CAA30314.1; JOINED; Genomic_DNA.
DR EMBL; X07432; CAA30314.1; JOINED; Genomic_DNA.
DR EMBL; X07433; CAA30314.1; JOINED; Genomic_DNA.
DR EMBL; X07577; CAA30469.1; -; mRNA.
DR EMBL; X54486; CAA38358.1; -; Genomic_DNA.
DR EMBL; AF435921; AAM21515.1; -; Genomic_DNA.
DR EMBL; AK293054; BAF85743.1; -; mRNA.
DR EMBL; AK312626; BAG35512.1; -; mRNA.
DR EMBL; BT006966; AAP35612.1; -; mRNA.
DR EMBL; AB209826; BAD93063.1; -; mRNA.
DR EMBL; AY904027; AAW69393.1; -; Genomic_DNA.
DR EMBL; AP000662; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AP002893; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471076; EAW73764.1; -; Genomic_DNA.
DR EMBL; BC011171; AAH11171.1; -; mRNA.
DR EMBL; AY291075; AAQ19269.1; -; Genomic_DNA.
DR EMBL; M30688; AAA53096.1; ALT_SEQ; Genomic_DNA.
DR EMBL; M14036; AAA51848.1; -; mRNA.
DR EMBL; M13203; AAA51849.1; -; mRNA.
DR EMBL; S76944; AAB33044.2; -; Genomic_DNA.
DR PIR; S15386; ITHUC1.
DR RefSeq; NP_000053.2; NM_000062.2.
DR RefSeq; NP_001027466.1; NM_001032295.1.
DR RefSeq; XP_005274262.1; XM_005274205.1.
DR UniGene; Hs.384598; -.
DR PDB; 1M6Q; Model; -; A=138-500.
DR PDB; 2OAY; X-ray; 2.35 A; A=119-500.
DR PDBsum; 1M6Q; -.
DR PDBsum; 2OAY; -.
DR ProteinModelPortal; P05155; -.
DR SMR; P05155; 102-498.
DR DIP; DIP-45635N; -.
DR IntAct; P05155; 5.
DR MEROPS; I04.024; -.
DR PhosphoSite; P05155; -.
DR DMDM; 124096; -.
DR PaxDb; P05155; -.
DR PeptideAtlas; P05155; -.
DR PRIDE; P05155; -.
DR DNASU; 710; -.
DR Ensembl; ENST00000278407; ENSP00000278407; ENSG00000149131.
DR GeneID; 710; -.
DR KEGG; hsa:710; -.
DR UCSC; uc001nkp.1; human.
DR CTD; 710; -.
DR GeneCards; GC11P057364; -.
DR HGNC; HGNC:1228; SERPING1.
DR HPA; CAB026161; -.
DR MIM; 106100; phenotype.
DR MIM; 606860; gene.
DR neXtProt; NX_P05155; -.
DR Orphanet; 100050; Hereditary angioedema type 1.
DR Orphanet; 100051; Hereditary angioedema type 2.
DR Orphanet; 169147; Immunodeficiency due to an early component of complement deficiency.
DR PharmGKB; PA35029; -.
DR eggNOG; COG4826; -.
DR HOVERGEN; HBG104060; -.
DR KO; K04001; -.
DR PhylomeDB; P05155; -.
DR Reactome; REACT_604; Hemostasis.
DR ChiTaRS; SERPING1; human.
DR EvolutionaryTrace; P05155; -.
DR GeneWiki; C1-inhibitor; -.
DR GenomeRNAi; 710; -.
DR NextBio; 2886; -.
DR PMAP-CutDB; P05155; -.
DR PRO; PR:P05155; -.
DR ArrayExpress; P05155; -.
DR Bgee; P05155; -.
DR Genevestigator; P05155; -.
DR GO; GO:0005615; C:extracellular space; IBA:RefGenome.
DR GO; GO:0031093; C:platelet alpha granule lumen; TAS:Reactome.
DR GO; GO:0004867; F:serine-type endopeptidase inhibitor activity; IDA:UniProtKB.
DR GO; GO:0008015; P:blood circulation; TAS:ProtInc.
DR GO; GO:0007597; P:blood coagulation, intrinsic pathway; TAS:Reactome.
DR GO; GO:0006958; P:complement activation, classical pathway; IEA:UniProtKB-KW.
DR GO; GO:0042730; P:fibrinolysis; IEA:UniProtKB-KW.
DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
DR GO; GO:0001869; P:negative regulation of complement activation, lectin pathway; IDA:UniProtKB.
DR GO; GO:0030168; P:platelet activation; TAS:Reactome.
DR GO; GO:0002576; P:platelet degranulation; TAS:Reactome.
DR InterPro; IPR015553; C1-inh.
DR InterPro; IPR023795; Serpin_CS.
DR InterPro; IPR023796; Serpin_dom.
DR InterPro; IPR000215; Serpin_fam.
DR PANTHER; PTHR11461; PTHR11461; 1.
DR PANTHER; PTHR11461:SF21; PTHR11461:SF21; 1.
DR Pfam; PF00079; Serpin; 1.
DR SMART; SM00093; SERPIN; 1.
DR SUPFAM; SSF56574; SSF56574; 1.
DR PROSITE; PS00284; SERPIN; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Blood coagulation; Complement pathway;
KW Complete proteome; Direct protein sequencing; Disease mutation;
KW Disulfide bond; Fibrinolysis; Glycoprotein; Hemostasis; Immunity;
KW Innate immunity; Polymorphism; Protease inhibitor; Reference proteome;
KW Repeat; Secreted; Serine protease inhibitor; Signal.
FT SIGNAL 1 22
FT CHAIN 23 500 Plasma protease C1 inhibitor.
FT /FTId=PRO_0000032514.
FT REPEAT 85 88 1.
FT REPEAT 89 92 2.
FT REPEAT 93 96 3.
FT REPEAT 97 100 4.
FT REPEAT 101 104 5.
FT REPEAT 105 108 6.
FT REPEAT 116 119 7.
FT REGION 85 119 7 X 4 AA tandem repeats of [QE]-P-T-[TQ].
FT SITE 465 466 Reactive bond for chymotrypsin.
FT SITE 466 467 Reactive bond.
FT CARBOHYD 25 25 N-linked (GlcNAc...) (complex).
FT CARBOHYD 47 47 O-linked (GalNAc...).
FT CARBOHYD 48 48 O-linked (GalNAc...).
FT CARBOHYD 64 64 O-linked (GalNAc...).
FT CARBOHYD 69 69 N-linked (GlcNAc...).
FT CARBOHYD 71 71 O-linked (GalNAc...).
FT CARBOHYD 81 81 N-linked (GlcNAc...).
FT CARBOHYD 83 83 O-linked (GalNAc...).
FT CARBOHYD 88 88 O-linked (GalNAc...).
FT CARBOHYD 92 92 O-linked (GalNAc...).
FT CARBOHYD 96 96 O-linked (GalNAc...).
FT CARBOHYD 238 238 N-linked (GlcNAc...) (complex).
FT CARBOHYD 253 253 N-linked (GlcNAc...) (complex).
FT CARBOHYD 272 272 N-linked (GlcNAc...); in variant TA.
FT CARBOHYD 352 352 N-linked (GlcNAc...) (complex).
FT DISULFID 123 428
FT DISULFID 130 205
FT VARIANT 39 39 D -> E (in dbSNP:rs11229062).
FT /FTId=VAR_027374.
FT VARIANT 56 56 V -> A (in dbSNP:rs11546660).
FT /FTId=VAR_027375.
FT VARIANT 84 138 Missing (in HAE; phenotype consistent
FT with hereditary angioedema type 2).
FT /FTId=VAR_046202.
FT VARIANT 118 118 T -> A (in HAE; dbSNP:rs200534715).
FT /FTId=VAR_068832.
FT VARIANT 130 130 C -> Y (in HAE; phenotype consistent with
FT hereditary angioedema type 1).
FT /FTId=VAR_027379.
FT VARIANT 154 154 Y -> C (in HAE; dbSNP:rs281875168).
FT /FTId=VAR_068833.
FT VARIANT 170 170 S -> F (in HAE; dbSNP:rs281875169).
FT /FTId=VAR_068834.
FT VARIANT 184 184 G -> R (in HAE; dbSNP:rs281875170).
FT /FTId=VAR_068835.
FT VARIANT 230 230 L -> P (in HAE; dbSNP:rs281875171).
FT /FTId=VAR_068836.
FT VARIANT 232 232 I -> K (in HAE; dbSNP:rs281875172).
FT /FTId=VAR_068837.
FT VARIANT 272 272 Missing (in HAE).
FT /FTId=VAR_068838.
FT VARIANT 273 273 Missing (in HAE; phenotype consistent
FT with hereditary angioedema type 2;
FT creates a new glycosylation site).
FT /FTId=VAR_007012.
FT VARIANT 299 299 W -> R (in HAE; dbSNP:rs281875173).
FT /FTId=VAR_068839.
FT VARIANT 308 308 T -> S (in dbSNP:rs1803212).
FT /FTId=VAR_011751.
FT VARIANT 345 345 G -> R (in HAE; phenotype consistent with
FT hereditary angioedema type 1).
FT /FTId=VAR_027376.
FT VARIANT 394 394 T -> P (in HAE; phenotype consistent with
FT hereditary angioedema type 1).
FT /FTId=VAR_027380.
FT VARIANT 408 408 D -> V (in HAE; phenotype consistent with
FT hereditary angioedema type 1).
FT /FTId=VAR_027381.
FT VARIANT 429 429 G -> R (in HAE; phenotype consistent with
FT hereditary angioedema type 2).
FT /FTId=VAR_007013.
FT VARIANT 430 430 L -> Q (in HAE; dbSNP:rs281875174).
FT /FTId=VAR_068840.
FT VARIANT 441 441 M -> T (in HAE; dbSNP:rs281875175).
FT /FTId=VAR_068841.
FT VARIANT 447 447 L -> P (in HAE; dbSNP:rs281875176).
FT /FTId=VAR_068842.
FT VARIANT 454 454 V -> E (in HAE; phenotype consistent with
FT hereditary angioedema type 2).
FT /FTId=VAR_007014.
FT VARIANT 456 456 A -> E (in HAE; phenotype consistent with
FT hereditary angioedema type 2).
FT /FTId=VAR_007015.
FT VARIANT 458 458 A -> T (in HAE; phenotype consistent with
FT hereditary angioedema type 2).
FT /FTId=VAR_007016.
FT VARIANT 458 458 A -> V (in HAE; phenotype consistent with
FT hereditary angioedema type 2).
FT /FTId=VAR_007017.
FT VARIANT 465 465 A -> V (in HAE; phenotype consistent with
FT hereditary angioedema type 2).
FT /FTId=VAR_007018.
FT VARIANT 466 466 R -> C (in HAE; phenotype consistent with
FT hereditary angioedema type 2;
FT dbSNP:rs28940870).
FT /FTId=VAR_007019.
FT VARIANT 466 466 R -> H (in HAE; phenotype consistent with
FT hereditary angioedema type 2).
FT /FTId=VAR_007020.
FT VARIANT 466 466 R -> L (in HAE; phenotype consistent with
FT hereditary angioedema type 2;
FT dbSNP:rs121907948).
FT /FTId=VAR_007021.
FT VARIANT 466 466 R -> S (in HAE; phenotype consistent with
FT hereditary angioedema type 2;
FT dbSNP:rs28940870).
FT /FTId=VAR_007022.
FT VARIANT 467 467 T -> P (in HAE; phenotype consistent with
FT hereditary angioedema type 2).
FT /FTId=VAR_007023.
FT VARIANT 473 473 V -> E (in HAE; phenotype consistent with
FT hereditary angioedema type 1).
FT /FTId=VAR_027382.
FT VARIANT 473 473 V -> G (in HAE; dbSNP:rs281875177).
FT /FTId=VAR_068843.
FT VARIANT 473 473 V -> M (in HAE; phenotype consistent with
FT hereditary angioedema type 2).
FT /FTId=VAR_007024.
FT VARIANT 474 474 Q -> E.
FT /FTId=VAR_007025.
FT VARIANT 477 477 F -> S (in HAE; phenotype consistent with
FT hereditary angioedema type 2).
FT /FTId=VAR_007026.
FT VARIANT 480 480 V -> M (in dbSNP:rs4926).
FT /FTId=VAR_007027.
FT VARIANT 481 481 L -> P (in HAE; phenotype consistent with
FT hereditary angioedema type 2).
FT /FTId=VAR_007028.
FT VARIANT 481 481 L -> R (in HAE; phenotype consistent with
FT hereditary angioedema type 2).
FT /FTId=VAR_007029.
FT VARIANT 489 489 P -> R (in HAE; phenotype consistent with
FT hereditary angioedema type 2).
FT /FTId=VAR_007030.
FT VARIANT 493 493 G -> E (in HAE; phenotype consistent with
FT hereditary angioedema type 1).
FT /FTId=VAR_027383.
FT VARIANT 497 497 D -> G (in HAE; dbSNP:rs281875178).
FT /FTId=VAR_068844.
FT VARIANT 498 498 P -> R (in HAE; phenotype consistent with
FT hereditary angioedema type 1).
FT /FTId=VAR_027384.
FT VARIANT 498 498 P -> S (in HAE; phenotype consistent with
FT hereditary angioedema type 2).
FT /FTId=VAR_007031.
FT CONFLICT 103 103 T -> S (in Ref. 6; BAF85743).
FT CONFLICT 187 187 E -> Q (in Ref. 2; AAB59387).
FT CONFLICT 306 306 K -> R (in Ref. 1; AAA35613).
FT CONFLICT 314 320 HFKNSVI -> QLQKLSY (in Ref. 19; AA
FT sequence).
FT CONFLICT 322 322 V -> M (in Ref. 19; AA sequence).
FT CONFLICT 332 332 V -> L (in Ref. 19; AA sequence).
FT CONFLICT 370 375 MEQALS -> TGTGSQ (in Ref. 19; AA
FT sequence).
FT CONFLICT 417 417 E -> V (in Ref. 19; AA sequence).
FT CONFLICT 439 439 S -> F (in Ref. 19; AA sequence).
FT HELIX 135 157
FT STRAND 167 169
FT HELIX 171 183
FT HELIX 187 197
FT HELIX 206 211
FT STRAND 216 226
FT HELIX 234 244
FT HELIX 255 268
FT TURN 269 272
FT STRAND 287 301
FT STRAND 309 313
FT STRAND 320 337
FT TURN 338 341
FT STRAND 342 350
FT STRAND 353 362
FT HELIX 367 373
FT HELIX 376 387
FT STRAND 391 399
FT STRAND 402 408
FT HELIX 409 413
FT HELIX 414 416
FT STRAND 417 419
FT HELIX 421 424
FT TURN 428 430
FT STRAND 441 449
FT STRAND 451 463
FT STRAND 468 470
FT STRAND 477 483
FT TURN 484 487
FT STRAND 488 495
SQ SEQUENCE 500 AA; 55154 MW; 8B5E874833EA6C05 CRC64;
MASRLTLLTL LLLLLAGDRA SSNPNATSSS SQDPESLQDR GEGKVATTVI SKMLFVEPIL
EVSSLPTTNS TTNSATKITA NTTDEPTTQP TTEPTTQPTI QPTQPTTQLP TDSPTQPTTG
SFCPGPVTLC SDLESHSTEA VLGDALVDFS LKLYHAFSAM KKVETNMAFS PFSIASLLTQ
VLLGAGENTK TNLESILSYP KDFTCVHQAL KGFTTKGVTS VSQIFHSPDL AIRDTFVNAS
RTLYSSSPRV LSNNSDANLE LINTWVAKNT NNKISRLLDS LPSDTRLVLL NAIYLSAKWK
TTFDPKKTRM EPFHFKNSVI KVPMMNSKKY PVAHFIDQTL KAKVGQLQLS HNLSLVILVP
QNLKHRLEDM EQALSPSVFK AIMEKLEMSK FQPTLLTLPR IKVTTSQDML SIMEKLEFFD
FSYDLNLCGL TEDPDLQVSA MQHQTVLELT ETGVEAAAAS AISVARTLLV FEVQQPFLFV
LWDQQHKFPV FMGRVYDPRA
//

MIM 106100
*RECORD*
*FIELD* NO
106100
*FIELD* TI
#106100 ANGIOEDEMA, HEREDITARY, TYPE I; HAE1
;;ANGIONEUROTIC EDEMA, HEREDITARY; HANE;;
read moreC1 ESTERASE INHIBITOR, DEFICIENCY OF
ANGIOEDEMA, HEREDITARY, TYPE II, INCLUDED; HAE2, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because hereditary angioedema
types I and II are caused by heterozygous mutation in the C1 inhibitor
gene (C1NH, SERPING1; 606860) on chromosome 11q.

Another type of hereditary angioedema, HAE type III (610618), is caused
by mutation in the gene encoding coagulation factor XII (F12; 610619) on
chromosome 5q.

DESCRIPTION

Hereditary angioedema (HAE) is an autosomal dominant disorder
characterized by episodic local subcutaneous edema and submucosal edema
involving the upper respiratory and gastrointestinal tracts. There are 2
classic types of the disorder. In type I, representing 85% of patients,
serum levels of C1NH are less than 35% of normal (Cicardi and Agostoni,
1996; Bowen et al., 2001). In type II, the levels are normal or
elevated, but the protein is nonfunctional. The 2 types are clinically
indistinguishable.

See 300145 for a discussion of angioedema induced by ACE inhibitors.

Zuraw (2008) provided a detailed review of the clinical features,
management, and pathogenesis of hereditary angioedema.

CLINICAL FEATURES

Edema of the larynx and other portions of the airways is the most
fearsome feature of this disorder. Visceral involvement with abdominal
pain can lead to unnecessary laparotomy (Weinstock et al., 1987; Waytes
et al., 1996).

Weinstock et al. (1987) described a family in which lifelong abdominal
pain was the only manifestation of hereditary angioedema. A 40-year-old
man, 2 of his brothers, his mother, and his daughter were affected. In
addition to abdominal pain, nausea, diarrhea, and vomiting occurred, but
there were no cutaneous, oropharyngeal, or respiratory manifestations.
Barium studies during painful attacks showed transient intestinal wall
edema.

In rare patients the deficiency is acquired, with symptoms first
emerging well into adulthood. Jackson et al. (1986), Alsenz et al.
(1987), and Malbran et al. (1988) described patients with acquired C1
inhibitor deficiency resulting from anti-C1NH autoantibodies. These
patients had no evidence of an underlying disease, followed a benign
course, and showed variable responses to therapy. Frigas (1989)
described a patient with acquired C1 inhibitor deficiency who had no
evidence of underlying disease 11 years after onset.

Muhlemann et al. (1987) found an increased frequency of thyroglobulin
antibodies and thyroid microsomal antibodies in patients with hereditary
angioedema. They reported the occurrence of systemic lupus erythematosus
and glomerulonephritis in patients with this disorder.

Perricone et al. (1992) concluded that polycystic ovaries (PCO syndrome;
184700) or multifollicular ovaries occur with unusually high frequency
in women with HANE. Weidenbach et al. (1993) reported a 25-year-old
woman, with no family history of the disorder, in whom infectious
mononucleosis appeared to precipitate the acute onset of HAE.

Yakushiji et al. (2007) reported a 35-year-old woman who presented with
rapid onset of severe numbness and weakness of all 4 extremities.
Detailed laboratory investigations revealed decreased serum levels of
several complement components, including C2, C4, C1q, and C1INH. Nerve
conduction studies indicated a sensorimotor axonal peripheral
neuropathy. Peripheral nerve biopsies showed enlarged nerves with
vasculitis and lymphocytic infiltration; most of the proliferating
capillaries were strongly positive for anti-C1q, consistent with
activation of the classic complement pathway. There was also a decrease
of myelinated fibers and axonal degeneration. The patient's asymptomatic
mother and sister were also found to have decreased serum C1INH,
prompting the diagnosis of HAE, which was confirmed by genetic analysis.
Yakushiji et al. (2007) noted that vasculitic neuropathy had not
previously been described in patients with HAE.

- Association with Lymphoproliferative Disorders

Angioedema due to acquired C1 inhibitor deficiency has been associated
with benign or malignant B-cell lymphoproliferative disorders such as
chronic lymphocytic leukemia, multiple myeloma, or essential
cryoglobulinemia (Gelfand et al., 1979) and is due not to defective
synthesis but to markedly increased catabolism of the C1 inhibitor
protein. Frigas (1989) reported a patient with angioedema associated
with a B-cell lymphoproliferative disorder that became evident 9 months
after C1NH deficiency was diagnosed.

DIAGNOSIS

Laurent et al. (1988) showed that sonographic demonstration of fluid in
the abdomen in association with an attack of abdominal pain could be
used in diagnosis.

- Prenatal Diagnosis

Stoppa-Lyonnet et al. (1987) suggested that unique familial variants of
the C1NH gene may be used for prenatal or early diagnosis of the
disease. In 1 subject in an affected family, the C1 inhibitor level
determined at birth in cord blood was inconclusive. Later the
measurement showed a level in agreement with the diagnosis predicted by
DNA analysis.

BIOCHEMICAL FEATURES

Three types of C1 esterase inhibitor were described by Rosen et al.
(1971) in different families with angioneurotic edema. Immunologically,
one group had levels of inhibitor (an alpha-2 neuraminoglycoprotein)
17.5% of normal, a second group had levels 111% of normal, and a third
group represented by affected persons in a single kindred had levels
more than 400% of normal. Although immunologically identical, the three
types of inhibitor differed in electrophoretic and other characteristics
from the normal and from each other.

PATHOGENESIS

From immunofluorescence studies, Johnson et al. (1971) concluded that
deficient hepatic synthesis of C1 inhibitor is the basis of the
deficiency in plasma inhibitor.

Cicardi et al. (1982) reported on 104 cases in 31 families. In 22%,
functionally defective C1 esterase inhibitor was present (HANE type II).
In 78%, both antigen levels and functional activity of C1 esterase
inhibitor were low (HANE type I).

Quastel et al. (1983) studied the catabolism of C1 inhibitor in HANE I.
The fact that serum concentrations of a structurally normal C1 inhibitor
is 5 to 31% of normal rather than the 50% expected in heterozygotes is
explained, the authors suggested, by the presence of only one functional
gene and increased catabolism of the protein. On the basis of in vivo
turnover studies, Quastel et al. (1983) suggested that there is
activation of C1 or other protease systems in which this protein acts as
an inhibitor. This, in turn, could lead to consumption of normal C1
inhibitor that falls below normal.

Although the hepatocyte is the main site of synthesis of the inhibitor,
cultured human peripheral blood monocytes also synthesize and secrete
this protein. Cicardi et al. (1987) found that in the supernatant of
such cells, the inhibitor was present at levels of about 20% of normal,
whereas intracellular reduction approached 50%. The Northern blot
analysis showed inhibitor mRNA to be present at about half-normal
concentrations. One of the patients showed a genetically abnormal mRNA
(1.9 kb) in addition to the normal mRNA (2.1 kb).

To ascertain the mechanism for decreased synthesis of C1 inhibitor in
certain patients with type I HANE, Kramer et al. (1993) studied
expression of C1NH in fibroblasts in which the mutant and wildtype mRNA
and protein could be distinguished because of deletion of exon 7
(606860.0001). In the mutant cells, the amount of wildtype mRNA was
expressed at 52% of normal, whereas the mutant mRNA was 27% of normal.
Rates of synthesis of both wildtype and mutant proteins were lower than
predicted from the mRNA levels. There was no evidence of increased C1NH
protein catabolism. Thus, there appear to be multiple levels of control
of C1NH synthesis in type I HANE. Pretranslational regulation results in
less than 50% of the mutant truncated 1.9-kb mRNA; translational
regulation results in decreased synthesis of both wildtype and mutant
proteins. These data suggested a transinhibition of wildtype C1NH
translation by mutant mRNA and/or protein.

In an editorial, Cicardi and Agostoni (1996) used an instructive diagram
to demonstrate the pathophysiology of hereditary angioedema.

INHERITANCE

A considerable number of kindreds with angioneurotic edema transmitted
in a typical autosomal dominant pattern have been described. In the
family studied by Trigg (1961), about twice as many males as females
were affected. A family studied by Donaldson and Rosen (1964) had
previously been reported by Heiner and Blitzer (1957). Cohen (1961)
described a family with many cases in 5 generations. Although reported
as giant urticaria, the same family was studied by Rosen et al. (1965)
and shown to have a defect in a component of complement. Agostoni and
Cicardi (1992) pointed out that in more than 20% of those with
hereditary angioedema, the mutations are de novo and therefore there is
no family history of the disease.

Verpy et al. (1996) found a homozygous mutation (606860.0013) in a
promoter for the C1NH gene in 2 affected members of a family. In this
family, homozygosity correlated with low C1 inhibitor levels and severe
HANE. In contrast, heterozygotes for this mutation had C1 inhibitor
within the normal range, although often at its lower level, and were
free of angioedema attacks. These results suggest autosomal recessive
inheritance of this mutation.

MAPPING

Theriault et al. (1989, 1990) used in situ hybridization to map the
human C1 inhibitor gene (606860) to chromosome 11q11-q13.1.

CLINICAL MANAGEMENT

Nzeako et al. (2001) and Winkelstein and Colten (1989) reviewed the
clinical features and therapy of HANE.

Spaulding (1960) and Dennehy (1970) described apparently effective
prophylaxis with testosterone, and Frank et al. (1972) reported that
epsilon aminocaproic acid is efficacious in treatment. The therapeutic
benefit of Danazol, an 'impeded' androgen, is of interest from the point
of view of the basic defect in this disorder (Gelfand et al., 1976).
Danazol also raises the levels of the deficient protein in
alpha-1-antitrypsin deficiency (Gadek et al., 1980) and in hemophilias A
and B (Gralnick and Rick, 1983). Cicardi et al. (1982) found
concentrates of C1 inhibitor to be effective and without side effects in
the treatment of severe acute attacks. Androgen derivatives were useful
for long-term prophylaxis.

Sheffer et al. (1988) reported that stanozolol is a safe and effective
agent. Borum and Howard (1998) stated that prophylactic therapy with
attenuated androgens or antifibrinolytic agents is useful, and that
plasma concentrate of C1NH is the treatment of choice in an acute
episode.

Waytes et al. (1996) concluded that infusions of vapor-heated C1
inhibitor concentrate are a safe and effective means of both preventing
attacks of hereditary angioedema and treating acute attacks. The
concentrate was vapor-heated to inactivate hepatitis and human
immunodeficiency viruses.

Zuraw et al. (2010) conducted 2 randomized trials to evaluate
nanofiltered C1 inhibitor concentrate with placebo for treatment of an
acute attack of angioedema. A total of 68 subjects (35 in the C1
inhibitor group and 33 in the placebo group) were given 1 or 2
intravenous injections of the study drug (1,000 units each). The primary
endpoint was the time to the onset of unequivocal relief. In this study,
the median time to the onset of unequivocal relief from an attack was 2
hours in the subjects treated with C1 inhibitor concentrate but longer
than 4 hours in those given placebo (P = 0.02). The second study was a
crossover trial involving 22 subjects with hereditary angioedema that
compared prophylactic twice-weekly injections of nanofiltered C1
inhibitor concentrate (1,000 units) with placebo during two 12-week
periods. The primary endpoint was the number of attacks of angioedema
per period, with each subject acting as his or her own control. In this
study, the number of attacks per 12-week period was 6.26 with C1
inhibitor concentrate given as prophylaxis, as compared with 12.73 with
placebo (P less than 0.001); the subjects who received the C1 inhibitor
concentrate also had significant reductions in both the severity and the
duration of attacks, in the need for open-label rescue therapy, and in
the total number of days with swelling.

Cicardi et al. (2010) performed a double-blind, placebo-controlled
clinical trial in which patients with hereditary angioedema presenting
with an acute attack were randomly assigned in a 1-to-1 ratio to receive
subcutaneous ecallantide at a dose of 30 mg or placebo. Patients were
evaluated using treatment outcome scores and change from baseline in the
mean symptom complex severity score. The primary endpoint was the
treatment outcome score 4 hours after study-drug administration. A total
of 71 of the 72 patients completed the trial. The median treatment
outcome score at 4 hours was 50.0 in the ecallantide group and 0.0 in
the placebo group (interquartile range (IQR), 0.0 to 100.0 in both
groups; P = 0.004). The median change in the mean symptom complex
severity score at 4 hours was -1.00 (IQR, -1.50 to 0.00) with
ecallantide, versus -0.50 (IQR, -1.00 to 0.00) with placebo (P = 0.01).
The estimated time to significant improvement was 165 minutes with
ecallantide versus more than 240 minutes with placebo (P = 0.14). There
were no deaths, treatment-related serious adverse events, or withdrawals
owing to adverse events.

Cicardi et al. (2010) described 2 double-blind, randomized, multicenter
trials in which they evaluated the effect of icatibant, a selective
bradykinin B2 receptor (113503) antagonist, in patients with hereditary
angioedema presenting with cutaneous or abdominal attacks. In the For
Angioedema Subcutaneous Treatment (FAST)-1 trial, patients received
either icatibant or placebo; in FAST-2, patients received either
icatibant or oral tranexamic acid, at a dose of 3 g daily for 2 days.
Icatibant was given once, subcutaneously, at a dose of 30 mg. The
primary endpoint was the median time to clinically significant relief of
symptoms. A total of 56 and 74 patients underwent randomization in the
FAST-1 and FAST-2 trials, respectively. The primary endpoint was reached
in 2.5 hours with icatibant versus 4.6 hours with placebo in the FAST-1
trial (P = 0.14) and in 2.0 hours with icatibant versus 12.0 hours with
tranexamic acid in the FAST-2 trial (P less than 0.001). In the FAST-1
study, 3 recipients of icatibant and 13 recipients of placebo needed
treatment with rescue medication. The median time to first improvement
of symptoms, as assessed by patients and by investigators, was
significantly shorter with icatibant in both trials. No
icatibant-related serious adverse events were reported.

In an accompanying editorial to the articles by Zuraw et al. (2010),
Cicardi et al. (2010), and Cicardi et al. (2010), Morgan (2010)
suggested that the existence of several agents available to treat
hereditary angioedema will significantly improve survival for affected
individuals.

Wuillemin (2011) commented on the studies of Zuraw et al. (2010),
Cicardi et al. (2010), and Cicardi et al. (2010) and noted the
availability of a pasteurized C1 inhibitor preparation in several
European countries. He also mentioned the successful experience in
Switzerland of C1 inhibitor concentrate self-administration, with
regular practical training, for hereditary angioedema patients, and
concluded that self-administration leads to better medical outcome and
enhanced quality of life. Zuraw (2011) concurred. Morgan (2011) noted
that guidelines and requirements for possession and self-administration
of C1 inhibitor would exclude many patients, including children, and
that practitioners fear that drug use would escalate as patients treat
minor swellings or false prodromes. He suggested that the Swiss
experience might provide reassurance about these matters, and that
available data should be disseminated.

Referring to the studies of Cicardi et al. (2010) and Cicardi et al.
(2010), Giavina-Bianchi et al. (2011) stated that the registration in
only a few countries of formulations of C1 esterase-inhibitor
concentrate is not an adequate justification to use a placebo comparison
drug, and called for studies comparing icatibant and ecallantide with C1
esterase-inhibitor concentrate. Cicardi and Banerji (2011) replied that
since their studies were performed in accordance with both the
Declaration of Helsinki and expert consensus, they considered them
ethically acceptable.

- Management in Pregnancy

Chappatte and De Swiet (1988) gave an account of pregnancy in 2 patients
with HANE. They suggested that prophylaxis against attacks should not be
used during pregnancy and that severe attacks should be treated with
purified C1NH concentrate.

Cox and Holdcroft (1995) discussed the management of pregnancy and
delivery in a 20-year-old primiparous woman with a history of type I HAE
first diagnosed at age 12. She had been treated with an attenuated
androgen in low dose (danazol and then amicar), which raised her C1
esterase inhibitor level and controlled her symptoms. Danazol rendered
the patient oligomenorrheic. Since it is also teratogenic (Duck and
Katayama, 1981), it was withdrawn under hospital observation when she
decided to start a family. The recurrent symptoms were controlled with
intravenous administration of C1 esterase inhibitor. Vaginal delivery in
HAE may be impeded by perineal edema and abdominal pain may obscure
obstetric disorders. In this case, successful spontaneous vaginal
delivery was achieved using prophylactic C1 esterase inhibitor and
epidural analgesia.

MOLECULAR GENETICS

Stoppa-Lyonnet et al. (1987) studied DNA from multiple members of 2
families with hereditary angioedema and from 6 unrelated patients. Their
results indicated that a defective structural gene was responsible for
the disease. In a patient with type I HANE, Ariga et al. (1989) found a
deletion in exon 7 (606860.0001) of the C1NH gene. In 2 unrelated
families with HANE type II, Levy et al. (1990) demonstrated a G-to-A
change in codon 436 of the C1NH gene, resulting in an
alanine-to-threonine residue change (606860.0002).

Patients with HANE type I appear to have a deletion of the C1 inhibitor
gene or a truncated transcript because of a stop codon, whereas patients
with HANE type II have a single base substitution. The 2 forms are
clinically indistinguishable.

Guarino et al. (2006) reported 2 brothers with type I hereditary
angioedema in whom they identified heterozygosity for a nonsense
mutation in the C1NH gene (606860.0014). Clinical and laboratory
findings of both parents and relatives were normal. The mutation
occurred on the maternally transmitted chromosome, but was not detected
in DNA derived from the mother's buccal cells, urinary cells, hair
roots, or cultured fibroblasts, suggesting that the mother was a true
gonadal mosaic.

HISTORY

Quincke (1882) first described (and named) angioneurotic edema. Osler
(1888), while in Philadelphia, was first to describe the hereditary
form.

Dennehy (1970) called attention to the fact that Nathaniel Hawthorne was
apparently familiar with this disorder for in his 'House of the Seven
Gables' he described a family with members who gurgled in the throat and
chest when excited and who would sometimes die this way, ever since a
curse to choke on blood had been placed on 1 of their ancestors. Dennehy
(1970) interpreted the following passage as an indication that Hawthorne
recognized that a hereditary disease, not a curse, was responsible for
the deaths: 'This mode of death has been an idiosyncrasy with his
family, for generations past....Old Maule's prophecy was probably
founded on a knowledge of this physical predisposition in the Pyncheon
race.'

Six years before Quincke (1882) introduced the term angioneurotic edema,
Milton (1876) described 1 of his patients with angioedema in the
following words: 'So soon as ever she came into the room I recognized
the affection, for there lay, across the face from temple to temple, an
oblong tumor almost closing both eyes.'

Robson et al. (1979) demonstrated that HANE is not linked to HLA or PGM1
on chromosome 6 and not linked to C6, which had not been assigned.
Linkage to markers on 1p (Rh), 4q (MNSs), 9q (ABO), 16q (Hp), and 7 (Km)
was also excluded. Furthermore, HANE was not linked to Gm. Linkage to
HLA was excluded by Eggert et al. (1982). In family linkage studies,
Olaisen et al. (1985) obtained 'a clear hint' that the HANE locus may be
distal to F13A (134570) on 6p; the maximum lod score with F13A was 1.0
at a recombination fraction of 10%.

*FIELD* SA
Alper (1978); Austen and Sheaffer (1965); Blumenthal et al. (1978);
DeMarchi et al. (1973); Donaldson and Evans (1963); Gleich et al.
(1984); Harrington et al. (1984); Hartmann (1983); Landerman (1962);
Pickering et al. (1969); Schwarz et al. (1981); Sheffer et al. (1972);
Shokeir (1973); Small and Frenkiel (1983); Stewart et al. (1979);
Van Dellen and Myers (1980); Wuillemin (2011); Young et al. (1980);
Zuraw and Curd (1986)
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York: McGraw-Hill (pub.) (6th ed.) II: 1989. Pp. 2711-2737.

74. Wuillemin, W. A.: Comment on therapeutic agents for hereditary
angioedema. New Eng. J. Med. 364: 84-85, 2011.

75. Wuillemin, W. A.: Therapeutic agents for hereditary angioedema.
(Letter) New Eng. J. Med. 364: 84-85, 2011.

76. Yakushiji, Y.; Mizuta, H.; Kurohara, K.; Onoue, H.; Okada, R.;
Yoshimura, T.; Kuroda, Y.: Vasculitic neuropathy in a patient with
hereditary C1 inhibitor deficiency. Arch. Neurol. 64: 731-733, 2007.

77. Young, D. W.; Thompson, R. A.; Mackie, P. H.: Plasmapheresis
in hereditary angioneurotic edema and systemic lupus erythematosus. Arch.
Intern. Med. 140: 127-128, 1980.

78. Zuraw, B. L.: Hereditary angioedema. New Eng. J. Med. 359:
1027-1036, 2008.

79. Zuraw, B. L.: Reply to Wuillemin. (Letter) New Eng. J. Med. 364:
85-86, 2011.

80. Zuraw, B. L.; Busse, P. J.; White, M.; Jacobs, J.; Lumry, W.;
Baker, J.; Craig, T.; Grant, J. A.; Hurewitz, D.; Bielory, L.; Cartwright,
W. E.; Koleilat, M.; and 18 others: Nonofiltered C1 inhibitor concentrate
for treatment of hereditary angioedema. New Eng. J. Med. 363: 513-522,
2010.

81. Zuraw, B. L.; Curd, J. G.: Demonstration of modified inactive
first component of complement (C1) inhibitor in the plasmas of C1
inhibitor-deficient patients. J. Clin. Invest. 78: 567-575, 1986.

*FIELD* CS
INHERITANCE:
Autosomal dominant

RESPIRATORY:
[Nasopharynx];
Pharyngeal edema;
[Larynx];
Laryngeal edema

ABDOMEN:
Abdominal pain;
[Gastrointestinal];
Intestinal edema;
Diarrhea;
Vomiting

SKIN, NAILS, HAIR:
[Skin];
Erythema marginatum

MUSCLE, SOFT TISSUE:
Episodic, nonpruritic, nonurticarial, nonpitting edema

NEUROLOGIC:
[Peripheral nervous system];
Peripheral axonal neuropathy, distal, vasculitic;
Sural nerve biopsy shows axonal degeneration;
Impaired sensation of all modalities, distal

LABORATORY ABNORMALITIES:
C1 esterase inhibitor deficiency;
Low level of C4 and C2

MISCELLANEOUS:
Symptoms typically begin in childhood;
Prevalence estimated at 1 in 50,000;
Highly variable frequency and severity of attacks;
Trauma, anxiety, and/or stress can precipitate or aggravate edema;
Laryngeal edema can result in asphyxiation;
Associated with increased frequency of autoimmune diseases

MOLECULAR BASIS:
Caused by mutation in the C1 esterase inhibitor gene (C1NH, 106100.0001)

*FIELD* CN
Cassandra L. Kniffin - updated: 9/9/2008
Cassandra L. Kniffin - updated: 5/23/2008
Ada Hamosh - reviewed: 5/15/2000
Kelly A. Przylepa - revised: 2/25/2000

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 01/28/2009
ckniffin: 9/9/2008
ckniffin: 5/23/2008
joanna: 4/22/2008
joanna: 5/16/2000
joanna: 5/15/2000
kayiaros: 2/25/2000
kayiaros: 2/18/2000

*FIELD* CN
Ada Hamosh - updated: 1/19/2011
Ada Hamosh - updated: 8/20/2010
Cassandra L. Kniffin - updated: 9/9/2008
Cassandra L. Kniffin - updated: 4/1/2008
Marla J. F. O'Neill - updated: 9/8/2006
Cassandra L. Kniffin - reorganized: 4/25/2002
Cassandra L. Kniffin - updated: 4/25/2002
Victor A. McKusick - updated: 2/19/1998

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
alopez: 08/07/2013
terry: 3/28/2013
carol: 1/9/2013
terry: 12/19/2012
carol: 11/28/2011
terry: 5/16/2011
terry: 5/2/2011
carol: 4/29/2011
alopez: 1/25/2011
terry: 1/19/2011
alopez: 8/30/2010
terry: 8/20/2010
terry: 1/7/2009
wwang: 9/10/2008
ckniffin: 9/9/2008
wwang: 4/10/2008
ckniffin: 4/1/2008
alopez: 12/4/2006
wwang: 9/13/2006
wwang: 9/12/2006
terry: 9/8/2006
alopez: 11/10/2005
carol: 4/25/2002
ckniffin: 4/25/2002
ckniffin: 4/24/2002
ckniffin: 4/18/2002
terry: 3/13/2002
alopez: 3/13/2001
mcapotos: 3/5/2001
carol: 5/8/2000
carol: 9/8/1999
terry: 8/11/1998
dkim: 7/24/1998
dkim: 6/30/1998
terry: 2/19/1998
jamie: 10/23/1996
jamie: 10/16/1996
mark: 9/10/1996
terry: 9/3/1996
mark: 8/19/1996
mark: 8/14/1996
terry: 7/24/1996
terry: 10/30/1995
mark: 6/11/1995
jason: 6/17/1994
warfield: 4/7/1994
carol: 4/5/1994
mimadm: 2/21/1994

MIM 606860
*RECORD*
*FIELD* NO
606860
*FIELD* TI
*606860 COMPLEMENT COMPONENT 1 INHIBITOR; C1NH
;;C1I; C1INH;;
SERPIN PEPTIDASE INHIBITOR, CLADE G, MEMBER 1; SERPING1
read more*FIELD* TX

DESCRIPTION

C1 inhibitor is a plasma protein involved in the regulation of the
complement cascade. It is a member of a large serine protease inhibitor
(serpin) gene family.

CLONING

With 35% carbohydrate by weight, C1 inhibitor is the most highly
glycosylated serum protein. It is synthesized in the liver as a single
amino acid chain. Davis et al. (1986) characterized a cDNA clone that
represents about half the coding sequence of the protein. In the region
sequenced, C1NH showed about 22% identity with antithrombin III
(107300), 26% with alpha-1-antitrypsin (107400) and
alpha-1-antichymotrypsin (107280), and 18% with angiotensinogen.

Bock et al. (1986) cloned the cDNA of the human C1 inhibitor by peptide
and DNA sequencing, and determined that the single chain moiety, which
has 478 amino acid residues, accounts for little more than half the
molecular weight of the circulating protein, which is 104 kD. Comparison
of the amino acid and cDNA sequences showed that secretion is mediated
by a 22-residue signal peptide and that further proteolytic processing
does not occur.

GENE FUNCTION

C1 inhibitor regulates the first component of complement (C1) by
inhibition of the proteolytic activity of its subcomponents C1r and C1s.
This prevents activation of C4 and C2 by C1s. C1 inhibitor also inhibits
several other serine proteinases including plasmin, kallikrein, and
coagulation factors XIa and XIIa (Davis et al., 1986).

GENE STRUCTURE

Zahedi et al. (1993) determined that the C1NH gene contains 8 exons.

MAPPING

By study of hybrids between human fetal liver and rat hepatoma cells,
Cox and Francke (1985) concluded that the C1 inhibitor gene is on
chromosome 4, 8, 12, 20, or 21. Davis et al. (1986) demonstrated that
the C1NH gene is on chromosome 11, by using the cDNA clone to study
hybrid cells. By means of a cDNA probe in somatic cell hybrids,
Cohen-Haguenauer et al. (1986) confirmed the assignment to chromosome
11. Bock et al. (1986) assigned the gene to 11p11.2-q13 by Southern blot
analysis of DNA of mouse-human hybrid cells, some containing chromosomal
rearrangements. Theriault et al. (1989, 1990) used in situ hybridization
to obtain a more precise localization of the human C1 inhibitor gene to
chromosome 11q11-q13.1.

Lener et al. (1998) mapped the C1inh gene to mouse chromosome 2 by study
of recombinant inbred strains and by fluorescence in situ hybridization.

MOLECULAR GENETICS

Mutation in the C1NH gene has been shown to cause hereditary angioedema
(HAE; 106100). Patients with HAE type I (absent or low levels of an
antigenically-normal protein) appear to have a deletion of the C1
inhibitor gene or a truncated transcript because of a stop codon,
whereas patients with HAE type II (elevated or normal levels of a
dysfunctional protein) have a single base substitution (Davis et al.,
1992; Cicardi and Agostoni, 1996). The 2 forms are clinically
indistinguishable.

Stoppa-Lyonnet et al. (1987) studied DNA from multiple members of 2
families with hereditary angioedema type I and from 6 unrelated
patients. Using a cDNA probe, they identified in the larger of the 2
families a cluster of 4 distinctive restriction sites. The strict
cosegregation of these markers with a low C1 inhibitor level indicated
that a defective structural gene was responsible for the disease. In
this family they found alterations in the 5-prime half of the C1
inhibitor gene. In 2 other instances, structural changes appeared to
reside in that part of the gene. They concluded that probably each
family with type I hereditary angioedema carries a unique variant of the
C1 inhibitor gene and that the gene alterations arise more often from
DNA rearrangements than from nucleotide substitutions.

In contrast, Cicardi et al. (1987) found RFLPs in only 2 of 24 type I
families and in 1 of 5 families with type II hereditary angioedema. They
interpreted these findings as indicating that most of the mutations are
point mutations or other 'minor' defects and not major deletions or
rearrangements. In addition, Cicardi et al. (1987) concluded from
Northern and Southern blot analyses that the defect (or defects) in type
I HAE is pretranslational but is not due to a deletion or to a major
chromosomal rearrangement.

In 2 families with C1 inhibitor deficiency, Ariga et al. (1990) found
that deletions were the consequence of recombination of 2 Alu repetitive
DNA elements. In 1 family with a deletion measuring approximately 2 kb
and including exon 7, Alu repeat sequences from introns 6 and 7 combined
to make a novel Alu; in a second family, Alu sequences in introns 3 and
6 were spliced to make a new Alu with a resulting deletion measuring
approximately 8.5 kb and including exons 4-6. Unequal crossing-over
seemed the likely mechanism of these mutations.

Using 38 restriction enzymes, McPhaden et al. (1991) found a different
unique disease-related RFLP in 1 allele of the C1NH gene in 4 of 12
kindreds with HAE. The 4 mutations affected exons 4, 6, 7, and 8;
mutations in exons 6 and 8 had not previously been described. The C1NH
gene contains unusually dense clusters of Alu repeats in various
orientations. Among patients belonging to 45 unrelated families,
Stoppa-Lyonnet et al. (1991) found 8 partial C1NH gene deletions and a
partial duplication. Four deletions had one of the boundaries within the
gene and the other in extragenic regions--in 3 cases 5-prime of the gene
and in 1 case 3-prime of the gene. The boundaries of the partial
duplication and of the remaining 4 deletions mapped instead within a few
kilobases of exon 4. In each of these 5 rearrangements, one of the
breakpoints was in Alu 1, the first of 3 tandem Alu repeats preceding
exon 4. Moreover, these recombination breakpoints were spread over the
entire length of Alu 1, in contrast with the tight clustering observed
near the 5-prime end of Alu sequences rearranged in other human genes.
Stoppa-Lyonnet et al. (1991) suggested that a region of potential Z-DNA
structure, located 1.7 kb upstream of Alu 1, may contribute to these
peculiarities.

Kalmar et al. (2005) described an interactive, locus-specific mutation
database for the C1 inhibitor gene.

Among 87 Spanish families with HAE, Roche et al. (2005) identified 13
large rearrangements of the C1NH gene, 10 microdeletions/insertions, 10
missense, 5 nonsense, 8 splicing, and 3 splicing or missense mutations.
Two exonic mutations resulted in splice site abnormalities, suggesting
the presence of an exonic splicing enhancer in exon 5.

Guarino et al. (2006) reported 2 brothers with type I HAE in whom they
identified a nonsense mutation in the C1NH gene (606860.0014). Their
mother was found to be a gonadal mosaic for the mutation.

HISTORY

Shokeir (1973) suggested that the mutation is in a repressor which fails
to bind an inducer so that the operator site remains repressed. He
suggested that the repressor molecule has a very high affinity for the
operator site so that the amount of unbound repressor present in the
heterozygote suffices for repression of both operators. Shokeir (1973)
encountered greater difficulty in explaining the 'genetic variant' form
of angioedema. He presented the possibility that these persons are
heterozygous for an enzyme which attaches an auxiliary group to the
molecule (e.g., neuraminic acid), thereby altering its biologic but not
its immunologic properties. If true, this hypothesis points to the
existence of at least two loci at which mutation can lead to angioedema.

*FIELD* AV
.0001
ANGIOEDEMA, HEREDITARY, TYPE I
SERPING1, EX7DEL

In a patient with type I HAE (106100), Ariga et al. (1989) found 2
classes of mRNA, one abnormally short and one normal. Restriction
analysis suggested that exon 7 and portions of both flanking introns
were deleted in the mutant gene. This was confirmed by further studies
involving PCR amplification. Deletions in either exon 4 or exon 7 have
been identified in some type I kindreds (Cicardi et al., 1987;
Stoppa-Lyonnet et al., 1987; Ariga et al., 1989).

.0002
ANGIOEDEMA, HEREDITARY, TYPE II
SERPING1, ALA436THR

In 2 unrelated families with HAE type II (106100), Levy et al. (1990)
demonstrated a G-to-A change in codon 436 resulting in replacement of
alanine with a threonine residue. This position is 9 amino acid residues
amino-terminal to the reactive-center arginylthreonine peptide bond.
Previously defined mutations in type II HAE resulted in replacement of
the reactive-center arginine. Davis et al. (1992) showed that the
dysfunction demonstrated by this mutation results from a block in the
interaction with target protease.

.0003
ANGIOEDEMA, HEREDITARY, TYPE II
SERPING1, ARG444HIS

This and the arg444-to-cys mutation occur in the reactive center and
represent a change in the arginine codon (CGC) to either TGC (cysteine)
or CAC (histidine). These presumably result from deamination of
5-methylcytosine to thymidine within the CpG dinucleotide in either the
coding or the noncoding strand. See Aulak et al. (1988).

.0004
ANGIOEDEMA, HEREDITARY, TYPE II
SERPING1, ARG444CYS

See Skriver et al. (1989).

.0005
ANGIOEDEMA, HEREDITARY, TYPE II
SERPING1, ARG444SER

Aulak et al. (1990) identified a CGC-to-AGC mutation in codon 444 in a
case of type II hereditary angioedema (106100). The mutation is in the
reactive-center P1 residue. The arginine codon CGC can give rise to 6
possible products: pro, gly, leu, ser, his, and cys. Previously observed
mutations have been restricted either to histidine or to cysteine. This
limited mutational variability may be explained by the hypermutability
of the CpG dinucleotide, generating CpA (hence CAC, histidine) or TpG
(hence TGC, cysteine) dinucleotides.

.0006
ANGIOEDEMA, HEREDITARY, TYPE I
SERPING1, 1-BP INS, 1304A

In affected members of 2 unrelated families with type I hereditary
angioedema (106100) accompanied by elevated levels of C1NH mRNA, Frangi
et al. (1991) found normal and mutant transcripts. Single base mutations
near the 3-prime end of the coding sequence were identified in affected
members of each family. One mutation consisted of insertion of an
adenosine at position 1304 which created a premature termination codon
(TAA), whereas the second consisted of deletion of thymidine-1298 which
created a premature termination codon (TGA) 23 nucleotides downstream
(606860.0007). These mutations were located approximately 250
nucleotides upstream of the natural termination codon. The elevation in
the levels of the mutant transcript was ascribed to decreased
catabolism.

.0007
ANGIOEDEMA, HEREDITARY, TYPE I
SERPING1, 1-BP DEL, 1298T

See 606860.0006.

.0008
ANGIOEDEMA, HEREDITARY, TYPE I
SERPING1, IVS6, G-T, +1

In a family with type I hereditary angioedema (106100), Siddique et al.
(1991) identified a single base substitution (G-to-T) at nucleotide
8863. The mutation destroyed the 5-prime donor splice site recognition
motif of the sixth intron.

.0009
ANGIOEDEMA, HEREDITARY, TYPE I
SERPING1, 1-BP DEL, 11698C

Siddique et al. (1992) found deletion of a single base, C11698, from the
eighth exon of the C1NH gene. The mutation altered the reading frame and
generated a premature translation termination codon.

.0010
ANGIOEDEMA, HEREDITARY, TYPE II
SERPING1, VAL432GLU

In a patient heterozygous for a mutant dysfunctional C1 inhibitor
protein, Davis et al. (1992) identified a 'hinge' region mutation in C1
inhibitor: an A to T substitution at position 1396 producing a
val-to-glu replacement at residue 432. Recombinant C1 inhibitor with the
val432-to-glu mutation did not form stable complexes with fluid phase
C1s or kallikrein. The val432-to-glu mutant form was cleaved to a 96-K
form by C1s. Thus the mutation results in dysfunction, converting the
inhibitor to a substrate. Davis et al. (1992) demonstrated that this
mutation and the ala436-to-thr mutation (606860.0002) result in
dysfunction by different mechanisms.

.0011
ANGIOEDEMA, HEREDITARY, TYPE II
SERPING1, 3-BP INS, 16749TGT

In a 47-year-old male with type II HAE (106100), Siddique et al. (1993)
used PCR and nucleotide sequence analysis to characterize a 3-nucleotide
(TGT) insertion between nucleotides 16749 and 16750 in exon 8 of the
C1NH gene. The insertion caused a change at amino acid 431 from polar
glycine to nonpolar valine as well as the insertion of an additional
tryptophan residue. This was the first report of a nucleotide insertion
in the C1NH gene causing type II HAE.

.0012
COMPLEMENT COMPONENT 4, PARTIAL DEFICIENCY OF, DUE TO DYSFUNCTIONAL
C1 INHIBITOR
SERPING1, ALA443VAL

In 11 members of a 5-family kindred spanning 3 generations who had
partial deficiency of complement component-4 (120790), Zahedi et al.
(1995) demonstrated an ala443-to-val mutation in the C1NH gene,
resulting in a dysfunctional C1 inhibitor. The pattern of inheritance
was autosomal dominant, and there was no HLA linkage. The proband had
systemic lupus erythematosus, but no member had had angioedema. Serum C4
levels in affected members were less than 10 mg/dl (less than 33% of
pooled normal human serum) and did not fluctuate. Serum C2 levels
measured by hemolytic titration had always been normal. A mutant C1
inhibitor containing the ala443-to-val mutation, constructed by
site-directed mutagenesis and expressed in COS-1 cells, failed to
complex completely with C1r and showed impaired complexing with C1s. The
mutant inhibitor also formed a complex with trypsin, a serine protease
that normally cleaves, and is not inhibited by, C1 inhibitor. The
ala443-to-val mutation therefore converts C1 inhibitor from a substrate
to an inhibitor of trypsin.

.0013
ANGIOEDEMA, HEREDITARY, AUTOSOMAL RECESSIVE
SERPING1, C-T, -103

In 36 unrelated patients with hereditary angioedema (106100), Verpy et
al. (1996) performed a complete mutational scan of the C1NH gene,
comprising all 8 exons and adjacent intron sequences and the 550 bp
preceding the transcription start site, by using fluorescence-assisted
mismatched analysis (FAMA). Mutations accounting for C1 inhibitor
deficiency were identified in 34 patients; the 2 failures turned out to
be spurious cases resulting from the development of antibodies against
the C1 inhibitor (in one case, an acquired form of the disorder).
Homozygosity for a promoter mutation, a C-to-T transition at position
-103, was found in 2 members of a family. The mutation occurred in a
putative CAAT box and was the first promoter mutation reported in the
C1NH gene. In this family homozygosity correlated with low C1 inhibitor
levels and severe HAE. In contrast, heterozygous individuals had C1
inhibitor levels within the normal range, although often at its lower
level, and were free of angioedema attacks. No other idiomorphic
nucleotide change was found in this kindred to account for the
angioedema.

.0014
ANGIOEDEMA, HEREDITARY, TYPE I
SERPING1, TYR199TER

In 2 brothers with type I hereditary angioedema (106100), Guarino et al.
(2006) identified heterozygosity for a 597C-G transversion in exon 4 of
the C1NH gene, causing a tyr199-to-ter (Y199X) substitution, resulting
in a truncated protein lacking 302 amino acids. The mutation occurred on
the maternally transmitted chromosome, but was not detected in DNA
derived from the mother's buccal cells, urinary cells, hair roots, or
cultured fibroblasts, suggesting that the mother was a true gonadal
mosaic.

*FIELD* SA
Bock et al. (1986); Carter et al. (1988); Cicardi et al. (1987); Cohen
(1961)
*FIELD* RF
1. Ariga, T.; Carter, P. E.; Davis, A. E., III: Recombinations between
the Alu repeat sequences that result in partial deletions within the
C1 inhibitor gene. Genomics 8: 607-613, 1990.

2. Ariga, T.; Igarashi, T.; Ramesh, N.; Parad, R.; Cicardi, M.; Davis,
A. E., III: Type I C1 inhibitor deficiency with a small messenger
RNA resulting from deletion of one exon. J. Clin. Invest. 83: 1888-1893,
1989.

3. Aulak, K. S.; Cicardi, M.; Harrison, R. A.: Identification of
a new P1 residue mutation (444arg-to-ser) in a dysfunctional C1 inhibitor
protein contained in a type II hereditary angioedema plasma. FEBS
Lett. 266: 13-16, 1990.

4. Aulak, K. S.; Pemberton, P. A.; Rosen, F. S.; Carrell, R. W.; Lachmann,
P. J.; Harrison, R. A.: Dysfunctional C1-inhibitor (At), isolated
from a type II hereditary angiooedema plasma, contains a P1 'reactive
centre' (arg444-to-his) mutation. Biochem. J. 253: 615-618, 1988.

5. Bock, S. C.; Harrinan, J. A.; Radziejewska, E.; Donaldson, V. H.
: Structure of the normal human C1 inhibitor gene and preliminary
analysis of C1 inhibitor genes from patients with hereditary angioneurotic
edema. (Abstract) Am. J. Hum. Genet. 39: A189 only, 1986.

6. Bock, S. C.; Skriver, K.; Nielsen, E.; Thogersen, H.-C.; Wiman,
B.; Donaldson, V. H.; Eddy, R. L.; Marrinan, J.; Radziejewska, E.;
Huber, R.; Shows, T. B.; Magnusson, S.: Human C1 inhibitor: primary
structure, cDNA cloning, and chromosomal localization. Biochemistry 25:
4292-4301, 1986.

7. Carter, P. E.; Dunbar, B.; Fothergill, J. E.: Genomic and cDNA
cloning of the human C1 inhibitor: intron-exon junctions and comparison
with other serpins. Europ. J. Biochem. 173: 163-169, 1988.

8. Cicardi, M.; Agostoni, A.: Hereditary angioedema. (Editorial) New
Eng. J. Med. 334: 1666-1667, 1996.

9. Cicardi, M.; Igarashi, T.; Kim, M. S.; Frangi, D.; Agostoni, A.;
Davis, A. E., III: Restriction fragment length polymorphism of the
C1 inhibitor gene in hereditary angioneurotic edema. J. Clin. Invest. 80:
1640-1643, 1987.

10. Cicardi, M.; Igarashi, T.; Rosen, F. S.; Davis, A. E., III: Molecular
basis for the deficiency of complement 1 inhibitor in type I hereditary
angioneurotic edema. J. Clin. Invest. 79: 698-702, 1987.

11. Cohen, J. D.: Chronic familial giant urticaria. Ann. Intern.
Med. 54: 331-335, 1961.

12. Cohen-Haguenauer, O.; Tosi, M.; Meo, T.; Van Cong, N.; Frezal,
J.: Assignment of human complement C1r and C1s genes to chromosome
12 and of human C1-esterase inhibitor gene to chromosome 11. (Abstract) 7th
Int. Cong. Hum. Genet., Berlin 617 only, 1986.

13. Cox, D. W.; Francke, U.: Direct assignment of orosomucoid to
human chromosome 9 and alpha-2-HS-glycoprotein to chromosome 3 using
human fetal liver x rat hepatoma hybrids. Hum. Genet. 70: 109-115,
1985.

14. Davis, A. E., III; Aulak, K.; Parad, R. B.; Stecklein, H. P.;
Eldering, E.; Hack, C. E.; Kramer, J.; Strunk, R. C.; Bissler, J.;
Rosen, F. S.: C1 inhibitor hinge region mutations produce dysfunction
by different mechanisms. Nature Genet. 1: 354-358, 1992.

15. Davis, A. E., III; Whitehead, A. S.; Harrison, R. A.; Dauphinais,
A.; Bruns, G. A. P.; Cicardi, M.; Rosen, F. S.: Human inhibitor of
the first component of complement, C1: characterization of cDNA clones
and localization of the gene to chromosome 11. Proc. Nat. Acad. Sci. 83:
3161-3165, 1986.

16. Frangi, D.; Cicardi, M.; Sica, A.; Colotta, F.; Agostoni, A.;
Davis, A. E., III: Nonsense mutations affect C1 inhibitor messenger
RNA levels in patients with type I hereditary angioneurotic edema. J.
Clin. Invest. 88: 755-759, 1991.

17. Guarino, S.; Perricone, C.; Guarino, M. D.; Giardina, E.; Gambardella,
S.; D'Apice, M. R.; Bulli, C.; Perricone, R.; Novelli, G.: Gonadal
mosaicism in hereditary angioedema. (Letter) Clin. Genet. 70: 83-85,
2006.

18. Kalmar, L.; Hegedus, T.; Farkas, H.; Nagy, M.; Tordai, A.: HAEdb:
a novel interactive, locus-specific mutation database for the C1 inhibitor
gene. Hum. Mutat. 25: 1-5, 2005.

19. Lener, M.; Fernandes, M.; Poirier, C.; Bazzali-Hernandez, C.;
Tosi, M.; Meo, T.: The C1 inhibitor encoding gene (C1nh) maps to
mouse chromosome 2. Mammalian Genome 9: 94 only, 1998.

20. Levy, N. J.; Ramesh, N.; Cicardi, M.; Harrison, R. A.; Davis,
A. E., III: Type II hereditary angioneurotic edema that may result
from a single nucleotide change in the codon for alanine-436 in the
C1 inhibitor gene. Proc. Nat. Acad. Sci. 87: 265-268, 1990.

21. McPhaden, A. R.; Birnie, G. D.; Whaley, K.: Restriction fragment
length polymorphism analysis of the C1-inhibitor gene in hereditary
C1-inhibitor deficiency. Clin. Genet. 39: 161-171, 1991.

22. Roche, O.; Blanch, A.; Duponchel, C.; Fontan, G.; Tosi, M.; Lopez-Trascasa,
M.: Hereditary angioedema: the mutation spectrum of SERPING1/C1NH
in a large Spanish cohort. Hum. Mutat. 26: 135-144, 2005.

23. Shokeir, M. H. K.: The genetics of hereditary angioedema: a hypothesis. Clin.
Genet. 4: 494-499, 1973.

24. Siddique, Z.; McPhaden, A. R.; Lappin, D. F.; Whaley, K.: An
RNA splice site mutation in the C1-inhibitor gene causes type I hereditary
angio-oedema. Hum. Genet. 88: 231-232, 1991.

25. Siddique, Z.; McPhaden, A. R.; McCluskey, D.; Whaley, K.: A single
base deletion from the C1-inhibitor gene causes type I hereditary
angio-oedema. Hum. Hered. 42: 231-234, 1992.

26. Siddique, Z.; McPhaden, A. R.; Whaley, K.: C1-inhibitor gene
nucleotide insertion causes type II hereditary angio-oedema. Hum.
Genet. 92: 189-190, 1993.

27. Skriver, K.; Radziejewska, E.; Siebermann, J. A.; Donaldson, V.
H.; Bock, S. C.: CpG mutations in the reactive site of human C1 inhibitor. J.
Biol. Chem. 264: 3066-3071, 1989.

28. Stoppa-Lyonnet, D.; Duponchel, C.; Meo, T.; Laurent, J.; Carter,
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*FIELD* CN
Marla J. F. O'Neill - updated: 9/8/2006
Cassandra L. Kniffin - updated: 8/14/2006
Victor A. McKusick - updated: 2/4/2005

*FIELD* CD
Cassandra L. Kniffin: 4/17/2002

*FIELD* ED
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