RBCC

Full text data of C9

C9 [Confidence: low (only semi-automatic identification from reviews)]
Complement component C9; Complement component C9a; Complement component C9b; Flags: Precursor

UniProt P02748
ID CO9_HUMAN Reviewed; 559 AA.
AC P02748;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-FEB-1996, sequence version 2.
DT 22-JAN-2014, entry version 148.
DE RecName: Full=Complement component C9;
DE Contains:
DE RecName: Full=Complement component C9a;
DE Contains:
DE RecName: Full=Complement component C9b;
DE Flags: Precursor;
GN Name=C9;
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=4018030;
RA Stanley K.K., Kocher H.-P., Luzio J.P., Jackson P., Tschopp J.;
RT "The sequence and topology of human complement component C9.";
RL EMBO J. 4:375-382(1985).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Liver;
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 [3]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 2-559, AND PROTEIN SEQUENCE OF
RP N-TERMINUS.
RX PubMed=6095282; DOI=10.1073/pnas.81.23.7298;
RA Discipio R.G., Gehring M.R., Podack E.R., Kan C.C., Hugli T.E.,
RA Fey G.H.;
RT "Nucleotide sequence of cDNA and derived amino acid sequence of human
RT complement component C9.";
RL Proc. Natl. Acad. Sci. U.S.A. 81:7298-7302(1984).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 62-159.
RX PubMed=3219351; DOI=10.1021/bi00417a050;
RA Marazziti D., Eggertsen G., Fey G.H., Stanley K.K.;
RT "Relationships between the gene and protein structure in human
RT complement component C9.";
RL Biochemistry 27:6529-6534(1988).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 27-559, AND VARIANT C9D GLY-119.
RX PubMed=9634479; DOI=10.1007/s002510050415;
RA Witzel-Schloemp K., Hobart M.J., Fernie B.A., Orren A., Wuerzner R.,
RA Rittner C., Kaufmann T., Schneider P.M.;
RT "Heterogeneity in the genetic basis of human complement C9
RT deficiency.";
RL Immunogenetics 48:144-147(1998).
RN [6]
RP PARTIAL PROTEIN SEQUENCE, ELECTRON MICROSCOPY, AND GLYCOSYLATION AT
RP ASN-277 AND ASN-415.
RX PubMed=4055801;
RA DiScipio R.G., Hugli T.E.;
RT "The architecture of complement component C9 and poly(C9).";
RL J. Biol. Chem. 260:14802-14809(1985).
RN [7]
RP DISULFIDE BONDS.
RX PubMed=8603752; DOI=10.1016/0014-5793(95)01541-8;
RA Lengweiler S., Schaller J., Rickli E.E.;
RT "Identification of disulfide bonds in the ninth component (C9) of
RT human complement.";
RL FEBS Lett. 380:8-12(1996).
RN [8]
RP GLYCOSYLATION AT TRP-48 AND TRP-51.
RX PubMed=10551839; DOI=10.1074/jbc.274.46.32786;
RA Hofsteenge J., Blommers M., Hess D., Furmanek A., Miroshnichenko O.;
RT "The four terminal components of the complement system are C-
RT mannosylated on multiple tryptophan residues.";
RL J. Biol. Chem. 274:32786-32794(1999).
RN [9]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-415, AND MASS
RP 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 [10]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-277 AND ASN-415, AND MASS
RP 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 [11]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-415, AND MASS
RP SPECTROMETRY.
RC TISSUE=Platelet;
RX PubMed=16263699; DOI=10.1074/mcp.M500324-MCP200;
RA Lewandrowski U., Moebius J., Walter U., Sickmann A.;
RT "Elucidation of N-glycosylation sites on human platelet proteins: a
RT glycoproteomic approach.";
RL Mol. Cell. Proteomics 5:226-233(2006).
RN [12]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-277 AND ASN-415, 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 [13]
RP GLYCOSYLATION AT ASN-415.
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 [14]
RP 3D-STRUCTURE MODELING OF MEMBRANE-SPANNING DOMAIN (MSB).
RX PubMed=2395434; DOI=10.1016/0161-5890(90)90001-G;
RA Peitsch M.C., Amiguet P., Guy R., Brunner J., Maizel J.V. Jr.,
RA Tschopp J.;
RT "Localization and molecular modelling of the membrane-inserted domain
RT of the ninth component of human complement and perforin.";
RL Mol. Immunol. 27:589-602(1990).
CC -!- FUNCTION: Constituent of the membrane attack complex (MAC) that
CC plays a key role in the innate and adaptive immune response by
CC forming pores in the plasma membrane of target cells. C9 is the
CC pore-forming subunit of the MAC.
CC -!- SUBUNIT: Component of the membrane attack complex (MAC). MAC
CC assembly is initiated by protelytic cleavage of C5 into C5a and
CC C5b. C5b binds sequentially C6, C7, C8 and multiple copies of the
CC pore-forming subunit C9.
CC -!- SUBCELLULAR LOCATION: Secreted. Cell membrane; Multi-pass membrane
CC protein. Note=Secreted as soluble monomer. Oligomerizes at target
CC membranes, forming a pre-pore. A conformation change then leads to
CC the formation of a 100 Angstrom diameter pore.
CC -!- TISSUE SPECIFICITY: Plasma.
CC -!- PTM: Thrombin cleaves factor C9 to produce C9a and C9b.
CC -!- PTM: Phosphorylation sites are present in the extracellular
CC medium.
CC -!- DISEASE: Complement component 9 deficiency (C9D) [MIM:613825]: A
CC rare defect of the complement classical pathway associated with
CC susceptibility to severe recurrent infections predominantly by
CC Neisseria gonorrhoeae or Neisseria meningitidis. Some patients may
CC develop dermatomyositis. Note=Disease susceptibility is associated
CC with variations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the complement C6/C7/C8/C9 family.
CC -!- SIMILARITY: Contains 1 EGF-like domain.
CC -!- SIMILARITY: Contains 1 LDL-receptor class A domain.
CC -!- SIMILARITY: Contains 1 MACPF domain.
CC -!- SIMILARITY: Contains 1 TSP type-1 domain.
CC -!- WEB RESOURCE: Name=C9base; Note=C9 mutation db;
CC URL="http://bioinf.uta.fi/C9base/";
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DR EMBL; X02176; CAA26117.1; -; mRNA.
DR EMBL; BC020721; AAH20721.1; -; mRNA.
DR EMBL; K02766; AAA51889.1; -; mRNA.
DR EMBL; J02833; AAA51890.1; -; Genomic_DNA.
DR EMBL; Y08545; CAA69849.1; -; Genomic_DNA.
DR EMBL; Y08546; CAA69849.1; JOINED; Genomic_DNA.
DR EMBL; Y08547; CAA69849.1; JOINED; Genomic_DNA.
DR EMBL; Y08548; CAA69849.1; JOINED; Genomic_DNA.
DR EMBL; Y08549; CAA69849.1; JOINED; Genomic_DNA.
DR EMBL; Y08550; CAA69849.1; JOINED; Genomic_DNA.
DR EMBL; Y08551; CAA69849.1; JOINED; Genomic_DNA.
DR EMBL; Y08552; CAA69849.1; JOINED; Genomic_DNA.
DR EMBL; Y08553; CAA69849.1; JOINED; Genomic_DNA.
DR EMBL; Y08554; CAA69849.1; JOINED; Genomic_DNA.
DR PIR; A59363; C9HU.
DR RefSeq; NP_001728.1; NM_001737.3.
DR UniGene; Hs.654443; -.
DR ProteinModelPortal; P02748; -.
DR SMR; P02748; 36-540.
DR DIP; DIP-1124N; -.
DR MINT; MINT-2800316; -.
DR STRING; 9606.ENSP00000263408; -.
DR PhosphoSite; P02748; -.
DR DMDM; 1352108; -.
DR PaxDb; P02748; -.
DR PeptideAtlas; P02748; -.
DR PRIDE; P02748; -.
DR DNASU; 735; -.
DR Ensembl; ENST00000263408; ENSP00000263408; ENSG00000113600.
DR GeneID; 735; -.
DR KEGG; hsa:735; -.
DR UCSC; uc003jlv.4; human.
DR CTD; 735; -.
DR GeneCards; GC05M039320; -.
DR HGNC; HGNC:1358; C9.
DR HPA; CAB002151; -.
DR HPA; HPA029577; -.
DR MIM; 120940; gene.
DR MIM; 613825; phenotype.
DR neXtProt; NX_P02748; -.
DR Orphanet; 169150; Immunodeficiency due to a late component of complements deficiency.
DR PharmGKB; PA25968; -.
DR eggNOG; NOG46204; -.
DR HOGENOM; HOG000111869; -.
DR HOVERGEN; HBG106792; -.
DR InParanoid; P02748; -.
DR KO; K04000; -.
DR OMA; PWNVASL; -.
DR OrthoDB; EOG7D85W9; -.
DR PhylomeDB; P02748; -.
DR Reactome; REACT_6900; Immune System.
DR GenomeRNAi; 735; -.
DR NextBio; 2992; -.
DR PRO; PR:P02748; -.
DR ArrayExpress; P02748; -.
DR Bgee; P02748; -.
DR CleanEx; HS_C9; -.
DR Genevestigator; P02748; -.
DR GO; GO:0005737; C:cytoplasm; IDA:HPA.
DR GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR GO; GO:0005887; C:integral to plasma membrane; TAS:ProtInc.
DR GO; GO:0005579; C:membrane attack complex; IEA:UniProtKB-KW.
DR GO; GO:0006957; P:complement activation, alternative pathway; IEA:UniProtKB-KW.
DR GO; GO:0006958; P:complement activation, classical pathway; IEA:UniProtKB-KW.
DR GO; GO:0019835; P:cytolysis; IEA:UniProtKB-KW.
DR GO; GO:0019836; P:hemolysis by symbiont of host erythrocytes; TAS:ProtInc.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR GO; GO:0030449; P:regulation of complement activation; TAS:Reactome.
DR Gene3D; 4.10.400.10; -; 1.
DR InterPro; IPR009030; Growth_fac_rcpt_N_dom.
DR InterPro; IPR023415; LDLR_class-A_CS.
DR InterPro; IPR002172; LDrepeatLR_classA_rpt.
DR InterPro; IPR001862; MAC_perforin.
DR InterPro; IPR020864; MACPF.
DR InterPro; IPR020863; MACPF_CS.
DR InterPro; IPR000884; Thrombospondin_1_rpt.
DR Pfam; PF00057; Ldl_recept_a; 1.
DR Pfam; PF01823; MACPF; 1.
DR Pfam; PF00090; TSP_1; 1.
DR PRINTS; PR00764; COMPLEMENTC9.
DR SMART; SM00192; LDLa; 1.
DR SMART; SM00457; MACPF; 1.
DR SMART; SM00209; TSP1; 1.
DR SUPFAM; SSF57184; SSF57184; 2.
DR SUPFAM; SSF57424; SSF57424; 1.
DR SUPFAM; SSF82895; SSF82895; 1.
DR PROSITE; PS00022; EGF_1; 1.
DR PROSITE; PS01186; EGF_2; 1.
DR PROSITE; PS50026; EGF_3; FALSE_NEG.
DR PROSITE; PS01209; LDLRA_1; 1.
DR PROSITE; PS50068; LDLRA_2; 1.
DR PROSITE; PS00279; MACPF_1; 1.
DR PROSITE; PS51412; MACPF_2; 1.
DR PROSITE; PS50092; TSP1; 1.
PE 1: Evidence at protein level;
KW Cell membrane; Complement alternate pathway; Complement pathway;
KW Complete proteome; Cytolysis; Direct protein sequencing;
KW Disease mutation; Disulfide bond; EGF-like domain; Glycoprotein;
KW Immunity; Innate immunity; Membrane; Membrane attack complex;
KW Phosphoprotein; Polymorphism; Reference proteome; Secreted; Signal;
KW Transmembrane; Transmembrane beta strand.
FT SIGNAL 1 21
FT CHAIN 22 559 Complement component C9.
FT /FTId=PRO_0000023602.
FT CHAIN 22 265 Complement component C9a.
FT /FTId=PRO_0000023603.
FT CHAIN 266 559 Complement component C9b.
FT /FTId=PRO_0000023604.
FT TRANSMEM 314 330 Beta stranded; (Potential).
FT TRANSMEM 335 354 Beta stranded; (Potential).
FT DOMAIN 42 95 TSP type-1.
FT DOMAIN 99 136 LDL-receptor class A.
FT DOMAIN 138 509 MACPF.
FT DOMAIN 510 540 EGF-like.
FT SITE 265 266 Cleavage; by thrombin.
FT CARBOHYD 48 48 C-linked (Man).
FT CARBOHYD 51 51 C-linked (Man); partial.
FT CARBOHYD 277 277 N-linked (GlcNAc...).
FT CARBOHYD 415 415 N-linked (GlcNAc...) (complex).
FT DISULFID 43 78
FT DISULFID 54 57
FT DISULFID 88 94
FT DISULFID 101 112
FT DISULFID 107 125
FT DISULFID 119 134
FT DISULFID 142 181
FT DISULFID 254 255
FT DISULFID 380 405
FT DISULFID 510 526
FT DISULFID 513 528
FT DISULFID 530 539
FT VARIANT 5 5 R -> W (in dbSNP:rs700233).
FT /FTId=VAR_022024.
FT VARIANT 119 119 C -> G (in C9D).
FT /FTId=VAR_012648.
FT VARIANT 127 127 D -> Y (in dbSNP:rs696763).
FT /FTId=VAR_050481.
FT VARIANT 203 203 I -> V (in dbSNP:rs13361416).
FT /FTId=VAR_027651.
FT VARIANT 279 279 T -> S (in dbSNP:rs34625111).
FT /FTId=VAR_033802.
FT VARIANT 427 427 S -> T (in dbSNP:rs34421659).
FT /FTId=VAR_061503.
FT CONFLICT 43 43 C -> R (in Ref. 3; AAA51889).
FT CONFLICT 314 314 Missing (in Ref. 3; AAA51889).
FT CONFLICT 417 417 T -> P (in Ref. 3; AAA51889).
SQ SEQUENCE 559 AA; 63173 MW; 7403F6AD77B3ECE1 CRC64;
MSACRSFAVA ICILEISILT AQYTTSYDPE LTESSGSASH IDCRMSPWSE WSQCDPCLRQ
MFRSRSIEVF GQFNGKRCTD AVGDRRQCVP TEPCEDAEDD CGNDFQCSTG RCIKMRLRCN
GDNDCGDFSD EDDCESEPRP PCRDRVVEES ELARTAGYGI NILGMDPLST PFDNEFYNGL
CNRDRDGNTL TYYRRPWNVA SLIYETKGEK NFRTEHYEEQ IEAFKSIIQE KTSNFNAAIS
LKFTPTETNK AEQCCEETAS SISLHGKGSF RFSYSKNETY QLFLSYSSKK EKMFLHVKGE
IHLGRFVMRN RDVVLTTTFV DDIKALPTTY EKGEYFAFLE TYGTHYSSSG SLGGLYELIY
VLDKASMKRK GVELKDIKRC LGYHLDVSLA FSEISVGAEF NKDDCVKRGE GRAVNITSEN
LIDDVVSLIR GGTRKYAFEL KEKLLRGTVI DVTDFVNWAS SINDAPVLIS QKLSPIYNLV
PVKMKNAHLK KQNLERAIED YINEFSVRKC HTCQNGGTVI LMDGKCLCAC PFKFEGIACE
ISKQKISEGL PALEFPNEK
//

MIM 120940
*RECORD*
*FIELD* NO
120940
*FIELD* TI
*120940 COMPLEMENT COMPONENT 9; C9
*FIELD* TX

DESCRIPTION

Activation of the complement system results in formation of the membrane
read moreattack complex (MAC) on the membranes of target cells. The complex is
assembled by sequential addition of 1 molecule each of C5b (120900), C6
(217050), C7 (217070), and C8 (see 120950) and 6 to 16 molecules of the
ninth component, C9. MAC assembly results in membrane disruption,
leading to death of the target cell (summary by DiScipio et al., 1984).

CLONING

DiScipio et al. (1984) screened a human liver cDNA library by the
colony-hybridization technique using 2 radiolabelled oligonucleotide
probes corresponding to regions of the C9 amino acid sequence. The cDNA
coding for C9 was sequenced. The derived protein consists of 537 amino
acids in a single polypeptide chain. The N-terminal half of C9 is
predominantly hydrophilic, whereas the C-terminal half is more
hydrophobic. The amphipathic organization of the primary structure is
consistent with the potential of polymerized C9 to penetrate lipid
bilayers and cause the formation of transmembrane channels as part of
the lytic action of MAC.

Marazziti et al. (1988) compared the protein structure of C9 with that
of low density lipoprotein receptor (LDLR; 606945).

GENE STRUCTURE

Marazziti et al. (1988) compared the gene structure of C9 with that of
LDLR (606945). The C9 gene contains 11 exons with lengths of 100 to 250
bp, except for exon 11, which includes the 3-prime UTR and extends over
more than 1 kb. Witzel-Schlomp et al. (1997) gave revised information on
the structure of the C9 gene, especially the exon-intron boundaries.

MAPPING

By hybridizing a cloned cDNA coding for human complement factor C9 to
hybrid cells containing subsets of human chromosomes on a rodent
background, Rogne et al. (1989) localized the gene for C9 to chromosome
5. Abbott et al. (1989) used a novel application of PCR to amplify
specifically the human C9 gene on a background of rodent DNA in somatic
cell hybrids. The assignment of the gene to 5p13 was confirmed and
regionalized by in situ hybridization.

Coto et al. (1991) identified RFLPs for the C6, C7, and C9 loci and
showed that these 3 loci are tightly linked. When examining the
haplotypes of unrelated parents in their family study, they found
significant linkage disequilibrium between C6 and C7 and between C7 and
C9. Thus, the so-called terminal complement components are encoded by a
cluster of genes. Coto et al. (1991) suggested that this cluster be
referred to as MACII, MACI being the C8A (120950) and C8B (120960)
cluster. Rogne et al. (1991) used DNA polymorphism of C9 and protein
variants of C6 to show that the 2 genes are closely linked (maximum lod
= 9.28 at theta = 0.00). They found no indication of allelic
association. Setien et al. (1993) found that although the C6 and C7
genes are contained in the same NotI fragment of 500 kb, no evidence of
physical linkage between C9 and C6 or C7 could be found in a range 50 kb
to 2.5 Mb.

MOLECULAR GENETICS

- C9 Deficiency

Witzel-Schlomp et al. (1997) described 2 mutations of the C9 gene,
present in compound heterozygote state, in members of a Swiss family
with C9 deficiency (613825) reported by Zoppi et al. (1990).

Horiuchi et al. (1998) reported the molecular basis for C9 deficiency in
10 unrelated Japanese individuals. By use of exon-specific
PCR/single-strand conformation polymorphism analysis, they demonstrated
aberrantly migrating DNA bands in all 10 individuals. Subsequent direct
sequencing of exon 4 revealed that 8 of the 10 were homozygous for a
C-to-T transition at nucleotide 343 of the C9 gene, resulting in an
arg95-to-ter (R95X; 120940.0001) substitution. Family study for 1 of
these individuals confirmed the genetic nature of the defect. The
remaining 2 individuals with C9 deficiency were heterozygous for the
R95X mutation. One of these individuals was compound heterozygous for
R95X and a cys507-to-tyr (C507Y; 120940.0005) mutation, whereas the
genetic defect(s) in the other allele in the second heterozygous
individual was not identified.

Witzel-Schlomp et al. (1998) studied the genetic basis of inherited C9
deficiency in an adult of Irish origin reported previously by Hobart et
al. (1997) and in an unrelated Irish family in which 1 member had died
at the age of 22 years of meningitis, probably meningococcal. In the
first case, heterozygosity for C6, C7, and C9 DNA markers was found,
indicating probable compound heterozygosity of the C9 mutations. One
mutation was the same as one of those observed in the Swiss family of
Zoppi et al. (1990) (120940.0002). The second C9 mutation, a C-to-T
transition, was found in exon 4 at cDNA position 350, resulting in R95X.
Two different mutations were detected in the second Irish family: a
C-to-G transversion in exon 9 creating a TGA stop codon, located at cDNA
nucleotide 1284 (S406X; 120940.0004), and a T-to-G change in exon 4,
cDNA nucleotide 359, leading to a cys98-to-gly (C98G; 120940.0003)
substitution.

Ichikawa et al. (2001) reported a 28-year-old Japanese woman with C9
deficiency and dermatomyositis. DNA sequence analysis revealed a
nonsense mutation at arg95 of the C9 gene (120940.0001). This case
demonstrated that the muscle lesions of dermatomyositis can occur in the
presence of a complement defect that would prevent the formation of the
C5b-9 membrane attack complex.

- Age-Related Macular Degeneration

Seddon et al. (2013) sequenced the exons of 681 genes within all
reported age-related macular degeneration (ARMD) loci and related
pathways in 2,493 cases. They genotyped 5,115 independent samples and
confirmed association with ARMD of an allele in the C9 gene encoding a
pro167-to-ser variant (120940.0006).

*FIELD* AV
.0001
C9 DEFICIENCY
C9, ARG95TER

Horiuchi et al. (1998) found that 8 of 10 unrelated Japanese subjects
with C9 deficiency (613825) were homozygous for a C-to-T transition at
nucleotide 343, which converted codon 95 from CGA (arg) to TGA (stop).
Two other patients were heterozygous for the R95X mutation; one of these
had a C507Y (120940.0005) substitution, while the genetic defect in the
other allele of the second heterozygote remained unknown. Kira et al.
(1998) likewise found that all 4 Japanese C9-deficient patients who had
suffered from meningococcal meningitis had this CGA (arg)-to-TGA (stop)
mutation.

Ichikawa et al. (2001) found this mutation in a 28-year-old Japanese
woman with C9 deficiency and dermatomyositis. Whereas levels of serum
hemolytic complement (CH50) are characteristically normal or elevated in
patients with dermatomyositis, this patient showed markedly depressed
levels of CH50. This case demonstrated that the muscle lesions of
dermatomyositis can occur in the presence of a complement defect that
would prevent the formation of the C5b-9 membrane attack complex.

The R95X mutation is responsible for most Japanese C9 deficiency cases,
with a carrier frequency of 6.7%. Khajoee et al. (2003) showed that in
Koreans and Chinese, the R95X carrier frequencies were 2.0% and 1.0%,
respectively. The founder effect found in East Asians (Japanese,
Koreans, and Chinese) but not in Caucasians, as well as the haplotype
sharing in only a small chromosomal region, suggested that the R95X
mutation is ancient and occurred after the divergence of East Asians and
Caucasians, and before migration of the Yayoi people to Japan. Because
the mortality of meningococcal infections in complement-deficient
patients is lower than that in normal individuals, a founder effect and
a selective advantage in isolation might be the main reasons for the
high frequency of the R95X mutation in Japan.

.0002
C9 DEFICIENCY
C9, CYS33TER

Witzel-Schlomp et al. (1997) found heterozygosity at the C9 locus in
affected members of a Swiss family with C9 deficiency (613825) reported
by Zoppi et al. (1990). One of the mutations was located in exon 2 at
cDNA nucleotide 166, resulting in a change of amino acid 33 from cys
(TGC) to stop (TGA). The same mutation was found in compound
heterozygous state in an adult of Irish origin with inherited C9
deficiency. The second mutation in this case was a C-to-T transition in
exon 4 at cDNA nucleotide 350, changing arg95 (CGA) to stop (TGA)
(120940.0001).

.0003
C9 DEFICIENCY
C9, CYS98GLY

In an Irish family designated Y with C9 deficiency (613825),
Witzel-Schlomp et al. (1998) found compound heterozygosity for a
cys98-to-gly mutation, due to a T-to-G transversion in exon 4 (cDNA
nucleotide 359); and a C-to-G transversion in exon 9 at cDNA nucleotide
1284, changing amino acid 406 from ser (TCA) to stop (TGA)
(120940.0004).

.0004
C9 DEFICIENCY
C9, SER406TER

See 120940.0004 and Witzel-Schlomp et al. (1998).

.0005
C9 DEFICIENCY
C9, CYS507TYR

See 120940.0001 and Horiuchi et al. (1998).

.0006
MACULAR DEGENERATION, AGE-RELATED, 15, SUSCEPTIBILITY TO
C9, PRO167SER (dbSNP rs34882957)

Seddon et al. (2013) found an increased risk of age-related macular
degeneration (ARMD15; 615591) among individuals carrying a pro167-to-ser
(P167S) mutation in the C9 gene (dbSNP rs34882957), with a joint p value
of 6.5 x 10(-7) and an odds ratio of 2.2.

*FIELD* SA
Shiver et al. (1986)
*FIELD* RF
1. Abbott, C.; West, L.; Povey, S.; Jeremiah, S.; Murad, Z.; DiScipio,
R.; Fey, G.: The gene for human complement component C9 mapped to
chromosome 5 by polymerase chain reaction. Genomics 4: 606-609,
1989.

2. Coto, E.; Martinez-Naves, E.; Dominguez, O.; DiScipio, R. G.; Urra,
J. M.; Lopez-Larrea, C.: DNA polymorphism and linkage relationship
of the human complement component C6, C7, and C9 genes. Immunogenetics 33:
184-187, 1991.

3. DiScipio, R. G.; Gehring, M. R.; Podack, E. R.; Kan, C. C.; Hugli,
T. E.; Fey, G. H.: Nucleotide sequence of cDNA and derived amino
acid sequence of human complement component C9. Proc. Nat. Acad.
Sci. 81: 7298-7302, 1984.

4. Hobart, M. J.; Fernie, B. A.; Wurzner, R.; Oldroyd, R. G.; Harrison,
R. A.; Joysey, V.; Lachmann, P. J.: Difficulties in the ascertainment
of C9 deficiency: lessons to be drawn from a compound heterozygote
C9-deficient subject. Clin. Exp. Immun. 108: 500-506, 1997.

5. Horiuchi, T.; Nishizaka, H.; Kojima, T.; Sawabe, T.; Niho, Y.;
Schneider, P. M.; Inaba, S.; Sakai, K.; Hayashi, K.; Hashimura, C.;
Fukumori, Y.: A non-sense mutation at arg95 is predominant in complement
9 deficiency in Japanese. J. Immun. 160: 1509-1513, 1998.

6. Ichikawa, E.; Furuta, J.; Kawachi, Y.; Imakado, S.; Otsuka, F.
: Hereditary complement (C9) deficiency associated with dermatomyositis. Brit.
J. Derm. 144: 1080-1083, 2001.

7. Khajoee, V.; Ihara, K.; Kira, R.; Takemoto, M.; Torisu, H.; Sakai,
Y.; Guanjun, J.; Hee, P. M.; Tokunaga, K.; Hara, T.: Founder effect
of the C9 R95X mutation in Orientals. Hum. Genet. 112: 244-248,
2003.

8. Kira, R.; Ihara, K.; Takada, H.; Gondo, K.; Hara, T.: Nonsense
mutation in exon 4 of human complement C9 gene is the major cause
of Japanese complement C9 deficiency. Hum. Genet. 102: 605-610,
1998.

9. Marazziti, D.; Eggertsen, G.; Fey, G. H.; Stanley, K. K.: Relationships
between the gene and protein structure in human complement component
C9. Biochemistry 27: 6529-6534, 1988.

10. Rogne, S.; Myklebost, O.; Olving, J. H.; Tomter Kyrkjebo, H.;
Jonassen, R.; Olaisen, B.; Gedde-Dahl, T., Jr.: The human genes for
complement components 6 (C6) and 9 (C9) are closely linked on chromosome
5. J. Med. Genet. 28: 587-590, 1991.

11. Rogne, S.; Myklebost, O.; Stanley, K.; Geurts van Kessel, A.:
The gene for human complement C9 is on chromosome 5. Genomics 5:
149-152, 1989.

12. Seddon, J. M.; Yu, Y.; Miller, E. C.; Reynolds, R.; Tan, P. L.;
Gowrisankar, S.; Goldstein, J. I.; Triebwasser, M.; Anderson, H. E.;
Zerbib, J.; Kavanagh, D.; Souied, E.; Katsanis, N.; Daly, M. J.; Atkinson,
J. P.; Raychaudhuri, S.: Rare variants in CFI, C3 and C9 are associated
with high risk of advanced age-related macular degeneration. Nature
Genet. 45: 1366-1370, 2013.

13. Setien, F.; Alvarez, V.; Coto, E.; DiScipio, R. G.; Lopez-Larrea,
C.: A physical map of the human complement component C6, C7, and
C9 genes. Immunogenetics 38: 341-344, 1993.

14. Shiver, J. W.; Dankert, J. R.; Donovan, J. J.; Esser, A. F.:
The ninth component of human complement (C9): functional activity
of the b fragment. J. Biol. Chem. 261: 9629-9636, 1986.

15. Witzel-Schlomp, K.; Hobart, M. J.; Fernie, B. A.; Orren, A.; Wurzner,
R.; Rittner, C.; Kaufmann, T.; Schneider, P. M.: Heterogeneity in
the genetic basis of human complement C9 deficiency. Immunogenetics 48:
144-147, 1998.

16. Witzel-Schlomp, K.; Spath, P. J.; Hobart, M. J.; Fernie, B. A.;
Rittner, C.; Kaufmann, T.; Schneider, P. M.: The human complement
C9 gene: identification of two mutations causing deficiency and revision
in the gene structure. J. Immun. 158: 5043-5049, 1997.

17. Zoppi, M.; Weiss, M.; Nydegger, U. E.; Hess, T.; Spath, P. J.
: Recurrent meningitis in a patient with congenital deficiency of
the C9 component of complement: first case of C9 deficiency in Europe. Arch.
Intern. Med. 150: 2395-2399, 1990.

*FIELD* CN
Ada Hamosh - updated: 1/7/2014
Paul J. Converse - updated: 3/15/2011
Victor A. McKusick - updated: 3/25/2003
Gary A. Bellus - updated: 2/20/2003
Victor A. McKusick - updated: 4/12/1999
Victor A. McKusick - updated: 2/19/1999
Victor A. McKusick - updated: 8/3/1998
Victor A. McKusick - updated: 6/10/1998

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

*FIELD* ED
alopez: 01/07/2014
alopez: 1/7/2014
carol: 4/22/2011
mgross: 3/23/2011
terry: 3/15/2011
carol: 3/17/2004
cwells: 11/7/2003
tkritzer: 4/1/2003
terry: 3/25/2003
alopez: 2/20/2003
ckniffin: 6/5/2002
carol: 4/13/1999
terry: 4/12/1999
mgross: 3/10/1999
carol: 2/22/1999
terry: 2/19/1999
carol: 8/4/1998
terry: 8/3/1998
carol: 6/11/1998
terry: 6/11/1998
dholmes: 6/10/1998
mark: 11/27/1996
carol: 3/19/1995
carol: 11/9/1993
supermim: 3/16/1992
carol: 3/3/1992
carol: 11/8/1991
carol: 6/24/1991

MIM 613825
*RECORD*
*FIELD* NO
613825
*FIELD* TI
#613825 COMPLEMENT COMPONENT 9 DEFICIENCY; C9D
;;C9 DEFICIENCY
*FIELD* TX
A number sign (#) is used with this entry because complement component-9
read moredeficiency is caused by mutation in the C9 gene (120940).

CLINICAL FEATURES

Lint et al. (1980) reported C9 deficiency in a Caucasian family.

Kusaba et al. (1983) reported a large family with hereditary deficiency
of C9. The proposita was a 64-year-old Japanese woman with gastric
cancer. C9 was not detectable by either rocket immunoelectrophoresis or
hemolytic assay. C9 was also undetectable in 2 healthy sisters. Levels
presumably indicative of heterozygosity (22 to 46% of normal) were found
in 8 males and 7 females from 3 generations of the family. One instance
of male-to-male transmission was found, and all offspring of homozygotes
tested had heterozygous levels. No liability to specific disease was
detected in any. This appeared to be the ninth family with C9 deficiency
reported from Japan.

Yonemura et al. (1990) found that deficiency of C9 tempered the clinical
manifestations, specifically hemolysis, in a woman who also had
paroxysmal nocturnal hemoglobinuria.

MAPPING

C9 deficiency results from mutation in the C9 gene, which was mapped to
chromosome 5p13 by Abbott et al. (1989).

MOLECULAR GENETICS

- C9 Deficiency

Witzel-Schlomp et al. (1997) described 2 mutations of the C9 gene,
present in compound heterozygote state, in members of a Swiss family
with C9 deficiency reported by Zoppi et al. (1990).

Horiuchi et al. (1998) reported the molecular basis for C9 deficiency in
10 unrelated Japanese individuals. By use of exon-specific
PCR/single-strand conformation polymorphism analysis, they demonstrated
aberrantly migrating DNA bands in all 10 individuals. Subsequent direct
sequencing of exon 4 revealed that 8 of the 10 were homozygous for a
C-to-T transition at nucleotide 343 of the C9 gene, resulting in an
arg95-to-ter (R95X; 120940.0001) substitution. Family study for 1 of
these individuals confirmed the genetic nature of the defect. The
remaining 2 individuals with C9 deficiency were heterozygous for the
R95X mutation. One of these individuals was compound heterozygous for
R95X and a cys507-to-tyr (C507Y; 120940.0005) mutation, whereas the
genetic defect(s) in the other allele in the second heterozygous
individual was not identified.

Witzel-Schlomp et al. (1998) studied the genetic basis of inherited C9
deficiency in an adult of Irish origin reported previously by Hobart et
al. (1997) and in an unrelated Irish family in which 1 member had died
at the age of 22 years of meningitis, probably meningococcal. In the
first case, heterozygosity for C6, C7, and C9 DNA markers was found,
indicating probable compound heterozygosity of the C9 mutations. One
mutation was the same as one of those observed in the Swiss family of
Zoppi et al. (1990) (120940.0002). The second C9 mutation, a C-to-T
transition, was found in exon 4 at cDNA position 350, resulting in R95X.
Two different mutations were detected in the second Irish family: a
C-to-G transversion in exon 9 creating a TGA stop codon, located at cDNA
nucleotide 1284 (S406X; 120940.0004), and a T-to-G change in exon 4,
cDNA nucleotide 359, leading to a cys98-to-gly (C98G; 120940.0003)
substitution.

Ichikawa et al. (2001) reported a 28-year-old Japanese woman with C9
deficiency and dermatomyositis. DNA sequence analysis revealed a
nonsense mutation at arg95 of the C9 gene (R95X; 120940.0001). This case
demonstrated that the muscle lesions of dermatomyositis can occur in the
presence of a complement defect that would prevent the formation of the
C5b-9 membrane attack complex.

- Carrier Detection

Alvarez et al. (1995) analyzed RFLPs at the closely linked C6 (217050),
C7 (217070), and C9 loci in a family with brothers who had C9 deficiency
and recurrent Neisseria meningitidis. The haplotype carrying the
'silent' C9 allele was defined, allowing for detection of carriers among
asymptomatic relatives.

POPULATION GENETICS

Deficiency of C9 is one of the most common genetic abnormalities in
Japan with an incidence of 1 homozygote in 1,000. Very few cases of C9
deficiency have been reported in Caucasians. Although affected
individuals are usually healthy, it has been shown that they have a
significantly increased risk of developing meningococcal meningitis
(Nagata et al., 1989).

By screening for complement deficiencies in 145,640 blood donors from
Osaka and combining their results with reports of 92,686 donors from
throughout Japan, Fukumori and Horiuchi (1998) identified 5 individuals
with C5 deficiency (609536), 6 individuals with C6 deficiency (612446),
17 individuals with C7 deficiency (610102), 5 individuals with C8
alpha/gamma deficiency (613790), and 439 individuals with C9 deficiency.
A homozygous R95X (120940.0001) mutation in the C9 gene had been
identified in 8 of 10 unrelated Japanese individuals with C9 deficiency
by Horiuchi et al. (1998). The other 2 individuals were compound
heterozygous for R95X and a second mutation. Fukumori and Horiuchi
(1998) concluded that the R95X mutation is relatively common in all
Asian populations, but not in European populations.

To determine the prevalence of heterozygous carriers of R95X in a
Japanese population, Kira et al. (1999) collected DNA samples from 300
individuals in 2 of the 4 main islands of Japan. Twenty individuals were
heterozygous; none was homozygous. The prevalence of carriers was placed
at 6.7% (20/300). An estimated frequency (0.12%) of complete C9
deficiency due to homozygosity for this mutation was consistent with
frequencies determined by serologic studies.

*FIELD* RF
1. Abbott, C.; West, L.; Povey, S.; Jeremiah, S.; Murad, Z.; DiScipio,
R.; Fey, G.: The gene for human complement component C9 mapped to
chromosome 5 by polymerase chain reaction. Genomics 4: 606-609,
1989.

2. Alvarez, V.; Coto, E.; Setien, F.; Spath, P. J.; Lopez-Larrea,
C.: Genetic detection of the silent allele (*Q0) in hereditary deficiencies
of the human complement C6, C7, and C9 components. Am. J. Med. Genet. 55:
408-413, 1995.

3. Fukumori, Y.; Horiuchi, T.: Terminal complement component deficiencies
in Japan. Exp. Clin. Immunogenet. 15: 244-248, 1998.

4. Hobart, M. J.; Fernie, B. A.; Wurzner, R.; Oldroyd, R. G.; Harrison,
R. A.; Joysey, V.; Lachmann, P. J.: Difficulties in the ascertainment
of C9 deficiency: lessons to be drawn from a compound heterozygote
C9-deficient subject. Clin. Exp. Immun. 108: 500-506, 1997.

5. Horiuchi, T.; Nishizaka, H.; Kojima, T.; Sawabe, T.; Niho, Y.;
Schneider, P. M.; Inaba, S.; Sakai, K.; Hayashi, K.; Hashimura, C.;
Fukumori, Y.: A non-sense mutation at arg95 is predominant in complement
9 deficiency in Japanese. J. Immun. 160: 1509-1513, 1998.

6. Ichikawa, E.; Furuta, J.; Kawachi, Y.; Imakado, S.; Otsuka, F.
: Hereditary complement (C9) deficiency associated with dermatomyositis. Brit.
J. Derm. 144: 1080-1083, 2001.

7. Kira, R.; Ihara, K.; Watanabe, K.; Kanemitsu, S.; Ahmed, S. U.;
Gondo, K.; Takeshita, K.; Hara, T.: Molecular epidemiology of C9
deficiency heterozygotes with an arg95-to-stop mutation of the C9
gene in Japan. J. Hum. Genet. 44: 109-111, 1999.

8. Kusaba, T.; Kisu, T.; Inaba, S.; Sakai, K.; Okochi, K.; Yanase,
T.: A pedigree of deficiency of the ninth component of complement
(C9). Jpn. J. Hum. Genet. 28: 239-248, 1983.

9. Lint, T. F.; Zeitz, H. J.; Gewurz, H.: Inherited deficiency of
the ninth component of complement in man. J. Immun. 125: 2252-2257,
1980.

10. Nagata, M.; Hara, T.; Aoki, T.; Mizuno, Y.; Akeda, H.; Inaba;
Tsumoto, K.; Ueda, K.: Inherited deficiency of ninth component of
complement: an increased risk of meningococcal meningitis. J. Pediat. 114:
260-264, 1989.

11. Witzel-Schlomp, K.; Hobart, M. J.; Fernie, B. A.; Orren, A.; Wurzner,
R.; Rittner, C.; Kaufmann, T.; Schneider, P. M.: Heterogeneity in
the genetic basis of human complement C9 deficiency. Immunogenetics 48:
144-147, 1998.

12. Witzel-Schlomp, K.; Spath, P. J.; Hobart, M. J.; Fernie, B. A.;
Rittner, C.; Kaufmann, T.; Schneider, P. M.: The human complement
C9 gene: identification of two mutations causing deficiency and revision
in the gene structure. J. Immun. 158: 5043-5049, 1997.

13. Yonemura, Y.; Kawakita, M.; Koito, A.; Kawaguchi, T.; Nakakuma,
H.; Kagimoto, T.; Shichishima, T.; Terasawa, T.; Akagaki, Y.; Inai,
S.; Takatsuki, K.: Paroxysmal nocturnal haemoglobinuria with coexisting
deficiency of the ninth component of complement: lack of massive haemolytic
attack. Brit. J. Haemat. 74: 108-113, 1990.

14. Zoppi, M.; Weiss, M.; Nydegger, U. E.; Hess, T.; Spath, P. J.
: Recurrent meningitis in a patient with congenital deficiency of
the C9 component of complement: first case of C9 deficiency in Europe. Arch.
Intern. Med. 150: 2395-2399, 1990.

*FIELD* CD
Matthew B. Gross: 3/23/2011

*FIELD* ED
carol: 04/22/2011
mgross: 3/23/2011

RBCC Red Blood Cell Collection

Full text data of C9