RBCC Red Blood Cell Collection

NOD2 (CARD15, IBD1) [Confidence: low (only semi-automatic identification from reviews)]
Nucleotide-binding oligomerization domain-containing protein 2 (Caspase recruitment domain-containing protein 15; Inflammatory bowel disease protein 1)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt Q9HC29
ID NOD2_HUMAN Reviewed; 1040 AA.
AC Q9HC29; E2JEQ6; Q96RH5; Q96RH6; Q96RH8;
DT 31-JAN-2002, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-MAR-2001, sequence version 1.
DT 22-JAN-2014, entry version 138.
DE RecName: Full=Nucleotide-binding oligomerization domain-containing protein 2;
DE AltName: Full=Caspase recruitment domain-containing protein 15;
DE AltName: Full=Inflammatory bowel disease protein 1;
GN Name=NOD2; Synonyms=CARD15, IBD1;
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] (ISOFORMS 1 AND 2), MUTAGENESIS OF LYS-305,
RP AND VARIANT ARG-908.
RC TISSUE=Mammary gland;
RX PubMed=11087742; DOI=10.1074/jbc.M008072200;
RA Ogura Y., Inohara N., Benito A., Chen F.F., Yamaoka S., Nunez G.;
RT "Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and
RT activates NF-kappaB.";
RL J. Biol. Chem. 276:4812-4818(2001).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORMS 1 AND 2), VARIANTS
RP THR-140; ARG-157; MET-189; CYS-235; ARG-248; SER-268; SER-289;
RP ASN-291; VAL-301; TRP-311; VAL-348; ARG-352; CYS-373; SER-414;
RP LEU-431; VAL-432; LYS-441; VAL-612; THR-612; TRP-684; TRP-702;
RP CYS-703; CYS-713; GLY-725; VAL-755; VAL-758; LYS-778; MET-793;
RP LYS-843; SER-853; VAL-863; THR-885; ARG-908; ASP-918; ASP-924 AND
RP ILE-955, AND INVOLVEMENT IN IBD1.
RC TISSUE=Leukocyte;
RX PubMed=11385576; DOI=10.1038/35079107;
RA Hugot J.-P., Chamaillard M., Zouali H., Lesage S., Cezard J.-P.,
RA Belaiche J., Almer S., Tysk C., O'Morain C.A., Gassull M., Binder V.,
RA Finkel Y., Cortot A., Modigliani R., Laurent-Puig P.,
RA Gower-Rousseau C., Macry J., Colombel J.-F., Sahbatou M., Thomas G.;
RT "Association of NOD2 leucine-rich repeat variants with susceptibility
RT to Crohn's disease.";
RL Nature 411:599-603(2001).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3).
RX PubMed=20698950; DOI=10.1186/1756-0500-3-224;
RA Kramer M., Boeck J., Reichenbach D., Kaether C., Schreiber S.,
RA Platzer M., Rosenstiel P., Huse K.;
RT "NOD2-C2 - a novel NOD2 isoform activating NF-kappaB in a muramyl
RT dipeptide-independent manner.";
RL BMC Res. Notes 3:224-224(2010).
RN [4]
RP INTERACTION WITH RIPK2.
RX PubMed=19592251; DOI=10.1016/j.cub.2009.06.038;
RA Tao M., Scacheri P.C., Marinis J.M., Harhaj E.W., Matesic L.E.,
RA Abbott D.W.;
RT "ITCH K63-ubiquitinates the NOD2 binding protein, RIP2, to influence
RT inflammatory signaling pathways.";
RL Curr. Biol. 19:1255-1263(2009).
RN [5]
RP IDENTIFICATION IN A COMPLEX WITH ARHGEF2 AND RIPK2, AND INTERACTION
RP WITH RIPK2.
RX PubMed=21887730; DOI=10.1002/ibd.21851;
RA Zhao Y., Alonso C., Ballester I., Song J.H., Chang S.Y., Guleng B.,
RA Arihiro S., Murray P.J., Xavier R., Kobayashi K.S., Reinecker H.C.;
RT "Control of NOD2 and Rip2-dependent innate immune activation by GEF-
RT H1.";
RL Inflamm. Bowel Dis. 18:603-612(2012).
RN [6]
RP INTERACTION WITH ATG16L1.
RX PubMed=23376921; DOI=10.1038/emboj.2013.8;
RA Boada-Romero E., Letek M., Fleischer A., Pallauf K., Ramon-Barros C.,
RA Pimentel-Muinos F.X.;
RT "TMEM59 defines a novel ATG16L1-binding motif that promotes local
RT activation of LC3.";
RL EMBO J. 32:566-582(2013).
RN [7]
RP FUNCTION.
RX PubMed=23806334; DOI=10.1016/j.molcel.2013.06.004;
RA Fiil B.K., Damgaard R.B., Wagner S.A., Keusekotten K., Fritsch M.,
RA Bekker-Jensen S., Mailand N., Choudhary C., Komander D.,
RA Gyrd-Hansen M.;
RT "OTULIN restricts Met1-linked ubiquitination to control innate immune
RT signaling.";
RL Mol. Cell 50:818-830(2013).
RN [8]
RP VARIANTS BS GLN-334; TRP-334 AND PHE-469.
RX PubMed=11528384; DOI=10.1038/ng720;
RA Miceli-Richard C., Lesage S., Rybojad M., Prieur A.M.,
RA Manouvrier-Hanu S., Hafner R., Chamaillard M., Zouali H., Thomas G.,
RA Hugot J.-P.;
RT "CARD15 mutations in Blau syndrome.";
RL Nat. Genet. 29:19-20(2001).
RN [9]
RP VARIANTS EOS GLU-382; LEU-496 AND THR-612.
RX PubMed=15459013; DOI=10.1182/blood-2004-07-2972;
RA Kanazawa N., Okafuji I., Kambe N., Nishikomori R., Nakata-Hizume M.,
RA Nagai S., Fuji A., Yuasa T., Manki A., Sakurai Y., Nakajima M.,
RA Kobayashi H., Fujiwara I., Tsutsumi H., Utani A., Nishigori C.,
RA Heike T., Nakahata T., Miyachi Y.;
RT "Early-onset sarcoidosis and CARD15 mutations with constitutive
RT nuclear factor-kappaB activation: common genetic etiology with Blau
RT syndrome.";
RL Blood 105:1195-1197(2005).
RN [10]
RP VARIANT BS LYS-383.
RX PubMed=15812565; DOI=10.1038/sj.ejhg.5201404;
RA van Duist M.M., Albrecht M., Podswiadek M., Giachino D., Lengauer T.,
RA Punzi L., De Marchi M.;
RT "A new CARD15 mutation in Blau syndrome.";
RL Eur. J. Hum. Genet. 13:742-747(2005).
RN [11]
RP VARIANT BS ASN-605.
RX PubMed=19169908; DOI=10.1080/03009740802464194;
RA Milman N., Ursin K., Rodevand E., Nielsen F.C., Hansen T.V.;
RT "A novel mutation in the NOD2 gene associated with Blau syndrome: a
RT Norwegian family with four affected members.";
RL Scand. J. Rheumatol. 38:190-197(2009).
RN [12]
RP VARIANT BS TRP-334.
RX PubMed=20199415; DOI=10.1111/j.1525-1470.2009.01060.x;
RA Stoevesandt J., Morbach H., Martin T.M., Zierhut M., Girschick H.,
RA Hamm H.;
RT "Sporadic Blau syndrome with onset of widespread granulomatous
RT dermatitis in the newborn period.";
RL Pediatr. Dermatol. 27:69-73(2010).
CC -!- FUNCTION: Recognizes muramyl dipeptide (MDP) constituents of
CC bacterial peptidoglycans and plays a key role in gastrointestinal
CC immunity: upon stimulation, binds the proximal adapter receptor-
CC interacting RIPK2, which recruits ubiquitin ligases as XIAP,
CC BIRC2, BIRC3 and the LUBAC complex, triggering activation of MAP
CC kinases and activation of NF-kappa-B signaling, leading to
CC activate the transcription of hundreds of genes involved in immune
CC response.
CC -!- SUBUNIT: Found in a signaling complex consisting of ARHGEF2, NOD2
CC and RIPK2. Interacts (via CARD domain) with RIPK2 (via CARD
CC domain). Interacts with ATG16L1.
CC -!- SUBCELLULAR LOCATION: Cytoplasm.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative initiation; Named isoforms=3;
CC Name=1; Synonyms=Nod2;
CC IsoId=Q9HC29-1; Sequence=Displayed;
CC Note=Can activate NF-kappa-B. More abundant;
CC Name=2; Synonyms=Nod2b;
CC IsoId=Q9HC29-2; Sequence=VSP_018689;
CC Note=Can activate NF-kappa-B;
CC Name=3; Synonyms=NOD2-C2;
CC IsoId=Q9HC29-3; Sequence=VSP_018689, VSP_046567, VSP_046568;
CC Note=Can activate NF-kappa-B;
CC -!- TISSUE SPECIFICITY: Monocytes-specific.
CC -!- DOMAIN: The ATG16L1-binding motif mediates interaction with
CC ATG16L1 (PubMed:23376921).
CC -!- DISEASE: Blau syndrome (BS) [MIM:186580]: Rare autosomal dominant
CC disorder characterized by early-onset granulomatous arthritis,
CC uveitis and skin rash. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- DISEASE: Inflammatory bowel disease 1 (IBD1) [MIM:266600]: A
CC chronic, relapsing inflammation of the gastrointestinal tract with
CC a complex etiology. It is subdivided into Crohn disease and
CC ulcerative colitis phenotypes. Crohn disease may affect any part
CC of the gastrointestinal tract from the mouth to the anus, but most
CC frequently it involves the terminal ileum and colon. Bowel
CC inflammation is transmural and discontinuous; it may contain
CC granulomas or be associated with intestinal or perianal fistulas.
CC In contrast, in ulcerative colitis, the inflammation is continuous
CC and limited to rectal and colonic mucosal layers; fistulas and
CC granulomas are not observed. Both diseases include extraintestinal
CC inflammation of the skin, eyes, or joints. Note=Disease
CC susceptibility is associated with variations affecting the gene
CC represented in this entry.
CC -!- DISEASE: Sarcoidosis early-onset (EOS) [MIM:609464]: A form of
CC sarcoidosis manifesting in children younger than 4 years of age.
CC Sarcoidosis is an idiopathic, systemic, inflammatory disease
CC characterized by the formation of immune granulomas in involved
CC organs. Granulomas predominantly invade the lungs and the
CC lymphatic system, but also skin, liver, spleen, eyes and other
CC organs may be involved. Early-onset sarcoidosis is quite rare and
CC has a distinct triad of skin, joint and eye disorders, without
CC apparent pulmonary involvement. Compared with an asymptomatic and
CC sometimes naturally disappearing course of the disease in older
CC children, early-onset sarcoidosis is progressive and in many cases
CC causes severe complications, such as blindness, joint destruction
CC and visceral involvement. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Contains 2 CARD domains.
CC -!- SIMILARITY: Contains 9 LRR (leucine-rich) repeats.
CC -!- SIMILARITY: Contains 1 NACHT domain.
CC -!- WEB RESOURCE: Name=INFEVERS; Note=Repertory of FMF and hereditary
CC autoinflammatory disorders mutations;
CC URL="http://fmf.igh.cnrs.fr/ISSAID/infevers/search.php?n=6";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/NOD2";
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DR EMBL; AF178930; AAG33677.1; -; mRNA.
DR EMBL; AF385089; AAK70867.1; -; Genomic_DNA.
DR EMBL; AF385090; AAK70868.1; -; Genomic_DNA.
DR EMBL; AJ303140; CAC42117.1; -; Genomic_DNA.
DR EMBL; HQ204571; ADN95581.1; -; mRNA.
DR RefSeq; NP_071445.1; NM_022162.1.
DR RefSeq; XP_005256141.1; XM_005256084.1.
DR UniGene; Hs.592072; -.
DR ProteinModelPortal; Q9HC29; -.
DR SMR; Q9HC29; 291-316, 747-1029.
DR DIP; DIP-41998N; -.
DR IntAct; Q9HC29; 1.
DR MINT; MINT-151071; -.
DR STRING; 9606.ENSP00000300589; -.
DR BindingDB; Q9HC29; -.
DR ChEMBL; CHEMBL1293266; -.
DR GuidetoPHARMACOLOGY; 1763; -.
DR PhosphoSite; Q9HC29; -.
DR DMDM; 20137973; -.
DR PaxDb; Q9HC29; -.
DR PRIDE; Q9HC29; -.
DR DNASU; 64127; -.
DR Ensembl; ENST00000300589; ENSP00000300589; ENSG00000167207.
DR GeneID; 64127; -.
DR KEGG; hsa:64127; -.
DR UCSC; uc010cbj.1; human.
DR CTD; 64127; -.
DR GeneCards; GC16P050729; -.
DR HGNC; HGNC:5331; NOD2.
DR MIM; 186580; phenotype.
DR MIM; 266600; phenotype.
DR MIM; 605956; gene.
DR MIM; 609464; phenotype.
DR neXtProt; NX_Q9HC29; -.
DR Orphanet; 117; Behcet disease.
DR Orphanet; 90340; Blau syndrome.
DR Orphanet; 206; Crohn disease.
DR Orphanet; 771; Ulcerative colitis.
DR PharmGKB; PA26074; -.
DR eggNOG; NOG248107; -.
DR HOGENOM; HOG000113814; -.
DR HOVERGEN; HBG050792; -.
DR InParanoid; Q9HC29; -.
DR KO; K10165; -.
DR OMA; VWNKGTW; -.
DR OrthoDB; EOG7P5T07; -.
DR PhylomeDB; Q9HC29; -.
DR Reactome; REACT_6782; TRAF6 Mediated Induction of proinflammatory cytokines.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; Q9HC29; -.
DR GeneWiki; NOD2; -.
DR GenomeRNAi; 64127; -.
DR NextBio; 35496989; -.
DR PRO; PR:Q9HC29; -.
DR ArrayExpress; Q9HC29; -.
DR Bgee; Q9HC29; -.
DR CleanEx; HS_NOD2; -.
DR Genevestigator; Q9HC29; -.
DR GO; GO:0009986; C:cell surface; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; IDA:HGNC.
DR GO; GO:0005886; C:plasma membrane; IDA:HGNC.
DR GO; GO:0031982; C:vesicle; IDA:HGNC.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0032500; F:muramyl dipeptide binding; IDA:HGNC.
DR GO; GO:0042834; F:peptidoglycan binding; IDA:HGNC.
DR GO; GO:0035419; P:activation of MAPK activity involved in innate immune response; ISS:BHF-UCL.
DR GO; GO:0071224; P:cellular response to peptidoglycan; IEA:Ensembl.
DR GO; GO:0002367; P:cytokine production involved in immune response; IMP:UniProtKB.
DR GO; GO:0042742; P:defense response to bacterium; IDA:HGNC.
DR GO; GO:0050830; P:defense response to Gram-positive bacterium; IEA:Ensembl.
DR GO; GO:0016045; P:detection of bacterium; IDA:HGNC.
DR GO; GO:0032498; P:detection of muramyl dipeptide; IDA:HGNC.
DR GO; GO:0002381; P:immunoglobulin production involved in immunoglobulin mediated immune response; IEA:Ensembl.
DR GO; GO:0045087; P:innate immune response; IDA:UniProtKB.
DR GO; GO:0002227; P:innate immune response in mucosa; IEA:Ensembl.
DR GO; GO:0007254; P:JNK cascade; TAS:Reactome.
DR GO; GO:0071608; P:macrophage inflammatory protein-1 alpha production; IEA:Ensembl.
DR GO; GO:0002282; P:microglial cell activation involved in immune response; IEA:Ensembl.
DR GO; GO:0002755; P:MyD88-dependent toll-like receptor signaling pathway; TAS:Reactome.
DR GO; GO:0044130; P:negative regulation of growth of symbiont in host; IEA:Ensembl.
DR GO; GO:0002862; P:negative regulation of inflammatory response to antigenic stimulus; IEA:Ensembl.
DR GO; GO:0032689; P:negative regulation of interferon-gamma production; IEA:Ensembl.
DR GO; GO:0032695; P:negative regulation of interleukin-12 production; IEA:Ensembl.
DR GO; GO:0032701; P:negative regulation of interleukin-18 production; IEA:Ensembl.
DR GO; GO:0032703; P:negative regulation of interleukin-2 production; IEA:Ensembl.
DR GO; GO:2000110; P:negative regulation of macrophage apoptotic process; ISS:BHF-UCL.
DR GO; GO:0032088; P:negative regulation of NF-kappaB transcription factor activity; IEA:Ensembl.
DR GO; GO:0002710; P:negative regulation of T cell mediated immunity; IEA:Ensembl.
DR GO; GO:0034136; P:negative regulation of toll-like receptor 2 signaling pathway; IEA:Ensembl.
DR GO; GO:0032720; P:negative regulation of tumor necrosis factor production; IEA:Ensembl.
DR GO; GO:0070431; P:nucleotide-binding oligomerization domain containing 2 signaling pathway; IDA:UniProtKB.
DR GO; GO:0052033; P:pathogen-associated molecular pattern dependent induction by symbiont of host innate immune response; IEA:Ensembl.
DR GO; GO:0050871; P:positive regulation of B cell activation; IDA:BHF-UCL.
DR GO; GO:0006965; P:positive regulation of biosynthetic process of antibacterial peptides active against Gram-positive bacteria; IEA:Ensembl.
DR GO; GO:0002606; P:positive regulation of dendritic cell antigen processing and presentation; ISS:BHF-UCL.
DR GO; GO:0002732; P:positive regulation of dendritic cell cytokine production; IEA:Ensembl.
DR GO; GO:0050679; P:positive regulation of epithelial cell proliferation; ISS:BHF-UCL.
DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; ISS:BHF-UCL.
DR GO; GO:0046645; P:positive regulation of gamma-delta T cell activation; ISS:BHF-UCL.
DR GO; GO:0002925; P:positive regulation of humoral immune response mediated by circulating immunoglobulin; IEA:Ensembl.
DR GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB cascade; IDA:UniProtKB.
DR GO; GO:0050718; P:positive regulation of interleukin-1 beta secretion; IDA:HGNC.
DR GO; GO:0032733; P:positive regulation of interleukin-10 production; ISS:BHF-UCL.
DR GO; GO:0032735; P:positive regulation of interleukin-12 production; IEA:Ensembl.
DR GO; GO:0032740; P:positive regulation of interleukin-17 production; IMP:UniProtKB.
DR GO; GO:0032755; P:positive regulation of interleukin-6 production; IDA:BHF-UCL.
DR GO; GO:0046330; P:positive regulation of JNK cascade; IDA:MGI.
DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; IDA:UniProtKB.
DR GO; GO:0051770; P:positive regulation of nitric-oxide synthase biosynthetic process; ISS:BHF-UCL.
DR GO; GO:0045747; P:positive regulation of Notch signaling pathway; ISS:BHF-UCL.
DR GO; GO:0050731; P:positive regulation of peptidyl-tyrosine phosphorylation; IEA:Ensembl.
DR GO; GO:0050766; P:positive regulation of phagocytosis; IEA:Ensembl.
DR GO; GO:0043552; P:positive regulation of phosphatidylinositol 3-kinase activity; ISS:BHF-UCL.
DR GO; GO:2000363; P:positive regulation of prostaglandin-E synthase activity; ISS:BHF-UCL.
DR GO; GO:0060585; P:positive regulation of prostaglandin-endoperoxide synthase activity; ISS:BHF-UCL.
DR GO; GO:0032760; P:positive regulation of tumor necrosis factor production; IMP:BHF-UCL.
DR GO; GO:0002830; P:positive regulation of type 2 immune response; IMP:BHF-UCL.
DR GO; GO:0051259; P:protein oligomerization; TAS:HGNC.
DR GO; GO:0050727; P:regulation of inflammatory response; IC:BHF-UCL.
DR GO; GO:0090022; P:regulation of neutrophil chemotaxis; IEA:Ensembl.
DR GO; GO:0043330; P:response to exogenous dsRNA; IEA:Ensembl.
DR GO; GO:0032496; P:response to lipopolysaccharide; IEA:Ensembl.
DR GO; GO:0007584; P:response to nutrient; IEA:Ensembl.
DR GO; GO:0034166; P:toll-like receptor 10 signaling pathway; TAS:Reactome.
DR GO; GO:0034134; P:toll-like receptor 2 signaling pathway; TAS:Reactome.
DR GO; GO:0034138; P:toll-like receptor 3 signaling pathway; TAS:Reactome.
DR GO; GO:0034142; P:toll-like receptor 4 signaling pathway; TAS:Reactome.
DR GO; GO:0034146; P:toll-like receptor 5 signaling pathway; TAS:Reactome.
DR GO; GO:0034162; P:toll-like receptor 9 signaling pathway; TAS:Reactome.
DR GO; GO:0038123; P:toll-like receptor TLR1:TLR2 signaling pathway; TAS:Reactome.
DR GO; GO:0038124; P:toll-like receptor TLR6:TLR2 signaling pathway; TAS:Reactome.
DR GO; GO:0035666; P:TRIF-dependent toll-like receptor signaling pathway; TAS:Reactome.
DR Gene3D; 1.10.533.10; -; 2.
DR InterPro; IPR001315; CARD.
DR InterPro; IPR011029; DEATH-like_dom.
DR InterPro; IPR001611; Leu-rich_rpt.
DR InterPro; IPR007111; NACHT_NTPase.
DR InterPro; IPR027417; P-loop_NTPase.
DR Pfam; PF00619; CARD; 2.
DR SMART; SM00114; CARD; 1.
DR SUPFAM; SSF47986; SSF47986; 2.
DR SUPFAM; SSF52540; SSF52540; 1.
DR PROSITE; PS50209; CARD; 2.
DR PROSITE; PS51450; LRR; 4.
DR PROSITE; PS50837; NACHT; 1.
PE 1: Evidence at protein level;
KW Alternative initiation; ATP-binding; Complete proteome; Cytoplasm;
KW Disease mutation; Immunity; Innate immunity; Leucine-rich repeat;
KW Nucleotide-binding; Polymorphism; Reference proteome; Repeat.
FT CHAIN 1 1040 Nucleotide-binding oligomerization
FT domain-containing protein 2.
FT /FTId=PRO_0000004418.
FT DOMAIN 26 122 CARD 1.
FT DOMAIN 126 218 CARD 2.
FT DOMAIN 293 618 NACHT.
FT REPEAT 791 812 LRR 1.
FT REPEAT 816 839 LRR 2.
FT REPEAT 844 865 LRR 3.
FT REPEAT 872 884 LRR 4.
FT REPEAT 900 920 LRR 5.
FT REPEAT 928 949 LRR 6.
FT REPEAT 956 976 LRR 7.
FT REPEAT 984 1005 LRR 8.
FT REPEAT 1012 1032 LRR 9.
FT NP_BIND 299 306 ATP (Potential).
FT MOTIF 63 77 ATG16L1-binding motif.
FT VAR_SEQ 1 27 Missing (in isoform 2 and isoform 3).
FT /FTId=VSP_018689.
FT VAR_SEQ 216 224 AATCKKYMA -> DERTEAQKG (in isoform 3).
FT /FTId=VSP_046567.
FT VAR_SEQ 225 1040 Missing (in isoform 3).
FT /FTId=VSP_046568.
FT VARIANT 81 81 L -> V (in dbSNP:rs34936594).
FT /FTId=VAR_036871.
FT VARIANT 140 140 A -> T (associated with Crohn disease and
FT ulcerative colitis; dbSNP:rs34684955).
FT /FTId=VAR_012665.
FT VARIANT 157 157 W -> R (associated with Crohn disease).
FT /FTId=VAR_012666.
FT VARIANT 189 189 T -> M (in dbSNP:rs61755182).
FT /FTId=VAR_012667.
FT VARIANT 235 235 R -> C (associated with Crohn disease).
FT /FTId=VAR_012668.
FT VARIANT 248 248 L -> R (associated with Crohn disease;
FT dbSNP:rs104895423).
FT /FTId=VAR_012669.
FT VARIANT 268 268 P -> S (in dbSNP:rs2066842).
FT /FTId=VAR_012670.
FT VARIANT 289 289 N -> S (in dbSNP:rs5743271).
FT /FTId=VAR_012671.
FT VARIANT 291 291 D -> N (associated with Crohn disease).
FT /FTId=VAR_012672.
FT VARIANT 294 294 T -> S (associated with Crohn disease).
FT /FTId=VAR_012673.
FT VARIANT 301 301 A -> V (associated with Crohn disease).
FT /FTId=VAR_012674.
FT VARIANT 311 311 R -> W (associated with Crohn disease and
FT ulcerative colitis).
FT /FTId=VAR_012675.
FT VARIANT 334 334 R -> Q (in BS).
FT /FTId=VAR_012676.
FT VARIANT 334 334 R -> W (in BS).
FT /FTId=VAR_012677.
FT VARIANT 348 348 L -> V (associated with Crohn disease).
FT /FTId=VAR_012678.
FT VARIANT 352 352 H -> R (associated with Crohn disease;
FT dbSNP:rs5743272).
FT /FTId=VAR_012679.
FT VARIANT 373 373 R -> C (associated with Crohn disease).
FT /FTId=VAR_012680.
FT VARIANT 382 382 D -> E (in EOS).
FT /FTId=VAR_023822.
FT VARIANT 383 383 E -> K (in BS).
FT /FTId=VAR_023823.
FT VARIANT 414 414 N -> S (associated with Crohn disease).
FT /FTId=VAR_012681.
FT VARIANT 431 431 S -> L (associated with Crohn disease;
FT dbSNP:rs104895431).
FT /FTId=VAR_012682.
FT VARIANT 432 432 A -> V (associated with Crohn disease;
FT dbSNP:rs2076754).
FT /FTId=VAR_012683.
FT VARIANT 441 441 E -> K (associated with Crohn disease).
FT /FTId=VAR_012684.
FT VARIANT 469 469 L -> F (in BS).
FT /FTId=VAR_012685.
FT VARIANT 471 471 R -> C (in dbSNP:rs1078327).
FT /FTId=VAR_036872.
FT VARIANT 496 496 H -> L (in EOS).
FT /FTId=VAR_023824.
FT VARIANT 605 605 T -> N (in BS).
FT /FTId=VAR_065228.
FT VARIANT 612 612 A -> T (in EOS; associated with Crohn
FT disease).
FT /FTId=VAR_012686.
FT VARIANT 612 612 A -> V (associated with Crohn disease).
FT /FTId=VAR_012687.
FT VARIANT 684 684 R -> W (associated with Crohn disease;
FT dbSNP:rs5743276).
FT /FTId=VAR_012688.
FT VARIANT 702 702 R -> W (associated with Crohn disease;
FT dbSNP:rs2066844).
FT /FTId=VAR_012689.
FT VARIANT 703 703 R -> C (associated with Crohn disease and
FT ulcerative colitis; dbSNP:rs5743277).
FT /FTId=VAR_012690.
FT VARIANT 713 713 R -> C (associated with Crohn disease).
FT /FTId=VAR_012691.
FT VARIANT 725 725 A -> G (associated with Crohn disease;
FT dbSNP:rs5743278).
FT /FTId=VAR_012692.
FT VARIANT 755 755 A -> V (associated with Crohn disease and
FT ulcerative colitis; dbSNP:rs61747625).
FT /FTId=VAR_012693.
FT VARIANT 758 758 A -> V (associated with Crohn disease).
FT /FTId=VAR_012694.
FT VARIANT 778 778 E -> K (associated with Crohn disease).
FT /FTId=VAR_012695.
FT VARIANT 790 790 R -> Q (in dbSNP:rs5743279).
FT /FTId=VAR_024402.
FT VARIANT 793 793 V -> M (associated with Crohn disease;
FT dbSNP:rs104895444).
FT /FTId=VAR_012696.
FT VARIANT 843 843 E -> K (associated with Crohn disease).
FT /FTId=VAR_012697.
FT VARIANT 853 853 N -> S (associated with Crohn disease).
FT /FTId=VAR_012698.
FT VARIANT 863 863 M -> V (associated with Crohn disease;
FT dbSNP:rs104895447).
FT /FTId=VAR_012699.
FT VARIANT 885 885 A -> T (associated with ulcerative
FT colitis).
FT /FTId=VAR_012700.
FT VARIANT 908 908 G -> R (associated with Crohn disease;
FT dbSNP:rs2066845).
FT /FTId=VAR_012701.
FT VARIANT 918 918 A -> D (associated with Crohn disease;
FT dbSNP:rs104895452).
FT /FTId=VAR_012702.
FT VARIANT 924 924 G -> D (associated with Crohn disease).
FT /FTId=VAR_012703.
FT VARIANT 955 955 V -> I (in dbSNP:rs5743291).
FT /FTId=VAR_012704.
FT MUTAGEN 305 305 K->R: No activation.
SQ SEQUENCE 1040 AA; 115283 MW; 0037592D96D7DDFF CRC64;
MGEEGGSASH DEEERASVLL GHSPGCEMCS QEAFQAQRSQ LVELLVSGSL EGFESVLDWL
LSWEVLSWED YEGFHLLGQP LSHLARRLLD TVWNKGTWAC QKLIAAAQEA QADSQSPKLH
GCWDPHSLHP ARDLQSHRPA IVRRLHSHVE NMLDLAWERG FVSQYECDEI RLPIFTPSQR
ARRLLDLATV KANGLAAFLL QHVQELPVPL ALPLEAATCK KYMAKLRTTV SAQSRFLSTY
DGAETLCLED IYTENVLEVW ADVGMAGPPQ KSPATLGLEE LFSTPGHLND DADTVLVVGE
AGSGKSTLLQ RLHLLWAAGQ DFQEFLFVFP FSCRQLQCMA KPLSVRTLLF EHCCWPDVGQ
EDIFQLLLDH PDRVLLTFDG FDEFKFRFTD RERHCSPTDP TSVQTLLFNL LQGNLLKNAR
KVVTSRPAAV SAFLRKYIRT EFNLKGFSEQ GIELYLRKRH HEPGVADRLI RLLQETSALH
GLCHLPVFSW MVSKCHQELL LQEGGSPKTT TDMYLLILQH FLLHATPPDS ASQGLGPSLL
RGRLPTLLHL GRLALWGLGM CCYVFSAQQL QAAQVSPDDI SLGFLVRAKG VVPGSTAPLE
FLHITFQCFF AAFYLALSAD VPPALLRHLF NCGRPGNSPM ARLLPTMCIQ ASEGKDSSVA
ALLQKAEPHN LQITAAFLAG LLSREHWGLL AECQTSEKAL LRRQACARWC LARSLRKHFH
SIPPAAPGEA KSVHAMPGFI WLIRSLYEMQ EERLARKAAR GLNVGHLKLT FCSVGPTECA
ALAFVLQHLR RPVALQLDYN SVGDIGVEQL LPCLGVCKAL YLRDNNISDR GICKLIECAL
HCEQLQKLAL FNNKLTDGCA HSMAKLLACR QNFLALRLGN NYITAAGAQV LAEGLRGNTS
LQFLGFWGNR VGDEGAQALA EALGDHQSLR WLSLVGNNIG SVGAQALALM LAKNVMLEEL
CLEENHLQDE GVCSLAEGLK KNSSLKILKL SNNCITYLGA EALLQALERN DTILEVWLRG
NTFSLEEVDK LGCRDTRLLL
//

MIM 186580
*RECORD*
*FIELD* NO
186580
*FIELD* TI
#186580 BLAU SYNDROME
;;GRANULOMATOSIS, FAMILIAL JUVENILE SYSTEMIC;;
ARTHROCUTANEOUVEAL GRANULOMATOSIS; ACUG;;
read moreJABS SYNDROME;;
GRANULOMATOUS INFLAMMATORY ARTHRITIS, DERMATITIS, AND UVEITIS, FAMILIAL;;
GRANULOMATOSIS, FAMILIAL, BLAU TYPE
SYNOVITIS, GRANULOMATOUS, WITH UVEITIS AND CRANIAL NEUROPATHIES, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because Blau syndrome is
caused by mutations in the NOD2/CARD15 gene (605956).

Blau syndrome shows phenotypic overlap with early-onset sarcoidosis
(609464), which is also caused by mutations in the CARD15 gene.

CLINICAL FEATURES

Blau (1985) reported a large 4-generation family in which 11 members had
a variable constellation of granulomatous arthritis, iritis, and skin
rash. Ten had arthritis, 2 had skin, eye, and joint involvement, 1 had
skin and joint disease, and 1 had iritis only. The disease was
transmitted as an autosomal dominant trait. The major long-term problems
were iritis and joint contractures. The disorder was distinguished from
that described by Rotenstein et al. (1982) (see 108050) by the absence
of fever, hypertension, and large vessel vasculitis.

Jabs et al. (1985) reported a family in which 4 individuals had a
syndrome of granulomatous synovitis and nongranulomatous uveitis. The
proband, his brother, their father, and the deceased paternal
grandmother were affected. Disease onset was in childhood. All patients
had symmetric, boggy polysynovitis of the hands and wrists, resulting in
nearly identical boutonniere deformities. Synovectomy specimens in the
proband and his brother showed granulomatous inflammation with giant
cells. Recurrent, nongranulomatous, acute iridocyclitis with visual
impairment occurred in the proband, brother, and father. Hand
radiographs showed no erosions or joint destruction despite more than 20
years of disease. In addition, the proband had corticosteroid-responsive
hearing loss, and another patient had a transient sixth nerve palsy,
which Jabs et al. (1985) referred to as 'cranial neuropathies.'

Pastores et al. (1989) described a mother and 2 daughters with uveitis
and symmetric polyarthritis. Both daughters also had cysts over the
wrist and ankle joints and an intermittent generalized erythematous
papular rash, which on histopathologic examination was found to
represent noncaseating granulomatous infiltration. Response to
intermittent, low-dose steroid therapy was dramatic. Pastores et al.
(1989, 1990) thought the disorder was distinct from that reported by
Jabs et al. (1985) because there was no cranial neuropathy and because
Jabs' cases had no cysts. The authors also thought it was distinct from
the disorder reported by Rotenstein et al. (1982), but they thought it
was the same as the disorder reported by Blau (1985); indeed, they
referred to it as 'Blau syndrome.'

In a follow-up of the family reported by Blau (1985), Raphael (1993)
found flexion contractures of the fingers and toes (camptodactyly) as a
phenotypic characteristic. Raphael (1993) was impressed with earlier
onset and worsening of symptoms in succeeding generations, i.e.,
anticipation. Raphael et al. (1993) concluded that the illness in the
original family was distinct from classic sarcoidosis (181000). All 3
subjects tested with Kveim skin-test reagent showed no reactivity by
visual inspection; however, both subjects who had had skin biopsies
performed had evidence of granulomatous inflammation. No specific HLA
association could be demonstrated.

Saini and Rose (1996) described a family with Blau syndrome in whom
liver granulomata were found in one member of the family in whom liver
biopsy was performed. A mother and 2 sons of mixed Caucasian and black
ancestry were described. Camptodactyly-like contractures of the proximal
interphalangeal joints was noted. The authors postulated a relationship
to early-onset sarcoidosis (609464), which is an allelic disorder
(Kanazawa et al., 2005).

In a large affected family, Tromp et al. (1996) based diagnosis of Blau
syndrome was based on any one or combination of the following: (1)
persistent inflammation of any joint or tendon or both, characterized by
marked edema and giant cyst formation or biopsy-proved granulomatous
joint inflammation or both; (2) ophthalmologist-diagnosed anterior- or
posterior-tract uveitis, or both, in one or both eyes at any age, in the
absence of trauma or any other identifiable cause; and (3) persistent
rash characterized by biopsy-proved granulomatous inflammation. Color
photographs of striking arthritic, retinal, and cutaneous lesions were
provided. The retinal view showed multifocal chorioretinal lesions,
several pigmented scars, and marked perivascular sheathing.

Manouvrier-Hanu et al. (1998) described what they considered to be the
sixth family with this disorder. Affected individuals were monozygotic
twin brothers, the son of one and the daughter of the other.

Latkany et al. (2002) reviewed the ophthalmologic findings in 16
patients with juvenile systemic granulomatosis from 8 families examined
at 6 academic medical centers. Of the 16 patients, 15 had evidence of
panuveitis with multifocal choroiditis. One patient had only an anterior
uveitis. One patient each had ischemic optic neuropathy, presumably due
to small vessel vasculopathy, and retinal vasculopathy. Ocular
complications were common, including cataract in 11, glaucoma in 6, band
keratopathy in 6, cystoid macular edema in 6, and optic disc edema in 6.
All 16 patients had polyarthritis, and at least 9 had skin rash. Often
patients were misdiagnosed initially as having either juvenile
rheumatoid arthritis or sarcoidosis. Latkany et al. (2002) concluded
that patients with a diagnosis of juvenile rheumatoid arthritis but
having a family history of the disorder and multifocal choroiditis
should be suspected of having familial juvenile systemic granulomatosis.

Dhondt et al. (2008) reported a patient with Blau syndrome who had large
recalcitrant leg ulcers. Biopsies of 1 of the ulcers showed granulomas.
Molecular analysis identified a heterozygous mutation in the CARD15 gene
(605956.0006). There was no family history of the disorder.

INHERITANCE

Alonso et al. (2003) described a new kindred consisting of a mother and
3 affected children that demonstrated autosomal dominant inheritance and
anticipation. The patients had classic findings including cutaneous and
joint involvement with camptodactyly. Only the mother and daughter had
chronic uveitis.

MAPPING

In an extended family in which 16 members were affected with Blau
syndrome, Tromp et al. (1996) demonstrated linkage to DNA markers in the
16p12-q21 interval. With 2-point analysis, the marker D16S298 gave a
maximum lod score of 3.75 at theta = 0.04. Most affected patients were
examined by one of the authors, S. Raphael.

MOLECULAR GENETICS

Because mutations in the NOD2/CARD15 gene had been found in Crohn
disease (266600), a disorder characterized by episodic intestinal
inflammation with epithelioid granulomas, and because CARD15 is
expressed predominantly in monocytes, a cell type that can differentiate
into giant and epithelioid cells aggregating in granuloma formations,
Miceli-Richard et al. (2001) did a mutation screen of 4 families with
Blau syndrome and identified 3 different missense mutations in the
CARD15 gene (605956.0004-605956.0006). One of the families had been
reported by Manouvrier-Hanu et al. (1998).

CLINICAL MANAGEMENT

Goyal et al. (2007) reported an unusual case of a 12-year-old girl who
presented with persistent focal seizures and MRI signal abnormalities.
Brain biopsies showed marked dural granulomatous inflammation with focal
extension into the brain parenchyma. Studies for systemic sarcoidosis
were negative. Treatment with infliximab, a TNF-alpha inhibitor,
resulted in clinical improvement. Family history revealed a paternal
uncle and grandfather with Crohn disease, and molecular analysis
identified 3 missense mutations in the NOD2 gene in the proband.

*FIELD* RF
1. Alonso, D.; Elgart, G. W.; Schachner, L. A.: Blau syndrome: a
new kindred. J. Am. Acad. Derm. 49: 299-302, 2003.

2. Blau, E. B.: Familial granulomatous arthritis, iritis, and rash. J.
Pediat. 107: 689-693, 1985.

3. Dhondt, V.; Hofman, S.; Dahan, K.; Beele, H.: Leg ulcers: a new
symptom of Blau syndrome? Europ. J. Derm. 18: 635-637, 2008.

4. Goyal, M.; Cohen, M. L.; Bangert, B. A.; Robinson, S.; Singer,
N. G.: Rasmussen syndrome and CNS granulomatous disease with NOD2/CARD15
mutations. Neurology 69: 640-643, 2007.

5. Jabs, D. A.; Houk, J. L.; Bias, W. B.; Arnett, F. C.: Familial
granulomatous synovitis, uveitis, and cranial neuropathies. Am. J.
Med. 78: 801-804, 1985.

6. Kanazawa, N.; Okafuji, I.; Kambe, N.; Nishikomori, R.; Nakata-Hizume,
M.; Nagai, S.; Fuji, A.; Yuasa, T.; Manki, A.; Sakurai, Y.; Nakajima,
M.; Kobayashi, H.; Fujiwara, I.; Tsutsumi, H.; Utani, A.; Nishigori,
C.; Heike, T.; Nakahata, T.; Miyachi, Y.: Early-onset sarcoidosis
and CARD15 mutations with constitutive nuclear factor-kappa-B activation:
common genetic etiology with Blau syndrome. Blood 105: 1195-1197,
2005.

7. Latkany, P. A.; Jabs, D. A.; Smith, J. R.; Rosenbaum, J. T.; Tessler,
H.; Schwab, I. R.; Walton, R. C.; Thorne, J. E.; Maguire, A. M.:
Multifocal choroiditis in patients with familial juvenile systemic
granulomatosis. Am. J. Ophthal. 134: 897-904, 2002.

8. Manouvrier-Hanu, S.; Puech, B.; Piette, F.; Boute-Benejean, O.;
Desbonnet, A.; Duquesnoy, B.; Farriaux, J. P.: Blau syndrome of granulomatous
arthritis, iritis, and skin rash: a new family and review of the literature. Am.
J. Med. Genet. 76: 217-221, 1998.

9. Miceli-Richard, C.; Lesage, S.; Rybojad, M.; Prieur, A.-M.; Manouvrier-Hanu,
S.; Hafner, R.; Chamaillard, M.; Zouali, H.; Thomas, G.; Hugot, J.-P.
: CARD15 mutations in Blau syndrome. Nature Genet. 29: 19-20, 2001.

10. Pastores, G. M.; Michels, V. V.; Stickler, G. B.; Su, W. P. D.;
Nelson, A. M.: Autosomal dominant granulomatous arthritis, uveitis
and rash. (Abstract) Am. J. Hum. Genet. 45 (suppl.): A57, 1989.

11. Pastores, G. M.; Michels, V. V.; Stickler, G. B.; Su, W. P. D.;
Nelson, A. M.; Bovenmyer, D. A.: Autosomal dominant granulomatous
arthritis, uveitis, skin rash, and synovial cysts. J. Pediat. 117:
403-408, 1990.

12. Raphael, S. A.: Personal Communication. Philadelphia, Pa.
3/4/1993.

13. Raphael, S. A.; Blau, E. B.; Zhang, W. H.; Hsu, S. H.: Analysis
of a large kindred with Blau syndrome for HLA, autoimmunity, and sarcoidosis. Am.
J. Dis. Child. 147: 842-848, 1993.

14. Rotenstein, D.; Gibbas, D. L.; Majmudar, B.; Chastain, E. A.:
Familial granulomatous arteritis with polyarthritis of juvenile onset. New
Eng. J. Med. 306: 86-90, 1982.

15. Saini, S. K.; Rose, C. D.: Liver involvement in familial granulomatous
arthritis (Blau syndrome). J. Rheum. 23: 396-399, 1996.

16. Tromp, G.; Kuivaniemi, H.; Raphael, S.; Ala-Kokko, L.; Christiano,
A.; Considine, E.; Dhulipala, R.; Hyland, J.; Jokinen, A.; Kivirikko,
S.; Korn, R.; Madhatheri, S.; McCarron, S.; Pulkkinen, L.; Punnett,
H.; Shimoya, K.; Spotila, L.; Tate, A.; Williams, C. J.: Genetic
linkage of familial granulomatous inflammatory arthritis, skin rash,
and uveitis to chromosome 16. Am. J. Hum. Genet. 59: 1097-1107,
1996.

*FIELD* CS
INHERITANCE:
Autosomal dominant

HEAD AND NECK:
[Eyes];
Uveitis;
Iritis;
Multifocal choroiditis;
Cataracts;
Glaucoma;
Band keratopathy;
Cystoid macular edema;
Optic disc edema

SKELETAL:
Granulomatous synovitis;
Granulomatous arthritis;
Synovial cysts;
Joint swelling;
Joint contractures;
Tendonitis;
[Hands];
Flexion contractures of the fingers;
Camptodactyly;
[Feet];
Flexion contractures of the toes

SKIN, NAILS, HAIR:
[Skin];
Granulomatous dermatitis;
Intermittent generalized erythematous papular rash;
Skin ulceration;
Skin biopsy shows noncaseating granulomas;
Cysts over wrist and ankle joints

MISCELLANEOUS:
Onset in first 2 decades of life;
Variable manifestation of features;
Favorable response to intermittent, low-dose steroid therapy;
Allelic disorder to early-onset sarcoidosis (609464)

MOLECULAR BASIS:
Caused by mutation in the nucleotide-binding oligomerization domain
protein 2 gene (NOD2, 605956.0004).

*FIELD* CN
Cassandra L. Kniffin - revised: 6/2/2009

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

*FIELD* ED
joanna: 09/18/2009
ckniffin: 6/2/2009
alopez: 5/5/2004

*FIELD* CN
Cassandra L. Kniffin - updated: 6/2/2009
Cassandra L. Kniffin - updated: 12/7/2007
Victor A. McKusick - updated: 5/4/2004
Gary A. Bellus - updated: 9/3/2003
Victor A. McKusick - updated: 8/23/2001
Victor A. McKusick - updated: 4/6/1998

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

*FIELD* ED
alopez: 11/20/2012
terry: 4/12/2012
wwang: 6/22/2009
ckniffin: 6/2/2009
wwang: 12/7/2007
carol: 8/29/2005
carol: 7/5/2005
alopez: 5/5/2004
terry: 5/4/2004
alopez: 9/3/2003
carol: 1/29/2003
alopez: 8/27/2001
terry: 8/23/2001
carol: 4/6/1998
joanna: 8/12/1997
terry: 12/30/1996
terry: 12/20/1996
mark: 6/12/1996
terry: 6/5/1996
mimadm: 5/10/1995
pfoster: 4/25/1994
warfield: 4/14/1994
carol: 9/30/1993
carol: 3/18/1993
carol: 3/3/1993

MIM 266600
*RECORD*
*FIELD* NO
266600
*FIELD* TI
#266600 INFLAMMATORY BOWEL DISEASE 1; IBD1
REGIONAL ENTERITIS, INCLUDED;;
CROHN DISEASE, INCLUDED;;
read moreULCERATIVE COLITIS, INCLUDED;;
CROHN DISEASE-ASSOCIATED GROWTH FAILURE, SUSCEPTIBILITY TO, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
mutations in the NOD2/CARD15 gene (605956) are associated with
susceptibility to Crohn disease in families linked to chromosome 16. A
promoter polymorphism in the IL6 gene (147620) is associated with
susceptibility to Crohn disease-associated growth failure.

For information on genetic heterogeneity of IBD, see MAPPING and
MOLECULAR GENETICS sections.

CLINICAL FEATURES

Inflammatory bowel disease is characterized by a chronic relapsing
intestinal inflammation. IBD is subdivided into Crohn disease and
ulcerative colitis phenotypes. Crohn disease and ulcerative colitis have
a combined prevalence of 200 to 300 per 100,000 in the United States.
Crohn disease may involve any part of the gastrointestinal tract, but
most frequently the terminal ileum and colon. Bowel inflammation is
transmural and discontinuous; it may contain granulomas or be associated
with intestinal or perianal fistulas. In contrast, in ulcerative
colitis, the inflammation is continuous and limited to rectal and
colonic mucosal layers; fistulas and granulomas are not observed. In
approximately 10% of cases confined to the rectum and colon, definitive
classification of Crohn disease or ulcerative colitis cannot be made and
are designated 'indeterminate colitis.' Both diseases include
extraintestinal inflammation of the skin, eyes, or joints.

Crohn disease and ulcerative colitis are commonly classified as
autoimmune diseases. The prevalence of inflammatory bowel disease is
increased in individuals with other autoimmune diseases, particularly
ankylosing spondylitis, psoriasis, sclerosing cholangitis, and multiple
sclerosis. There is strong evidence from twin studies, familial risk
data, and segregation analysis that inflammatory bowel disease,
especially Crohn disease, is genetic (Yang and Rotter, 1994; Duerr,
1996). Crohn disease and ulcerative colitis are considered complex
genetic traits as inheritance does not follow any simple mendelian
models. Both genetic and environmental factors seem to be important in
its etiology.

Monsen et al. (1989) performed segregation analysis in 124 families with
ulcerative colitis in 2 or more members. They concluded that a rare
additive major gene causes the disease, with about 20% affected among
those heterozygous for the gene. They found no evidence for
multifactorial inheritance. They raised the possibility that the major
gene may be associated with a separate type of ulcerative colitis with
more extensive involvement, younger age of onset, and more immunologic
side effects such as extraintestinal manifestation.

Prevalence in first-degree relatives has been estimated to be between 4
and 16% (Lewkonia and McConnell, 1976; Farmer et al., 1980). Orholm et
al. (1991) found that first-degree relatives of patients with either
ulcerative colitis or Crohn disease had a 10-fold increase in the risk
of having the same disease as the patients. The risk of having the other
of the 2 diseases was also increased, but less so, and the increase in
the risk of having Crohn disease was not significant in the relatives of
patients with ulcerative colitis. Yang et al. (1993) found evidence of
higher frequency of inflammatory bowel disease among first-degree
relatives of Jewish patients than among the relatives of non-Jewish
patients. The first-degree relatives of Jewish patients had a lifetime
risk for inflammatory bowel disease of 7.8% and 4.5% when probands had
Crohn disease and ulcerative colitis, respectively. The values for
first-degree relatives of non-Jewish probands were 5.2% and 1.6%.

Satsangi et al. (1996) studied the clinical characteristics (disease
type, extent, age of onset, need for surgery, and presence of
extraintestinal manifestations) in affected subjects in
multiply-affected families with inflammatory bowel disease. They
identified 54 families in which 1 parent and at least 1 child were
affected (a total of 77 parent-child pairs) and 155 families in which 2
sibs were affected (a total of 190 affected sib pairs). In affected
parent-child pairs, parent and child were concordant for 'disease type'
(Crohn disease or ulcerative colitis) in 58 of 77 pairs (75.3%), for
extent in 63.6%, for extraintestinal manifestations in 70.1%, and for
smoking history in 85%. The median age of onset in parents was
significantly higher than in offspring (p = less than 0.0001). In 40
pairs (60.6%) the parent was at least 10 years older than the child at
age of onset. Sibs were concordant for disease type in 81.6% of the
affected sib pairs, extent in 76.0%, extraintestinal manifestations in
83.8%, and smoking history in 81.3%. In contrast with the parent-child
pairs, 68.1% of sibs (111 sib pairs) were diagnosed within 10 years of
each other. Median age of onset was 24.0 years. Satsangi et al. (1996)
felt that the differences in age of onset between parents and children
was not readily explained by a simple cohort effect or ascertainment
bias, and may it reflect effects of genetic factors, producing
anticipation between generations.

- Crohn Disease

About 10% of persons with regional enteritis have 1 or more close
relatives with granulomatous disease of the bowel. In 5 persons of
Ashkenazi Jewish origin (ancestors from area of Russia-Poland around
Vilna), Sheehan et al. (1967) found red cell glucose-6-phosphate
dehydrogenase deficiency associated with regional enteritis or
granulomatous colitis. The affected persons were 2 males and 3 females.
Regional enteritis and sarcoidosis have been observed in the same family
(see 181000); Gronhagen-Riska et al. (1983) commented on the
association. Schwartz et al. (1980) found no HLA association in sporadic
cases or in familial cases. However, in 5 affected sib pairs, 4 shared
both haplotypes (i.e., were HLA-identical) and the 5th shared one
haplotype. Only 1 unaffected sib shared both haplotypes with an affected
sib. Kuster et al. (1989) suggested that a recessive gene with
incomplete penetrance is responsible for susceptibility to Crohn
disease. McConnell (1988) suggested polygenic inheritance; an individual
inheriting few susceptibility genes would develop ulcerative colitis,
while someone inheriting a larger number of these genes would develop
regional enteritis.

Although controversial, epidemiologic evidence (Greenstein et al., 1988)
suggests that there may be 2 distinct clinical forms of Crohn disease:
perforating and nonperforating. Patients with perforating Crohn disease
have abscesses and/or free perforations. Perforating Crohn disease is
the more aggressive form with a higher reoperation rate. By contrast,
nonperforating Crohn disease has a more indolent clinical course and is
associated with obstruction and bleeding as the main features. Gilberts
et al. (1994) reasoned that the host immune response may determine which
clinical presentation the disease assumes. Leprosy is an
incontrovertible example of 2 clinical forms of disease, tuberculous and
lepromatous, with the same etiologic factor. Resected intestinal tissue
from control patients, as well as perforating and nonperforating Crohn
disease patients, was evaluated for mRNA levels of a housekeeping gene
(beta-actin; 102630), a human T-cell marker, CD3-delta (186790), and 6
cytokines. Differences were observed with interleukin-1-beta (IL1B;
147720) and with interleukin-1 receptor alpha (IL1RA; 147810).
Nonperforating Crohn disease, the more benign form, was associated with
increased IL1B and IL1RA mRNA expression.

PATHOGENESIS

Cattan et al. (2000) studied the incidence of IBD in non-Ashkenazi
Jewish patients with familial Mediterranean fever (FMF; 249100). The
association was 8 to 14 times greater than expected. The prevalence of
IBD in non-Ashkenazi Jews is 120 per 100,000, whereas Cattan et al.
(2000) estimated a prevalence of at least 3 per 300 (or 3 per 173 if the
calculation is done through probands) in non-Ashkenazi Jews with FMF.
They postulated that the inflammatory processes of FMF and IBD are
additive, resulting in increased severity of disease in the new
patients.

Lawrance et al. (2001) examined global gene expression profiles of
inflamed colonic tissue using DNA microarrays. They identified several
genes with altered expression not previously linked to IBD. In addition
to the expected upregulation of various cytokine and chemokine genes,
novel immune function-related genes such as IGHG3 (147120), IGLL2, and
CD74 (142790), inflammation-related lipocalins HNL and NGAL (600181),
and proliferation-related GRO genes (see, e.g., 139110) were
overexpressed in ulcerative colitis. Certain cancer-related genes such
as DD96, DRAL (602633), and MXI1 (600020) were differentially expressed
only in ulcerative colitis. Other genes overexpressed in both ulcerative
colitis and Crohn disease included the REG gene family (see 167770) and
the calcium-binding S100 protein genes S100A9 (123886) and S100P
(600614). The natural antimicrobial defensin DEFA5 (600472) and DEFA6
(600471) genes were particularly overexpressed in Crohn disease.
Overall, significant differences in the expression profiles of 170 genes
identified ulcerative colitis and Crohn disease as distinct molecular
entities.

By yeast 2-hybrid analysis and reciprocal immunoprecipitations, Barnich
et al. (2005) found that NOD2 interacts directly with GRIM19 (NDUFA13;
609435). The authors also found that expression of GRIM19 was
significantly reduced in affected mucosa from Crohn disease and
ulcerative colitis patients, whereas uninvolved patient mucosa showed
GRIM19 mRNA expression comparable with that in control patients.

By microarray analysis, Moehle et al. (2006) found coordinated
downregulation of mucins, including MUC1 (158340), MUC2 (158370), MUC4
(158372), MUC5AC (158373), MUC5B (600770), MUC12 (604609), MUC13
(612181), MUC17 (608424), and MUC20 (610360), in ileum and colon of
Crohn disease and ulcerative colitis patients compared with controls.
They identified NF-kappa-B (see 164011)-binding sites in all mucin
promoters and showed that activation of the NF-kappa-B signaling pathway
by inflammatory cytokines TNF-alpha (TNF; 191160) and TGF-beta (TGFB1;
190180) upregulated mRNA expression of all the mucin genes under study.

Baumgart and Carding (2007) reviewed the pathogenesis of Crohn disease
and ulcerative colitis, including environmental factors and
immunobiologic mechanisms.

Abraham and Cho (2009) reviewed normal function of the intestinal immune
system and discussed mechanisms of disease in inflammatory bowel
disease, including genetic associations with Crohn disease and
ulcerative colitis.

Khor et al. (2011) gave an excellent review of the genetics and
pathogenesis of inflammatory bowel disease.

- Crohn Disease

Targan and Murphy (1995) reviewed briefly the current literature on both
potential animal models for Crohn disease and human research on the
mechanisms of its pathogenesis and molecular genetics. They stated that
an updated hypothesis of Crohn disease pathogenicity 'holds that the
foundation for its heterogeneity is at the primary genetic level, and
expression of genetic susceptibility requires environmental triggers.'

Because of the parallel to the tuberculoid and lepromatous forms of
leprosy, Mishina et al. (1996) investigated the possibility of a
Mycobacterium, namely M. paratuberculosis, as a cause of Crohn disease.
They used RT-PCR with M. paratuberculosis subspecies-specific primers on
total RNA from 12 ileal mucosal specimens of which 8 were from patients
with Crohn disease, 2 represented cases of ulcerative colitis, and 2
represented cases of colonic cancer. As a negative control, they used M.
avium DNA, originally cultured from the drinking water of a major city
in the United States. Their cDNA sequence analysis showed that all 8
cases of Crohn disease and both samples from the patients with
ulcerative colitis contained M. paratuberculosis RNA. Additionally, the
M. avium control had the DNA sequence of M. paratuberculosis. They then
demonstrated the DNA sequence of M. paratuberculosis from mucosal
specimens in humans with Crohn disease. They concluded that the potable
water supply may be a reservoir of infection. They suggested that
clinical trials with therapy directed against M. paratuberculosis is
indicated in patients with Crohn disease.

Pizarro et al. (1999) detected increased IL18 (600953) mRNA and protein
expression in intestinal epithelial cells and lamina propria mononuclear
cells in Crohn disease tissue compared with ulcerative colitis and
normal tissue.

By immunohistochemical analysis, Corbaz et al. (2002) showed that
IL18-binding protein (IL18BP; 604113) expression in intestinal tissue is
increased in endothelial cells as well as cells of the submucosa and
overlying lymphoid aggregates in Crohn disease patients compared with
controls. Immunofluorescent microscopy demonstrated colocalization with
macrophage and endothelial cell markers, but not with those of
lymphocytes or epithelial cells. Real-time PCR and ELISA analysis
detected increased levels of both IL18 and IL18BP in the Crohn disease
intestinal tissue. Unbound neutralizing isoforms a and c of IL18BP were
in excess compared with IL18 in the Crohn disease patients, indicating
that IL18BP upregulation correlates with increased IL18 expression in
Crohn disease. Corbaz et al. (2002) suggested that despite the presence
of IL18BP, which has been shown to ameliorate colitis in a mouse model
(ten Hove et al., 2001), some IL18 activity may be available for
perpetuating the pathogenesis of Crohn disease.

Lovato et al. (2003) found that intestinal T cells from Crohn disease
patients, but not healthy volunteers, showed constitutive activation of
STAT3 (102582) and STAT4 (600558). SOCS3 (604176), a STAT3-regulated
protein, was also constitutively expressed in Crohn disease T cells.
Lovato et al. (2003) concluded that there is abnormal STAT/SOCS
signaling in Crohn disease.

Van Heel et al. (2005) analyzed the cytokine response of peripheral
blood mononuclear cells to muramyl dipeptide (MDP), the ligand for NOD2.
MDP induced strong IL8 (146930) secretion and substantially upregulated
the secretion of TNF-alpha (191160) and IL1B (147720) induced by
Toll-like receptor (see 601194) ligands. At low nanomolar MDP
concentrations, these effects were abolished by the most common Crohn
disease NOD2 double-mutant genotypes (702W (605956.0003)/1007fs
(605956.0001), 702W/702W, 1007fs/1007fs, and 908R (605956.0002)/1007fs).
Van Heel et al. (2005) suggested that NOD2 activation provides a priming
signal to condition a broad early immune response to pathogens, and that
the absence of this priming signal in NOD2-associated Crohn disease
causes failure of early immune pathogen clearance and explains the
abnormal adaptive immune responses to microbial antigens in Crohn
disease patients.

In 15 patients with CD and 9 controls, Barnich et al. (2007) found that
adherent-invasive E. coli (AIEC) adhesion was dependent on type 1 pili
expression on the bacterial surface and on CEACAM6 (163980) expression
on the apical surface of ileal epithelial cells. CEACAM6 acted as a
receptor for AIEC adhesion and was upregulated in the ileal mucosa of CD
patients compared to colonic mucosa or to controls. In vitro studies
showed increased CEACAM6 expression in cultured intestinal epithelial
cells after IFN-gamma (147570) or TNF-alpha (191160) stimulation and
after infection with AIEC.

Adolph et al. (2013) showed that impairment of either the unfolded
protein response (UPR) or autophagy function in intestinal epithelial
cells results in each other's compensatory engagement, and severe
spontaneous Crohn disease-like transmural ileitis if both mechanisms are
compromised. Xbp1 (194355)-deficient mouse intestinal epithelial cells
showed autophagosome formation in hypomorphic Paneth cells, which is
linked to endoplasmic reticulum (ER) stress via protein kinase RNA-like
ER kinase (PERK; 604032), elongation initiation factor 2-alpha
(eIF2-alpha; 609234), and activating transcription factor-4 (ATF4;
604064). Ileitis is dependent on commensal microbiota and derives from
increased intestinal epithelial cell death, inositol-requiring enzyme
1-alpha (IRE1-alpha; 604033)-regulated NF-kappa-B (see 164011)
activation, and TNF signaling, which are synergistically increased when
autophagy is deficient. ATG16L1 (610767) restrains IRE1-alpha activity,
and augmentation of autophagy in intestinal epithelial cells ameliorates
ER stress-induced intestinal inflammation and eases NF-kappa-B
overactivation and intestinal epithelial cell death. ER stress,
autophagy induction, and spontaneous ileitis emerge from Paneth
cell-specific deletion of Xbp1. Adolph et al. (2013) concluded that
genetically and environmentally controlled UPR function within Paneth
cells may therefore set the threshold for the development of intestinal
inflammation upon hypomorphic ATG16L1 function and implicate ileal Crohn
disease as a specific disorder of Paneth cells.

Yoneno et al. (2013) examined TGR5 (GPBAR1; 610147) expression in
peripheral blood monocytes and in vitro-differentiated macrophages and
dendritic cells. They found that macrophages differentiated with MCSF
(CSF1; 120420) and IFNG, which are similar to intestinal lamina propria
CD14 (158120)-positive macrophages that contribute to Crohn disease
pathogenesis by producing proinflammatory cytokines (e.g., TNF), highly
expressed TGR5 compared with other types of differentiated macrophages
and dendritic cells. TNF production was inhibited in these cells by 2
types of bile acid, deoxycholic acid and lithocholic acid, as well as by
a TGR5 agonist. The inhibitory effect was mediated through the TGR5-cAMP
pathway to induce phosphorylation of FOS (164810), which regulates NFKB
p65 (RELA; 164014) activation. Analysis of lamina propria mononuclear
cells from Crohn disease patients and controls showed increased TGR5
expression in Crohn disease patients compared with controls. A TGR5
agonist inhibited TNF production by isolated intestinal CD14-positive
differentiated macrophages from Crohn disease patients. Yoneno et al.
(2013) proposed that control of TGR5 signaling may modulate immune
responses in inflammatory bowel disease.

- Ulcerative Colitis

A role for PLA2G2A (172411) in the pathogenesis of ulcerative colitis
was postulated by Haapamaki et al. (1997), who demonstrated expression
of the PLA2G2A gene in metaplastic Paneth cells and columnar epithelial
cells in inflamed colonic mucosa from patients with ulcerative colitis.
No expression was detected in other tissues from the same patients or,
by Northern blot analysis, in colonic biopsies from disease-free
controls. Haapamaki et al. (1997) hypothesized that intraluminal
secretion of PLA2G2A during the active phase of ulcerative colitis is a
host defense mechanism.

Hofseth et al. (2003) studied the relationship between the chronic
inflammation of ulcerative colitis and the development of colon cancer.
They examined tissues from noncancerous colons of ulcerative colitis
patients to determine the activity of 2 base excision-repair enzymes,
3-methyladenine DNA glycosylase (AAG; 156565) and apurinic/apyrimidinic
endonuclease (APE1; 107748), and the prevalence of microsatellite
instability (MSI). AAG and APE1 were significantly increased in
ulcerative colitis colon epithelium undergoing elevated inflammation and
MSI was positively correlated with their imbalanced enzymatic
activities. These latter results were supported by mechanistic studies
using yeast and human cell models in which overexpression of AAG and/or
APE1 was associated with frameshift mutations and MSI. The results were
consistent with the hypothesis that the adaptive and imbalanced increase
in AAG and APE1 is a novel mechanism contributing to MSI in patients
with ulcerative colitis.

Fuss et al. (2004) examined lamina propria T cells from patients with
ulcerative colitis and found that they produced significantly greater
amounts of IL13 (147683) and IL5 (147850) than control or Crohn disease
cells and little IFN-gamma (147570). The authors stimulated ulcerative
colitis lamina propria T cells bearing the NK marker CD161 with anti-CD2
(186990)/anti-CD28 (186760) or with B cells expressing transfected CD1d
(188410) and observed substantial IL13 production. Fuss et al. (2004)
noted that these ulcerative colitis NKT cells did not express the
invariant cell receptors characteristic of most NKT cells. The authors
demonstrated that human NKT cell lines and the ulcerative colitis CD161+
lamina propria cells were cytotoxic for HT-29 epithelial cells and that
this cytotoxicity was augmented by IL13. Fuss et al. (2004) concluded
that ulcerative colitis is associated with an atypical Th2 response
mediated by nonclassic NKT cells that produce IL13 and have cytotoxic
potential for epithelial cells.

Pang et al. (2007) investigated the expression of IL12B (161561), IFNG
(147570), and the activational state of STAT4 (600558) signaling in
mucosal tissues at the site of disease in 30 Chinese patients with
active ulcerative colitis compared with 30 healthy controls. They found
increased mRNA expression of IL12B, but not IFNG, in the UC patients,
and Western blot analysis demonstrated increased levels of STAT4 in the
cytoplasm and phosphorylated STAT4 in the nucleus of mucosal cells from
UC patients. The authors concluded that a heightened, perhaps
persistent, activational state of IL12/STAT4 and/or IL23/STAT4 signaling
may be present in active Chinese UC patients and may be involved in the
chronic inflammation of UC.

CLINICAL MANAGEMENT

- Crohn Disease

Miller et al. (2003) and Ghosh et al. (2003) reported clinical trials of
natalizumab, a recombinant anticlonal antibody against alpha-4-integrins
(192975), for the treatment of multiple sclerosis (126200) and Crohn
disease, respectively. Miller et al. (2003) reported that a group of
patients with multiple sclerosis who received monthly injections of
natalizumab had significantly fewer new inflammatory central nervous
system lesions than the placebo group (a reduction of approximately 90%)
and had approximately half as many clinical relapses. Ghosh et al.
(2003) reported that patients with Crohn disease also had a favorable
response to natalizumab, with remission rates that were approximately
twice as high in patients who received 2 injections of the antibody as
in patients from the placebo group. The rate of adverse events did not
differ significantly between the natalizumab and placebo groups in
either trial. Von Andrian and Engelhardt (2003) stated that natalizumab
probably has therapeutic effects because it blocks the ability of
alpha-4/beta-1 and alpha-4/beta-7 to bind to their respective
endothelial counter-receptors, VCAM1 (192225) and MADCAM1 (102670). In
both disorders, lesions result from autoimmune responses involving
activated lymphocytes and monocytes. Alpha-4-integrin is expressed on
the surface of these cells and plays an integral part in their adhesion
to the vascular endothelium and migration into the parenchyma.

Using immunohistochemistry, immunofluorescence microscopy, and RT-PCR,
Ricciardelli et al. (2008) showed that children with Crohn disease
treated with infliximab, an anti-TNF antibody, had increased FOXP3
(300292)-positive T regulatory cells (Tregs) in their mucosa after
treatment. Before treatment, FOXP3-positive T cells were reduced
compared with controls. Ricciardelli et al. (2008) concluded that
infliximab not only neutralizes soluble TNF, but also affects the
activation and possibly the expansion of mucosal Tregs. They suggested
that anti-TNF immunotherapy may restore mucosal homeostasis in Crohn
disease.

MAPPING

- IBD1 on Chromosome 16q12

Hugot et al. (1996) performed a genomewide linkage study of 2
consecutive and independent panels of Crohn disease families with
multiple affected members using a nonparametric 2-point sib pair linkage
method. They identified a putative Crohn disease locus on chromosome 16
(P less than 0.01 for each panel) centered near loci D16S409 and D16S419
by using multipoint sib pair analysis. The authors stated that the locus
on chromosome 16 probably accounts for only a small fraction of the
10-fold increased risk for first-degree relatives of Crohn disease
patients. The most conspicuous examples of Crohn disease candidate genes
that map to the pericentromeric region of chromosome 16 are CD19
(107265), which is involved in B-lymphocyte function; sialophorin
(182160), which is involved in leukocyte adhesion; the CD11 integrin
cluster (153370), which is involved in mycobacterial cell adhesion; and
the interleukin-4 receptor (IL4R; 147781) because IL4-mediated
regulation of mononuclear phagocyte effector functions is altered in
inflammatory bowel diseases. The authors noted that some of the genetic
factors involved in Crohn disease may also contribute to ulcerative
colitis susceptibility. Indeed, Crohn disease and ulcerative colitis
share the same ethnic predisposition, and mixed families in which some
members are affected with Crohn disease and others with ulcerative
colitis are commonly found. The studies of Hugot et al. (1996) also
suggested the possible involvement of a locus on 1p.

In an accompanying editorial comment, Ott (1996) pointed to the study by
Hugot et al. (1996) in the analysis of complex traits. The parametric
approach determines the recombination fraction between disease and
marker loci on the basis of family data and the mode of inheritance and
penetrance assumed for the trait. A misspecification of mode of
inheritance generally results in an overestimation of the recombination
fraction. In sib pair analysis, pairs of affected sibs are studied and
all linkage information is gained from the inheritance of marker alleles
by the 2 sibs, with no assumptions as to mode of inheritance. One
determines the number of alleles inherited by sib 2 that are copies of
the same parental alleles as those inherited by sib 1, i.e., the number
of alleles shared identical by descent. Hugot et al. (1996) used
multipoint sib pair analysis, implemented in the MAPMAKER/SIBS computer
program, for their genomic screen for complex-trait loci. Although the
number of families was relatively small (78 in the final analysis), this
new approach allowed them to localize the gene for Crohn disease with
greater confidence than had been possible using conventional methods.

Ohmen et al. (1996) and Parkes et al. (1996) concluded that the
localization to chromosome 16 is important for susceptibility to Crohn
disease rather than ulcerative colitis. Cavanaugh et al. (1998)
investigated the contribution of this localization to the inheritance of
inflammatory bowel disease in 54 multiplex Australian families and
confirmed its importance in a significant proportion of Crohn disease
families. They refined the localization to a region near D16S409,
obtaining a maximum lod score of 6.3 between D16S409 and D16S753.

Annese et al. (1999) conducted a linkage study in a series of 58 Italian
families with inflammatory bowel disease: 16 with Crohn disease, 23 with
ulcerative colitis, and 19 with coexistent Crohn disease and ulcerative
colitis. The findings of their study supported the 16p localization; no
significant linkage was found for markers on chromosomes 3, 6, 7, and
12.

In an extended sample of 82 Italian families with inflammatory bowel
disease, Forabosco et al. (2000) performed combined linkage and
segregation analysis in the identified IBD1 region, which allowed them
to estimate the mode of inheritance. A 2-loci model gave a significantly
better fit than a single-locus model when information on severity was
included in the analysis. A model with a major dominant gene in linkage
with D16S408 (theta = 0.0) and a modifier recessive gene, with a major
effect on severity of the trait, provided the best fit. The possibility
that both putative major genes in the IBD1 region represent the same
gene could not be ruled out. The authors suggested the presence of a
major gene in the IBD1 region involved in both ulcerative colitis and
Crohn disease, with a single mutation in the gene leading more
frequently to ulcerative colitis and 2 mutant alleles resulting in the
more severe Crohn disease.

Zouali et al. (2001) genotyped 26 microsatellite markers from the
pericentromeric region of chromosome 16 in 77 multiplex Crohn disease
families that included 179 patients, or 100 independent affected pairs.
Nonparametric linkage analyses gave a maximum NPL score of 3.49 around
the marker D16S3117. A BAC contig map of 2.5 Mb spanning the genetic
region from D16S541 to D16S2623 in chromosome 16q12 was built,
consisting of 99 BAC clones and 102 STSs. The results provided a crucial
step toward linkage disequilibrium mapping for the identification of the
IBD1 gene.

The IBD International Genetics Consortium (2001) investigated the
proposed linkage to the pericentric region of chromosome 16 (IBD1) and
12p (IBD2; 601458) of Crohn disease susceptibility loci. They found
unequivocal evidence of a Crohn disease susceptibility locus on
chromosome 16 (maximum lod score 5.79). In this study of 12
microsatellite markers from the 2 chromosomal regions in 613 families
they could not replicate the previous evidence for linkage on chromosome
12; however, the results of their study indicated the need to
investigate further the potential role of the chromosome 12 locus in
susceptibility to ulcerative colitis.

Van Heel et al. (2004) obtained genome scan data (markers, significance
scores) from 10 separate IBD studies and performed metaanalysis using
the genome scan metaanalysis (GSMA) method. The studies comprised 1,952
inflammatory bowel disease, 1,068 Crohn disease, and 457 ulcerative
colitis affected relative pairs. Study results were divided into 34-cM
chromosomal bins, ranked, weighted by study size, summed across studies
and bin-by-bin significance obtained by simulation. The authors
identified the chromosome 16 locus (NOD2/CARD15 region) as one meeting
suggestive significance for both inflammatory bowel disease and Crohn
disease; they also obtained suggestive evidence for linkage to
chromosome 2q for ulcerative colitis, inflammatory bowel disease, and
Crohn disease.

Shugart et al. (2008) performed a high-density SNP genomewide linkage
study of 993 multiply affected IBD pedigrees, 25% of which were of
Jewish ancestry, and observed the strongest linkage evidence at the IBD1
locus on chromosome 16q12.1, for all CD pedigrees (peak lod score,
4.86).

Elding et al. (2011) reanalyzed Crohn disease GWAS data from the
Wellcome Trust Case-Control Consortium and National Institute of
Diabetes and Digestive and Kidney Diseases and found genetic
heterogeneity within the NOD2 locus, as well as independent involvement
of a neighboring gene, CYLD (605018). They also found associations on
chromosome 16q with the IRF8 (601565) region and the region containing
CDH1 (192090) and CDH3 (114021), as well as substantial phenotypic and
genetic heterogeneity for CD itself.

- IBD2 on Chromosome 12p13.2-q24.1

See IBD2 (601458) for an ulcerative colitis/Crohn disease susceptibility
locus on chromosome 12p13.2-q24.1.

- IBD3 on Chromosome 6p21.3

See IBD3 (604519) for an ulcerative colitis/Crohn disease susceptibility
locus on chromosome 6p21.3.

- IBD4 on Chromosome 14q11-q12

See IBD4 (606675) for a Crohn disease susceptibility locus on chromosome
14q11-q12.

- IBD5 on Chromosome 5q31

See IBD5 (606348) for a Crohn disease susceptibility locus on chromosome
5q31.

- IBD6 on Chromosome 19p13

See IBD6 (606674) for a Crohn disease/ulcerative colitis susceptibility
locus on chromosome 19p13.

- IBD7 on Chromosome 1p36

See IBD7 (605225) for an ulcerative colitis/Crohn disease susceptibility
locus on chromosome 1p36.

- IBD8 on Chromosome 16p

See IBD8 (606668) for an ulcerative colitis susceptibility locus on
chromosome 16p.

- IBD9 on Chromosome 3p26

See IBD9 (608448) for a Crohn disease/ulcerative colitis susceptibility
locus on chromosome 3p26.

- IBD10 on Chromosome 2q37.1

See IBD10 (611081) for a Crohn disease susceptibility locus on
chromosome 2q37.1. This locus is associated with variation in the
ATG16L1 gene (610767).

- IBD11 on Chromosome 7q22

See IBD11 (191390) for an ulcerative colitis/Crohn disease
susceptibility locus on chromosome 7q22. This locus may be associated
with variation in the MUC3A gene (158371).

- IBD12 on Chromosome 3p21

See IBD12 (612241) for an ulcerative colitis/Crohn disease
susceptibility locus on chromosome 3p21. This locus may be associated
with variation in the MST1 gene (142408) or in the BSN gene (604020).

- IBD13 on Chromosome 7q21.1

See IBD13 (612244) for a Crohn disease/ulcerative colitis susceptibility
locus on chromosome 7q21.1. This locus is associated with variation in
the ABCB1 gene (171050).

- IBD14 on Chromosome 7q32

See IBD14 (612245) for an ulcerative colitis/Crohn disease
susceptibility locus on chromosome 7q32. This locus is associated with
variation in the IRF5 gene (607218).

- IBD15 on Chromosome 10q21

See IBD15 (612255) for a Crohn disease/ulcerative colitis susceptibility
locus on chromosome 10q21.

- IBD16 on Chromosome 9q32

See IBD16 (612259) for a Crohn disease/ulcerative colitis susceptibility
locus on chromosome 9q32. This locus may be associated with variation in
the TNFSF15 gene (604052).

- IBD17 on Chromosome 1p31.1

See IBD17 (612261) for a Crohn disease/ulcerative colitis susceptibility
locus on chromosome 1p31.1. This locus is associated with variation in
the IL23R gene (607562).

- IBD18 on Chromosome 5p13.1

See IBD18 (612262) for a Crohn disease/ulcerative colitis susceptibility
locus on chromosome 5p13.1.

- IBD19 on Chromosome 5q33.1

See IBD19 (612278) for a Crohn disease susceptibility locus on
chromosome 5q33.1.

- IBD20 on Chromosome 10q24

See IBD20 (612288) for a Crohn disease/ulcerative colitis susceptibility
locus on chromosome 10q23-q24.

- IBD21 on Chromosome 18p11

See IBD21 (612354) for a Crohn disease/ulcerative colitis susceptibility
locus on chromosome 18p11.

- IBD22 on Chromosome 17q21

See IBD22 (612380) for a Crohn disease susceptibility locus on
chromosome 17q21.

- IBD23 on Chromosome 1q32

See IBD23 (612381) for a Crohn disease/ulcerative colitis susceptibility
locus on chromosome 1q32. This locus may be associated with variation in
the IL10 gene (124092).

- IBD24 on Chromosome 20q13

See IBD24 (612566) for a Crohn disease/ulcerative colitis susceptibility
locus on chromosome 20q13.

- IBD25 on Chromosome 21q22

See IBD25 (612567) for a Crohn disease/ulcerative colitis susceptibility
locus on chromosome 21q22. This locus is associated with mutation in the
IL10RB gene (123889).

- IBD26 on Chromosome 12q15

See IBD26 (612639) for an ulcerative colitis susceptibility locus on
chromosome 12q15.

- IBD27 on Chromosome 13q13.3

See IBD27 (612796) for a Crohn disease susceptibility locus on
chromosome 13q13.3.

- IBD28 on Chromosome 11q23.3

See IBD28 (613148) for a Crohn disease/ulcerative colitis susceptibility
locus on chromosome 11q23.3. This locus is associated with mutation in
the IL10RA gene (146933).

- Genomewide Association Studies

Satsangi et al. (1996) undertook a systematic screening of the entire
genome for identification of susceptibility genes for inflammatory bowel
disease involving 186 affected sib pairs from 160 nuclear families. They
provided strong evidence for the presence of susceptibility loci for
both Crohn disease and ulcerative colitis on chromosomes 3, 7, and 12.
The highest lod score (5.47) was obtained with marker D12S83 and lod
scores of 3.08 and 2.69 were obtained for markers D7S669 and D3S573,
respectively. The data suggested that Crohn disease and ulcerative
colitis are closely related but distinct polygenic disorders that share
some, but not all, susceptibility genes.

Cho et al. (1998) used 377 autosomal markers in a genomewide linkage
screen on 297 Crohn disease, ulcerative colitis, or mixed relative pairs
from 174 families, of which 37% were Ashkenazi Jewish. They observed
evidence for linkage at 3q for all families (multipoint lod score =
2.29), with greatest significance for non-Ashkenazi Caucasians
(multipoint lod = 3.39), and at chromosome 1p (multipoint lod = 2.65)
for all families. In a limited subset of mixed families, containing 1
member with Crohn disease and another with ulcerative colitis, evidence
for linkage was observed on 4q (multipoint lod = 2.76), especially among
Ashkenazim. There was confirmatory evidence for a Crohn disease locus,
overlapping IBD1, in the pericentromeric region of chromosome 16
(multipoint lod = 1.69), particularly among Ashkenazim; however,
positive multipoint lod scores were observed over a very broad region of
chromosome 16. Furthermore, evidence for epistasis between IBD1 and
chromosome 1p was observed. Thirteen additional loci demonstrated
nominal (multipoint lod less than 1.0) evidence for linkage. This screen
provided strong evidence that there are several major susceptibility
loci contributing to the genetic risk for Crohn disease and ulcerative
colitis.

In a large European cohort, Hampe et al. (1999) confirmed previously
described linkages on chromosomes 16 and 12. Evidence for a previous
chromosome 4 linkage was extended. New suggestive evidence for autosomal
linkage was observed on chromosomes 1, 6, 10, and 22. A maximum lod
score of 1.76 was observed on the X chromosome, for ulcerative colitis,
which is consistent with the clinical association of IBD with Turner
syndrome. The finding of linkage to 6p was of interest because of the
possible contribution of HLA and tumor necrosis factor genes in IBD.

In a genomewide search of 158 Canadian sib-pair families, Rioux et al.
(2000) identified 3 regions of suggestive linkage (3p, 5q31-q33, and 6p)
and 1 region of significant linkage to 19p13 (lod score 4.6).
Higher-density mapping in the 5q31-q33 region revealed a locus of
genomewide significance (lod score 3.9) that contributed to Crohn
disease susceptibility in families with early-onset disease. Both the
chromosome 19 and chromosome 5 regions contain numerous genes that are
important to the immune and inflammatory systems and that provided good
targets for candidate gene studies. Lo and Zheng (2004) applied a novel
approach to the analysis of the genome-scan data of Rioux et al. (2000):
the backward haplotype transmission association (BHTA) algorithm. They
showed that the method has increased efficiency in the use of available
data and can lead to novel and surprising results.

Dechairo et al. (2001) conducted a replication study on the chromosome
6p region (IBD3) and extension studies on 2 other regions on chromosomes
3p and 7q. Microsatellite markers across each region were genotyped in
284 IBD-affected sib pairs from 234 UK Caucasian families. A
nonparametric peak multipoint lod score of 3.04 was detected near
D6S291, thus replicating the previous linkage to chromosome 6p. There
was almost equal contribution from Crohn disease and ulcerative colitis
sib pairs to the linkage. Nominal evidence of linkage was observed at
both the 3p and 7q regions, and the largest LOD score for each region
was 1.25 and 1.26, respectively, for Crohn disease patients.

Van Heel et al. (2003) performed a genomewide scan of 137 Crohn disease
affected relative pairs from 112 families. The authors verified linkage
of Crohn disease to regions on chromosome 3 (p = 0.0009) and X (p =
0.001) in their cohort. Linkage to chromosome 16 was observed in Crohn
disease pairs not possessing common CARD15 mutations (p = 0.0007),
approximately 25 cM telomeric of CARD15. Evidence for linkage to
chromosome 19 was observed in Crohn disease pairs not possessing CARD15
mutations (p = 0.0001), and in pairs possessing 1 or 2 copies of the
IBD5 risk haplotype (p = 0.0005), with significant evidence for genetic
heterogeneity and epistasis, respectively. These analyses demonstrated
the complex genetic basis to Crohn disease, and that the discovery of
disease-causing variants may be used to aid identification of further
susceptibility loci in complex diseases.

Gaya et al. (2006) reviewed advances in genetics of IBD since the
discovery of the CARD15 gene and discussed plausible candidate genes for
analysis.

The Wellcome Trust Case Control Consortium (2007) described a joint
genomewide association study using the Affymetrix GeneChip 500K Mapping
Array Set, undertaken in the British population, which examined
approximately 2,000 individuals and a shared set of approximately 3,000
controls for each of 7 major diseases. They replicated associations of
Crohn disease with CARD15, IL23R (607562), and ATG16L1 (610767), and the
association of the risk haplotype represented by IBD5 (606348). They
also identified several new associations.

Rioux et al. (2007) reported a genomewide association study of ileal
Crohn disease and 2 independent replication studies that identified
several new regions of association to Crohn disease: in addition to the
previously established CARD15 (605956) and IL23R (607562) associations,
they identified strong and significantly replicated associations with an
intergenic region on 10q21.1 and the dbSNP rs2241880-coding variant in
ATG16L1 (610767). Rioux et al. (2007) also reported strong associations
with independent replication to variation in the genomic regions
encoding PHOX2B (603851), NCF4 (601488), and a predicted gene on
16q24.1.

Cho and Weaver (2007) reviewed the genetics of inflammatory bowel
disease, including murine genetic models relevant to IBD.

Mathew (2008) reviewed new links to the pathogenesis of CD provided by
genomewide association scans; they noted that because most of the SNPs
that were genotyped in these scans were selected to tag the genome
efficiently rather than for their possible effect on gene function, most
CD-associated SNPs are unlikely to be the causal variants that actually
confer disease susceptibility.

In a metaanalysis of data from 3 studies of Crohn disease involving a
total of 3,230 cases and 4,829 controls (Rioux et al., 2007, the
Wellcome Trust Case Control Consortium, 2007, and Libioulle et al.,
2007) with replication in 3,664 independent cases, Barrett et al. (2008)
strongly confirmed 11 previously reported loci, including the NOD2 locus
(combined p = 5.10 x 10(-24); case-control odds ratio, 3.99), and
identified 21 additional CD susceptibility loci on chromosomes 1, 5, 6,
7, 8, 9, 10, 11, 12, 13, 17, and 21.

Glas et al. (2009) attempted to replicate the findings of Rioux et al.
(2007) in a European cohort involving 854 German patients with CD, 476
with UC, and 1,503 healthy controls. Of the 7 strongest associations in
the earlier study, Glas et al. (2009) confirmed the 3 strongest, e.g.,
NOD2/CARD15, IL23R, and ATG16L1; however, they found no association
between CD and PHOX2B (dbSNP rs16853571), NCF4 (dbSNP rs4821544), FAM92B
(dbSNP rs8050910), or dbSNP rs224136, a SNP in the intergenic region on
chromosome 10q21.1, even after subanalysis of 529 German patients with
an ileal CD phenotype. Noting that other European studies had shown
similar results (e.g., Wellcome Trust Case Control Consortium, 2007,
Libioulle et al., 2007, and Barrett et al., 2008), Glas et al. (2009)
concluded that these findings were likely due to ethnic differences
between the North American and European IBD populations.

Franke et al. (2008) conducted a genomewide association study involving
440,794 SNPs genotyped in 1,167 ulcerative colitis patients and 777
healthy controls, followed by testing for replication of the 20 most
significantly associated SNPs in 3 independent European case-control
panels comprising a total of 1,855 ulcerative colitis patients and 3,091
controls, and confirmed association at chromosomes 6p21, 1p31, and 1q32.
They also found a new association at dbSNP rs12612347 near the ARPC2
locus (604224) on chromosome 2q35 (p = 8.42 x 10(-6) in the initial
panel, odds ratio = 1.60; combined p = 2.00 x 10(-4), combined odds
ratio 1.18), and noted that Van Heel et al. (2004) had previously
obtained suggestive linkage to chromosome 2q for ulcerative colitis, CD,
and IBD.

Wang et al. (2009) applied pathway analysis using Affymetrix SNP
genotype data from the Wellcome Trust Case Control Consortium and
uncovered significant association between Crohn disease and the
IL12/IL23 pathway (see 161561), harboring 20 genes (p = 8 x 10(-5)).
Interestingly, the pathway contains multiple genes (IL12B and JAK2,
147796) or homologs of genes (STAT3, 102582 and CCR6, 601835) that had
been identified as genuine susceptibility genes only through
metaanalysis of several genomewide association studies. In addition, the
pathway contains other susceptibility genes for Crohn disease, including
IL18R1 (604494), JUN (165160), IL12RB1 (601604), and TYK2 (176941),
which do not reach genomewide significance by single marker association
tests. The observed pathway-specific association signal was subsequently
replicated in 3 additional genomewide association studies of European
and African American ancestry generated on the Illumina HumanHap550
platform. Wang et al. (2009) concluded that examination beyond
individual SNP hits, by focusing on genetic networks and pathways, is
important to realizing the true power of genomewide association studies.
It was notable, however, that examination of the IL12/IL23 pathway
failed to detect the well-known association between Crohn disease and
NOD2 (605956).

In a study involving 2,731 Dutch and Belgian IBD patients, including
1,656 CD patients and 1,075 UC patients, Weersma et al. (2009) found
association at dbSNP rs916977 in the HERC2 gene (605837) on chromosome
15q13.1 for CD (corrected p = 4.48 x 10(-3); odds ratio, 1.39); there
was no significant association with UC.

In a genomewide association study involving 1,897,764 SNPs in 1,043
German UC cases and 1,703 controls, Franke et al. (2010) found
significant association at a nonsynonymous SNP (L333P; dbSNP rs5771069)
in the IL17REL gene (613414) on chromosome 22q13 (p = 4.37 x 10(-5)).
Combined analysis, including 6 replication panels involving a total of
2,539 UC cases and 5,428 controls, yielded a Cochran-Mantel-Haenzsel p =
8.81 x 10(-8) (odds ratio, 1.17; 95% CI 1.11-1.25). Gene ontology
analyses for the dbSNP rs5771069 G allele revealed downregulated
transcripts including IL17RE (614995), CSF3 (138970), and CD276
(605715).

McGovern et al. (2010) combined new data from 2 genomewide association
studies of ulcerative colitis involving 266,047 SNPs and performed a
metaanalysis with previously published data (Silverberg et al., 2009),
thus bringing together a discovery set of 2,693 European UC patients and
6,791 controls; the top results from the metaanalysis were then
independently replicated with 2,009 additional European UC cases and
1,580 controls. McGovern et al. (2010) identified 13 loci that were
significantly associated with UC (p less than 5 x 10(-8)), including
SNPs on chromosome 2p16 and 5p15.3, and confirmed association with 14
previously identified UC susceptibility loci. An analysis of known Crohn
disease loci showed that roughly half were shared with UC. Overall,
these data implicated approximately 30 loci in ulcerative colitis.

Momozawa et al. (2011) used high-throughput sequencing of DNA pools to
search for rare coding variants influencing susceptibility to Crohn
disease in 63 GWAS-identified positional candidate genes, but detected
significantly associated low-frequency coding variants only in the IL23R
gene (see 607562 and IBD17, 612261). Momozawa et al. (2011) concluded
that rare coding variants in positional candidates do not make a large
contribution to inherited predisposition to Crohn disease.

Jostins et al. (2012) expanded on the knowledge of relevant pathways of
inflammatory bowel disease by undertaking a metaanalysis of Crohn
disease and ulcerative colitis genomewide association scans, followed by
extensive validation of significant findings, with a combined total of
more than 75,000 cases and controls. They identified 71 new
associations, for a total of 163 IBD loci, that meet genomewide
significance thresholds. Most loci contribute to both phenotypes, and
both directional (consistently favoring one allele over the course of
human history) and balancing (favoring the retention of both alleles
within populations) selection effects are evident. Many IBD loci are
also implicated in other immune-mediated disorders, most notably with
ankylosing spondylitis and psoriasis. Jostins et al. (2012) also
observed considerable overlap between susceptibility loci for IBD and
mycobacterial infection. Gene coexpression network analysis emphasized
this relationship, with pathways shared between host responses to
mycobacteria and those predisposing to IBD.

McGovern et al. (2010) performed a GWAS in 896 CD cases and 3,204
healthy Caucasian controls. An association was identified with FUT2
(182100) on chromosome 19q13 (dbSNP rs602662, p = 3.4 x 10(-5)).
Replication was demonstrated in an independent cohort of 1,174 CD cases
and 357 controls between the 4 primary FUT2 SNPs and CD (dbSNP rs602662,
combined p = 4.90 x 10(-8)) and also association with FUT2 W143X
(182100.0001) (p = 2.6 x 10(-5)). McGovern et al. (2010) noted that
Barrett et al. (2008) had identified genomewide significant association
with CD for SNPs on chromosome 19p13 (combined p = 2.12 x 10(-9)). The
FUT2 gene product, alpha-(1,2)fucosyltransferase, regulates the
expression of the H antigen, a precursor of the blood group A and B
antigens, on the gastrointestinal mucosa. About 20% of Caucasians are
nonsecretors who do not express ABO antigens in saliva as a result of
homozygosity for the FUT2 W143X allele. McGovern et al. (2010) concluded
that FUT2 may play a role in CD susceptibility and highlighted the role
of the mucus layer in the development of CD.

- Association on 10p11

Franke et al. (2008) investigated 50 previously reported susceptibility
loci in a German sample of 1,850 CD patients, 1,103 UC patients, and
1,817 controls, and replicated the association between dbSNP rs3936503
in the CCNY gene (612786) on chromosome 10p11.2 for both CD and UC
(corrected p = 5.76 x 10(-5) and 8.90 x 10(-5), respectively). In a
metaanalysis of data from 3 studies of Crohn disease involving a total
of 3,230 cases and 4,829 controls (Rioux et al., 2007, the Wellcome
Trust Case Control Consortium, 2007, and Libioulle et al., 2007) with
replication in 3,664 independent cases, Barrett et al. (2008) identified
a new locus at dbSNP rs17582416 on chromosome 10p11 (combined p = 1.79 x
10(-9)) in a region containing 3 genes. In a study involving 2,731 Dutch
and Belgian IBD patients, including 1,656 CD patients and 1,075 UC
patients, Weersma et al. (2009) replicated association at dbSNP
rs3936503 for CD (corrected p = 8.36 x 10(-3); odds ratio, 1.31) but did
not find significant association with UC. Combined analysis with data
from the Wellcome Trust Case Control Consortium (2007) yielded a p of
1.46 x 10(-8). Anderson et al. (2009) analyzed 45 SNPs tagging 29
CD-associated loci in 2,527 UC cases and 4,070 controls and found
association at chromosome 10p11 with dbSNP rs17582416 (p = 4.27 x
10(-4)).

MOLECULAR GENETICS

- Association with NOD2/CARD15 on Chromosome 16q12

Using a positional cloning strategy based on linkage analysis followed
by linkage disequilibrium mapping, Hugot et al. (2001) identified 3
independent mutations in the NOD2 gene that were associated with Crohn
disease. They determined that the relative risk of Crohn disease for
individuals who were heterozygous, homozygous, or compound heterozygous
for the identified NOD2 mutations was 3-fold, 38-fold, and 44-fold
higher than for normal controls, respectively.

Raelson et al. (2007) performed a genomewide association study in 477
parent-proband trios with Crohn disease from the Quebec Founder
Population and tested for replication in 2 independent German samples.
They confirmed 3 of the most replicated loci, NOD2, IBD5, and IL23R, and
replicated a previously reported region on chromosome 3p21.3.

Rivas et al. (2011) used pooled next-generation sequencing to study 56
genes from regions associated with Crohn disease in 350 cases and 350
controls. Through follow-up genotyping of 70 rare and low-frequency
protein-altering variants in 9 independent case-control series (16,054
Crohn disease cases, 12,153 ulcerative colitis cases, and 17,575 healthy
controls), they identified 4 additional independent risk factors in
NOD2.

- Crohn Disease-Associated Growth Failure

Crohn disease inhibits growth in up to one-third of affected children.
Sawczenko et al. (2005) hypothesized that IL6 (147620) on chromosome
7p21, induced by intestinal inflammation, retards growth and suppresses
IGF1 (147440). They treated rats with trinitrobenzenesulfonic
acid-induced colitis with anti-IL6 and found that nutrient intake and
inflammation did not decrease, but linear growth was restored and plasma
and hepatic Igf1 levels increased. Sawczenko et al. (2005) suggested
that, in humans, Crohn disease-associated growth failure would vary with
the genotype at the IL6 -174 G/C promoter polymorphism (147620.0001).
They found that English and Swedish children with Crohn disease and the
-174 GG genotype were more growth retarded at diagnosis and had higher
levels of the IL6-induced inflammatory marker C-reactive protein (CRP;
123260) than children with GC or CC genotypes. After corticosteroid or
enteral feeding treatment, CRP levels decreased significantly and became
comparable to those in children with GC or CC genotypes. Sawczenko et
al. (2005) concluded that IL6 -174 genotype mediates growth failure in
Crohn disease.

- Associations Pending Confirmation

Polymorphism in the AGT gene (106150.0002) on chromosome 1q42-q43 has
been associated with Crohn disease.

Mwantembe et al. (2001) noted that IBD is more prevalent in South
African whites than in blacks, a pattern observed elsewhere as well. By
restriction enzyme and linkage disequilibrium analysis of IL1B (147720)
on chromosome 2q14, IL1RA (147810), and IL1RN (147679) polymorphisms,
Mwantembe et al. (2001) determined that a mutant IL1B allele (Taq-) was
significantly more common in white patients than in white controls,
whose frequency was similar to black patients and controls. On the other
hand, a mutant IL1RA allele (Pst-) was significantly more frequent in
blacks than in whites, regardless of disease status. Although other
population differences were observed, no other alleles were
significantly associated with disease in either group. Plasma IL1RN
levels were significantly higher in black patients than in black
controls or white patients and controls. Plasma concentrations of the
alpha-1 protease inhibitor (PI; 107400), an indicator of inflammation,
were significantly higher in both black and white patients than in black
and white controls. Mwantembe et al. (2001) concluded that the
inflammatory processes leading to IBD may be distinct in the different
population groups.

Karban et al. (2004) identified 6 nucleotide variants in the NFKB1 gene
on chromosome 4q, including a common insertion/deletion promoter
polymorphism (-94ins/delATTG). Using the family-based association test
and the pedigree disequilibrium test, they observed modest evidence for
linkage disequilibrium between the -94delATTG allele and ulcerative
colitis in 131 IBD pedigrees with ulcerative colitis offspring (p =
0.047 and p = 0.052, respectively). The -94delATTG association with
ulcerative colitis was replicated in a second set of 258 unrelated,
non-Jewish ulcerative colitis patients and 653 non-Jewish controls (p =
0.021). Nuclear proteins from normal human colon tissue and colonic cell
lines showed significant binding to -94insATTG-containing but not to
-94delATTG-containing oligonucleotides. Cells transfected with reporter
plasmid constructs containing the -94delATTG allele showed less promoter
activity than comparable constructs containing the -94insATTG allele.
Borm et al. (2005) confirmed the association in Dutch patients with
ulcerative colitis; however, Oliver et al. (2005) and Mirza et al.
(2005) found no association between the -94delATTG allele and ulcerative
colitis in Spanish and British ulcerative colitis patients,
respectively.

The NOD1 gene (605980), on chromosome 7p15-p14, encodes an intracellular
bacterial pathogen-associated molecular pattern receptor that is closely
related to NOD2 (605956). McGovern et al. (2005) identified strong
association between haplotypes in the terminal exons of NOD1 and IBD
(multiallelic p = 0.0000003) in a panel of 556 IBD trios. The deletion
allele of a complex functional NOD1 indel polymorphism (ND1+32656*1;
partially identified as dbSNP rs6958571) was significantly associated
with early-onset IBD (p = 0.0003) in unrelated cases and controls of 2
independent populations.

Defensins are endogenous antimicrobial peptides that protect the
intestinal mucosa against bacterial invasion. DNA copy number of the
beta-defensin gene cluster on 8p23.1 is highly polymorphic, and evidence
has been presented suggesting that low copy number of the
beta-defensin-2 gene (602215) predisposes to Crohn disease of the colon
(Fellermann et al., 2006).

In a panel of 1,182 individuals with Crohn disease and 2,024 controls,
Parkes et al. (2007) analyzed 37 SNPs from 31 distinct loci that were
associated at p values of less than 10(-5) in the Wellcome Trust Case
Control Consortium (2007) dataset and obtained replication for multiple
loci, including the NKX2C (606727), PTPN2 (176887), and IL12B (161561)
genes and the 'gene desert' on chromosome 1q.

In a 3-stage study involving a total of 1,851 patients with IBD and
1,936 controls, Zhernakova et al. (2008) analyzed 85 genes located in 74
genomic regions and found strong association for both Crohn disease and
ulcerative colitis with dbSNP rs917997 (uncorrected combined p = 1.9 x
10(-8)), a SNP located in an extended haplotype block on chromosome
2q11-2q12 that includes 4 genes: IL1RL1 (601203), IL18R1 (604494),
IL18RAP (604509), and SLC9A4 (600531). In addition, the authors found an
association for Crohn disease and ulcerative colitis with dbSNP
rs10870077 (uncorrected combined p = 3.25 x 10(-5)), located in an
extended haplotype block on chromosome 9q34.3 that encompasses multiple
genes, including the functional candidates CARD9 (607212), GPSM1
(609491), and SDCCAG3.

Martinez et al. (2008) genotyped 700 Spanish patients with inflammatory
bowel disease and 723 ethnically matched controls for a SNP in the STAT4
gene (dbSNP rs7574865) and found an association with IBD (p = 0.006;
odds ratio, 1.29).

In a 2-stage genomewide association and replication study involving a
total of 1,384 Japanese patients with ulcerative colitis (UC) and 3,057
controls, Asano et al. (2009) found significant association
(heterogeneity-corrected p = 1.56 x 10(-12)) between UC and a
nonsynonymous SNP (dbSNP rs1801274) in the FCGR2A gene (H121R;
146790.0001). The authors noted that the H131 variant was the
susceptibility allele for UC, a reversal of previous associations
observed between R131 and other autoimmune diseases.

Villani et al. (2009) used a candidate gene approach to identify a set
of SNPs located in a predicted regulatory region on chromosome 1q44
downstream of NLRP3 (606416) that are associated with Crohn disease. The
associations were consistently replicated in 4 sample sets from
individuals of European descent. In the combined analysis of all samples
(710 father-mother-child trios, 239 cases, and 107 controls), these SNPs
were strongly associated with risk of Crohn disease (P combined = 3.49 x
10(-9), odds ratio = 1.78, confidence interval = 1.47-2.16 for dbSNP
rs10733113). In addition, Villani et al. (2009) observed significant
associations between SNPs in the associated regions and NLRP3 expression
and IL1-beta (IL1B; 147720) production. Since mutations in NLRP3 are
responsible for 3 rare autoinflammatory disorders, these results
suggested that the NLRP3 region is also implicated in the susceptibility
of more common inflammatory diseases such as Crohn disease. In 2
independent samples of healthy donors, Villani et al. (2009) also found
that the risk allele of dbSNP rs6672995 (G) was associated with a
decrease in LPS-induced IL1-beta production, and the risk allele of
dbSNP rs4353135 (T) was associated with a decrease in baseline NLRP3
expression. All 3 SNPs in the associated 5.3-kb region influence NLRP3
at both the gene expression and functional levels.

Iliev et al. (2012) compared a group with medically refractory
ulcerative colitis who required colectomy with a group of ulcerative
colitis patients who did not, and found an association of CLEC7A dbSNP
rs2078178 in patients with medically refractory ulcerative colitis
(logistic regression, p = 0.007). Notably, a 2-marker haplotype, dbSNP
rs2078178 to dbSNP rs16910631, was more strongly associated with
medically refractory ulcerative colitis (AG haplotype: logistic
regression, p = 0.00013, and Fisher's test, p = 0.0005), a shorter time
to surgery, and thus with a more severe ulcerative colitis. Compared
with healthy controls, the haplotype was strongly associated with
medically refractory ulcerative colitis and not with nonmedically
refractory ulcerative colitis, further consistent with the idea that the
haplotype is associated with severe disease.

Rivas et al. (2011) used pooled next-generation sequencing to study 56
genes from regions associated with Crohn disease in 350 cases and 350
controls. Through follow-up genotyping of 70 rare and low-frequency
protein-altering variants in 9 independent case-control series (16,054
Crohn disease cases, 12,153 ulcerative colitis cases, and 17,575 healthy
controls), they identified a significant association with a protective
splice variant in CARD9. CARD9 is associated with both Crohn disease and
ulcerative colitis risk, with a common coding variant, dbSNP rs4077515,
creating protein substitution S12N with both alleles of roughly equal
frequency, that represents a typical GWAS hit (odds ratio approximately
1.2 in both disorders) (Franke et al., 2010; McGovern et al., 2010). In
the pooled sequencing, Rivas et al. (2011) identified a splice site
variant in CARD9 that altered the first base after exon 11 in 6 controls
and zero cases, suggesting a potentially strong protective effect.
Follow-up analyses confirmed a significant association (p less than
10(-16)), with the allele appearing in approximately 0.20% of cases and
0.64% of controls (odds ratio approximately 0.3). Although skipping exon
11 places translation out of frame, Rivas et al. (2011) predicted that
the resulting transcript would escape nonsense-mediated decay as
premature termination occurs close to the final splice junction in exon
12. Indeed, this hypothetical transcript has been observed in cDNA
libraries from spleen, lymph node, and peripheral blood mononuclear
cells. Notably, Rivas et al. (2011) pointed out that this rare
protective variant occurs on a haplotype carrying the risk allele at
dbSNP rs4077515, indicating not only that the 2 associations are
independent but also that the splice variant completely eliminates the
risk normally associated with the common haplotype. Because the Crohn
disease risk allele at dbSNP rs4077515 has been associated with higher
expression of CARD9, a consistent allelic series may exist if the splice
variant is substantially lower or nonfunctional and therefore highly
protective.

Rivas et al. (2011) found association of Crohn disease and inflammatory
bowel disease with coding variants in IL18RAP (604509), CUL2 (603135),
C1ORF106, PTPN22 (600716), and MUC19 (612170).

Inflammatory bowel disease, including Crohn disease (CD) and ulcerative
colitis (UC), and type 1 diabetes (T1D; see IDDM; 222100) are autoimmune
diseases that may share common susceptibility pathways. Wang et al.
(2010) examined known susceptibility loci for these diseases in a cohort
of 1,689 CD cases, 777 UC cases, 989 T1D cases, and 6,197 shared control
subjects of European ancestry. Multiple previously unreported or
unconfirmed disease-loci associations were identified, including CD loci
(ICOSLG, 605717; TNFSF15, 604052) and T1D loci (TNFAIP3; 191163) that
conferred UC risk; UC loci (HERC2, 605837; IL26, 605679) that conferred
T1D risk; and UC loci (IL10, 124092; CCNY, 612786) that conferred CD
risk. T1D risk alleles residing at the PTPN22, IL27 (608273), IL18RAP,
and IL10 loci protected against CD. The strongest risk alleles for T1D
within the major histocompatibility complex (MHC) conferred strong
protection against CD and UC. The authors suggested that many loci
involved in autoimmunity may be under a balancing selection due to
antagonistic pleiotropic effects, and variants with opposite effects on
different diseases may facilitate the maintenance of common
susceptibility alleles in human populations.

Fransen et al. (2010) selected SNPs from CD GWAS that showed a
correlation to gene expression (cis-expression quantitative trait loci,
or eQTLs). Ten such cis-eQTL SNPs were tested for association with CD in
2 independent cohorts of Dutch CD patients (1,539) and healthy controls
(2,648). Two cis-eQTL SNPs were associated with CD, dbSNP rs2298428 in
UBE2L3 (603721) (p = 5.22 x 10(-5)) and dbSNP rs2927488 in BCL3 (109560)
(p = 2.94 x 10(-4)). The authors concluded that UBE2L3 and BCL3 are
likely novel risk genes for CD, and that eQTL-based selection is a
useful approach for identifying risk loci from a moderately sized GWAS.

ANIMAL MODEL

Mouse models of colitis offer an avenue for identifying IBD genes or
pathways that may lead to identification of the human orthologs.
Targeted mutations in a variety of mouse genes produce colitis. Mice
homozygous for a disrupted interleukin-10 gene (Kuhn et al., 1993)
supported the hypothesis that a dysregulated immune response to enteric
flora can trigger IBD. The severity of the colitis depends on the inbred
strain background in which the disrupted gene is placed. The C3H strain
is highly susceptible to several experimentally induced forms of IBD,
whereas the B6 background is resistant.

Hermiston and Gordon (1995) transfected embryonic stem cells with a
dominant-negative N-cadherin (CDH2; 114020) mutant under the control of
promoters active in small intestinal epithelial cells and introduced
them into C57BL/6 blastocysts. Analysis of adult chimeric mice revealed
that expression of the mutant along the entire crypt-villus axis, but
not in the villus epithelium alone, produced an inflammatory bowel
disease resembling Crohn disease. The mutation perturbed proliferation,
migration, and death patterns in crypts, leading to adenomas. The model
provided insights into cadherin function in an adult organ and the
factors underlying inflammatory bowel disease and intestinal neoplasia.

Neurath et al. (1996) reported that chronic intestinal inflammation
induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS) is characterized
by a transmural granulomatous colitis that mimics some characteristics
of human Crohn disease. They demonstrated that the p65 subunit of
transcription factor NF-kappa-B (164014) was strongly activated in
TNBS-induced colitis and in colitis of interleukin-10 (IL10;
124092)-deficient mice. They administered a p65 antisense
phosphorothioate oligonucleotide to mice intravenously and
intrarectally. The p65 antisense treatment abrogated clinical and
histologic signs of colitis. The investigators noted that the p65
antisense treatment was more effective in treating TNBS-induced colitis
than single or daily administration of glucocorticoids. Neurath et al.
(1996) stated that their data provided direct evidence for the
involvement of p65 in chronic intestinal inflammation and suggested a
potential therapeutic role for p65 antisense oligonucleotides for the
treatment of patients with Crohn disease.

Farmer et al. (2001) used quantitative trait locus (QTL) analysis to
identify modifiers of cytokine deficiency-induced colitis
susceptibility. They found a colitogenic susceptibility QTL on mouse
chromosome 3 that exacerbated colitis in combination with modifiers
contributed from both parental genomes. The complex nature of
interactions among loci in this mouse model, coupled with separate
deleterious contributions from both parental strains, illustrated why
detection of human inflammatory bowel disease linkages has proven to be
so difficult. A human ortholog of the mouse chromosome 3 QTL, if one
exists, would map to chromosome 4q or 1p in the human.

Using semiquantitative RT-PCR analysis, Singh et al. (2003) detected
increased expression of Ip10 (CXCL10; 147310) and its receptor, Cxcr3
(300574), in mesenteric lymph nodes and inflamed colons of Il10 -/-
mice. The Crohn disease-like colitis in Il10 -/- mice was associated
with increased serum amyloid A (SAA; 104750), Il6, and Th1 cytokine
levels and weight loss, all of which could be abrogated by anti-Ip10
treatment. Singh et al. (2003) concluded that anti-IP10 treatment can
successfully impede development of inflammatory bowel disease, and that
SAA levels can reveal the intensity of colitis.

Maeda et al. (2005) generated mice with a Nod2 locus harboring the
homolog of the most common Crohn disease susceptibility allele, 3020insC
(605956.0001), which encodes a truncated protein lacking the last 33
amino acids. Homozygous Nod2 mutant mice were obtained at the expected
mendelian ratio, were healthy, and showed no abnormalities of the
gastrointestinal tract or other organs. The mutation had no effect on
Nod2 mRNA or protein amounts in bone marrow-derived macrophages. Mutant
mice exhibited elevated NFKB (164011) activation in response to
bacteria-derived muramyl dipeptide and more efficient processing and
secretion of the cytokine IL1B. These effects were linked to increased
susceptibility to bacteria-induced intestinal inflammation and
identified NOD2 as a positive regulator of NFKB activation and IL1B
secretion.

Mice deficient in Il10 develop spontaneous IBD. Yen et al. (2006) found
that mice deficient in both Il10 and Il12 p35 (IL12A; 161560), but not
mice deficient in both Il10 and Il23 p19 (IL23A; 605580), developed
spontaneous IBD, indicating that IL23, but not IL12, is necessary for
chronic intestinal inflammation. Adding recombinant IL23 to T cells from
Il10 -/- mice adoptively transferred to T cell-deficient mice
accelerated IBD development, which was accompanied by enhanced
production of Il6 and Il17 (603149). Blockade of Il6 and Il17
ameliorated IBD. Yen et al. (2006) concluded that IL23 promotes
development and expansion of a pathogenic IL6- and IL17-producing
memory-activated T-cell population that triggers the inflammatory
cascade leading to intestinal inflammation.

In a murine model of Crohn disease, Gonzalez-Rey et al. (2006)
demonstrated that cortistatin (602784) treatment significantly
ameliorated the clinical and histopathologic severity of inflammatory
colitis, abrogating weight loss, diarrhea, and inflammation and
increasing the survival rate of colitic mice. The therapeutic effect was
associated with downregulation of inflammatory and Th1-driven autoimmune
responses, including regulation of a wide spectrum of inflammatory
mediators. Cortistatin was effective in the treatment of established
colitis and in avoiding the recurrence of disease. Gonzalez-Rey et al.
(2006) concluded that cortistatin is an antiinflammatory factor capable
of deactivating intestinal inflammatory response and restoring mucosal
immune tolerance at multiple levels.

Using 2 mouse models of Helicobacter hepaticus-induced T-cell-dependent
colitis, Kullberg et al. (2006) showed that Il23, but not Il12, was
essential for development of maximal intestinal disease. They proposed
that IL23 drives both gamma-interferon (IFNG; 147570) and IL17 responses
that synergize to trigger severe intestinal inflammation.

Nenci et al. (2007) demonstrated that the transcription factor NFKB, a
master regulator of proinflammatory responses, functions in gut
epithelial cells to control epithelial integrity and the interaction
between the mucosal immune system and gut microflora. Intestinal
epithelial-specific inhibition of NFKB through conditional ablation of
NEMO (300248) or both IKK1 (600664) and IKK2 (603258), IKK subunits
essential for NFKB activation, spontaneously caused severe chronic
intestinal inflammation in mice. NFKB deficiency led to apoptosis of
colonic epithelial cells, impaired expression of antimicrobial peptides,
and translocation of bacteria into the mucosa. Concurrently, this
epithelial defect triggered a chronic inflammatory response in the
colon, initially dominated by innate immune cells but later also
involving T lymphocytes. Deficiency of the gene encoding the adaptor
protein MyD88 (602170) prevented the development of intestinal
inflammation, demonstrating that Toll-like receptor activation by
intestinal bacteria is essential for disease pathogenesis in this mouse
model. Furthermore, NEMO deficiency sensitized epithelial cells to
TNF-induced apoptosis, whereas TNF receptor-1 (TNFR1; 191190)
inactivation inhibited intestinal inflammation, demonstrating that TNFR1
signaling is crucial for disease induction. Nenci et al. (2007)
concluded that a primary NFKB signaling defect in intestinal epithelial
cells disrupts immune homeostasis in the gastrointestinal tract, causing
an inflammatory bowel disease-like phenotype. Their results further
identified NFKB signaling in the gut epithelium as a critical regulator
of epithelial integrity and intestinal immune homeostasis and have
important implications for understanding the mechanisms controlling the
pathogenesis of human inflammatory bowel disease.

HISTORY

In 25 families with multiple cases of Crohn disease, Hugot et al. (1994)
excluded the Crohn disease predisposing locus from the entire chromosome
6 with lod scores less than -2. The locus was excluded from the major
histocompatibility complex and from 91% of the chromosome 6 genetic map
with lod scores of less than -4.

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77. Parkes, M.; Satsangi, J.; Lathrop, G. M.; Bell, J. I.; Jewell,
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78. Pizarro, T. T.; Michie, M. H.; Bentz, M.; Woraratanadharm, J.;
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79. Raelson, J. V.; Little, R. D.; Ruether, A.; Fournier, H.; Paquin,
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80. Ricciardelli, I.; Lindley, K. J.; Londei, M.; Quaratino, S.:
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81. Rioux, J. D.; Silverberg, M. S.; Daly, M. J.; Steinhart, A. H.;
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82. Rioux, J. D.; Xavier, R. J.; Taylor, K. D.; Silverberg, M. S.;
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83. Rivas, M. A.; Beaudoin, M.; Gardet, A.; Stevens, C.; Sharma, Y.;
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84. Satsangi, J.; Grootscholten, C.; Holt, H.; Jewell, D. P.: Clinical
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85. Satsangi, J.; Parkes, M.; Louis, E.; Hashimoto, L.; Kato, N.;
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provides evidence for susceptibility loci on chromosomes 3, 7 and
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86. Sawczenko, A.; Azooz, O.; Paraszczuk, J.; Idestrom, M.; Croft,
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87. Schwartz, S. E.; Siegelbaum, S. P.; Fazio, T. L.; Hubbell, C.;
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88. Sheehan, R. G.; Necheles, T. F.; Lindeman, R. J.; Meyer, H. J.;
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89. Shugart, Y. Y.; Silverberg, M. S.; Duerr, R. H.; Taylor, K. D.;
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90. Silverberg, M. S.; Cho, J. H.; Rioux, J. D.; McGovern, D. P. B.;
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91. Singh, U. P.; Singh, S.; Taub, D. D.; Lillard, J. W., Jr.: Inhibition
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94. van Heel, D. A.; Dechairo, B. M.; Dawson, G.; McGovern, D. P.
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95. van Heel, D. A.; Fisher, S. A.; Kirby, A.; Daly, M. J.; Rioux,
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96. van Heel, D. A.; Ghosh, S.; Butler, M.; Hunt, K. A.; Lundberg,
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R. J.: Muramyl dipeptide and toll-like receptor sensitivity in NOD2-associated
Crohn's disease. (Letter) Lancet 365: 1794-1796, 2005.

97. Villani, A.-C.; Lemire, M.; Fortin, G.; Louis, E.; Silverberg,
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NLRP3 region contribute to Crohn's disease susceptibility. Nature
Genet. 41: 71-76, 2009.

98. von Andrian, U. H.; Engelhardt, B.: Alpha-4 integrins as therapeutic
targets in autoimmune disease. (Editorial) New Eng. J. Med. 348:
68-72, 2003.

99. Wang, K.; Baldassano, R.; Zhang, H.; Qu, H.-Q.; Imielinski, M.;
Kugathasan, S.; Annese, V.; Dubinsky, M.; Rotter, J. I.; Russell,
R. K.; Bradfield, J. P.; Sleiman, P. M. A.; and 22 others: Comparative
genetic analysis of inflammatory bowel disease and type 1 diabetes
implicates multiple loci with opposite effects. Hum. Molec. Genet. 19:
2059-2067, 2010.

100. Wang, K.; Zhang, H.; Kugathasan, S.; Annese, V.; Bradfield, J.
P.; Russell, R. K.; Sleiman, P. M. A.; Imielinski, M.; Glessner, J.;
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J. Hum. Genet. 84: 399-405, 2009.

101. Weersma, R. K.; Stokkers, P. C. F.; Cleynen, I.; Wolfkamp, S.
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I. M.; Rutgeerts, P.; Wijmenga, C.; Vermeire, S.: Confirmation of
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102. Wellcome Trust Case Control Consortium: Genome-wide association
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1993.

104. Yang, H.; Rotter, J. I.: Genetics of inflammatory bowel disease.In:
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105. Yen, D.; Cheung, J.; Scheerens, H.; Poulet, F.; McClanahan, T.;
Mckenzie, B.; Kleinschek, M. A.; Owyang, A.; Mattson, J.; Blumenschein,
W.; Murphy, E.; Sathe, M.; Cua, D. J.; Kastelein, R. A.; Rennick,
D.: IL-23 is essential for T cell-mediated colitis and promotes inflammation
via IL-17 and IL-6. J. Clin. Invest. 116: 1310-1316, 2006.

106. Yoneno, K.; Hisamatsu, T.; Shimamura, K.; Kamada, N.; Ichikawa,
R.; Kitazume, M. T.; Mori, M.; Uo, M.; Namikawa, Y.; Matsuoka, K.;
Sato, T.; Koganei, K.; Sugita, A.; Kanai, T.; Hibi, T.: TGR5 signalling
inhibits the production of pro-inflammatory cytokines by in vitro
differentiated inflammatory and intestinal macrophages in Crohn's
disease. Immunology 139: 19-29, 2013.

107. Zhernakova, A.; Festen, E. M.; Franke, L.; Trynka, G.; van Diemen,
C. C.; Monsuur, A. J.; Bevova, M.; Nijmeijer, R. M.; van't Slot, R.;
Heijmans, R.; Boezen, H. M.; van Heel, D. A.; van Bodegraven, A. A.;
Stokkers, P. C. F.; Wijmenga, C.; Crusius, J. B. A.; Weersma, R. K.
: Genetic analysis of innate immunity in Crohn's disease and ulcerative
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J. Hum. Genet. 82: 1202-1210, 2008.

108. Zouali, H.; Chamaillard, M.; Lesage, S.; Cezard, J.-P.; Colombel,
J.-F.; Belaiche, J.; Almer, S.; Tysk, C.; Montague, S.; Gassull, M.;
Christensen, S.; Finkel, Y.; Gower-Rousseau, C.; Modigliani, R.; Macry,
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and physical mapping of a chromosome 16q candidate region for inflammatory
bowel disease. Europ. J. Hum. Genet. 9: 731-742, 2001.

*FIELD* CS
INHERITANCE:
Multifactorial

GROWTH:
[Weight];
Weight loss

HEAD AND NECK:
[Mouth];
Aphthous ulcers (lips, gingiva, buccal mucosa)

ABDOMEN:
[Gastrointestinal];
Abdominal pain;
Diarrhea;
Bowel obstruction;
Aphthous ulcers;
Strictures;
Fistulas;
Transmural granulomatous inflammation with 'skip lesions'

MISCELLANEOUS:
Genetic heterogeneity;
5-10% of patients have a first degree relative with IBD (Crohn or
ulcerative colitis);
35% of cases involve ileum only (ileitis), 45% of cases involve ileum
and colon (ileocolitis), 20% of cases involve colon alone - rectum
spared (granulomatous colitis)

MOLECULAR BASIS:
Susceptibility conferred by mutation in the nucleotide-binding oligomerization
domain protein 2 gene (NOD2, 605956.0001)

*FIELD* CN
Joanna S. Amberger - updated: 10/13/2008
Kelly A. Przylepa - revised: 6/25/2007

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

*FIELD* ED
joanna: 10/13/2008
joanna: 6/25/2007

*FIELD* CN
Paul J. Converse - updated: 01/24/2014
Ada Hamosh - updated: 12/13/2013
George E. Tiller - updated: 9/19/2013
George E. Tiller - updated: 9/18/2013
George E. Tiller - updated: 9/16/2013
Ada Hamosh - updated: 12/4/2012
Ada Hamosh - updated: 7/23/2012
Ada Hamosh - updated: 6/21/2012
Marla J. F. O'Neill - updated: 1/23/2012
Ada Hamosh - updated: 7/26/2011
Marla J. F. O'Neill - updated: 3/22/2011
Marla J. F. O'Neill - updated: 5/14/2010
Ada Hamosh - updated: 1/15/2010
Marla J. F. O'Neill - updated: 12/15/2009
Marla J. F. O'Neill - updated: 12/10/2009
Marla J. F. O'Neill - updated: 11/24/2009
Paul J. Converse - updated: 10/20/2009
Marla J. F. O'Neill - updated: 5/22/2009
Ada Hamosh - updated: 5/19/2009
Marla J. F. O'Neill - updated: 5/7/2009
Marla J. F. O'Neill - updated: 4/30/2009
Marla J. F. O'Neill - updated: 2/20/2009
Ada Hamosh - updated: 1/20/2009
Marla J. F. O'Neill - updated: 11/24/2008
Marla J. F. O'Neill - updated: 10/29/2008
Marla J. F. O'Neill - updated: 10/28/2008
Marla J. F. O'Neill - updated: 9/12/2008
Marla J. F. O'Neill - updated: 9/8/2008
Marla J. F. O'Neill - updated: 9/2/2008
Marla J. F. O'Neill - updated: 8/29/2008
Marla J. F. O'Neill - updated: 8/26/2008
Marla J. F. O'Neill - updated: 8/18/2008
George E. Tiller - updated: 8/15/2008
Marla J. F. O'Neill - updated: 8/14/2008
George E. Tiller - updated: 5/30/2008
Marla J. F. O'Neill - updated: 3/20/2008
Marla J. F. O'Neill - updated: 12/4/2007
Marla J. F. O'Neill - updated: 11/12/2007
Paul J. Converse - updated: 10/25/2007
Ada Hamosh - updated: 7/19/2007
Victor A. McKusick - updated: 5/31/2007
Victor A. McKusick - updated: 5/24/2007
Ada Hamosh - updated: 4/12/2007
Ada Hamosh - updated: 2/6/2007
George E. Tiller - updated: 10/12/2006
Victor A. McKusick - updated: 8/23/2006
Paul J. Converse - updated: 6/20/2006
Paul J. Converse - updated: 6/2/2006
Marla J. F. O'Neill - updated: 4/12/2006
Paul J. Converse - updated: 9/22/2005
Marla J. F. O'Neill - updated: 9/1/2005
Marla J. F. O'Neill - updated: 7/21/2005
Ada Hamosh - updated: 2/25/2005
Victor A. McKusick - updated: 9/1/2004
Victor A. McKusick - updated: 4/26/2004
Patricia A. Hartz - updated: 4/1/2004
Cassandra L. Kniffin - updated: 1/5/2004
Victor A. McKusick - updated: 4/10/2003
Victor A. McKusick - updated: 2/12/2003
Michael B. Petersen - updated: 12/3/2002
Paul J. Converse - updated: 5/8/2002
Michael B. Petersen - updated: 3/4/2002
Paul J. Converse - updated: 2/20/2002
Victor A. McKusick - updated: 2/5/2002
Victor A. McKusick - updated: 1/7/2002
Michael B. Petersen - updated: 11/29/2001
George E. Tiller - updated: 11/9/2001
Michael B. Petersen - updated: 10/31/2001
Victor A. McKusick - updated: 10/2/2001
Victor A. McKusick - updated: 6/13/2001
Ada Hamosh - updated: 5/22/2001
George E. Tiller - updated: 5/17/2001
Paul J. Converse - updated: 3/27/2001
Michael B. Petersen - updated: 2/12/2001
Ada Hamosh - updated: 6/15/2000
Victor A. McKusick - updated: 11/22/1999
Victor A. McKusick - updated: 9/8/1999
Victor A. McKusick - updated: 4/12/1999
Victor A. McKusick - updated: 2/24/1999
Victor A. McKusick - updated: 7/14/1998
Moyra Smith - updated: 8/30/1996

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

*FIELD* ED
mgross: 01/24/2014
mcolton: 1/17/2014
alopez: 12/13/2013
alopez: 9/19/2013
alopez: 9/18/2013
alopez: 9/16/2013
carol: 9/6/2013
alopez: 12/19/2012
alopez: 12/5/2012
terry: 12/4/2012
terry: 11/29/2012
terry: 9/14/2012
alopez: 7/24/2012
terry: 7/23/2012
alopez: 6/28/2012
terry: 6/21/2012
terry: 6/8/2012
carol: 1/23/2012
carol: 12/5/2011
terry: 7/26/2011
terry: 7/21/2011
alopez: 7/15/2011
terry: 3/30/2011
terry: 3/23/2011
wwang: 3/22/2011
terry: 3/22/2011
wwang: 5/19/2010
terry: 5/14/2010
alopez: 1/26/2010
wwang: 1/15/2010
terry: 1/15/2010
alopez: 12/22/2009
terry: 12/15/2009
terry: 12/10/2009
joanna: 12/10/2009
wwang: 11/25/2009
terry: 11/24/2009
mgross: 10/27/2009
terry: 10/20/2009
alopez: 6/3/2009
terry: 6/3/2009
wwang: 5/22/2009
terry: 5/19/2009
wwang: 5/12/2009
terry: 5/7/2009
wwang: 5/5/2009
terry: 4/30/2009
terry: 3/25/2009
wwang: 2/23/2009
terry: 2/20/2009
carol: 2/12/2009
alopez: 1/30/2009
terry: 1/20/2009
alopez: 11/24/2008
carol: 10/30/2008
carol: 10/29/2008
carol: 10/22/2008
carol: 10/21/2008
wwang: 10/14/2008
carol: 9/12/2008
terry: 9/12/2008
carol: 9/9/2008
terry: 9/8/2008
carol: 9/3/2008
terry: 9/2/2008
terry: 8/29/2008
alopez: 8/28/2008
carol: 8/27/2008
terry: 8/27/2008
carol: 8/26/2008
carol: 8/19/2008
carol: 8/18/2008
terry: 8/15/2008
carol: 8/14/2008
carol: 8/13/2008
carol: 8/12/2008
mgross: 7/25/2008
carol: 7/25/2008
carol: 6/9/2008
wwang: 6/3/2008
terry: 5/30/2008
wwang: 3/25/2008
terry: 3/20/2008
carol: 12/4/2007
terry: 12/4/2007
wwang: 11/28/2007
wwang: 11/15/2007
terry: 11/12/2007
mgross: 10/26/2007
terry: 10/25/2007
alopez: 7/24/2007
terry: 7/19/2007
alopez: 6/5/2007
terry: 5/31/2007
terry: 5/24/2007
alopez: 4/12/2007
alopez: 2/8/2007
terry: 2/6/2007
wwang: 1/23/2007
alopez: 10/12/2006
alopez: 8/29/2006
terry: 8/23/2006
mgross: 6/20/2006
mgross: 6/2/2006
wwang: 4/17/2006
terry: 4/12/2006
joanna: 3/13/2006
wwang: 3/3/2006
terry: 2/17/2006
mgross: 10/4/2005
terry: 9/22/2005
wwang: 9/1/2005
wwang: 7/26/2005
terry: 7/21/2005
wwang: 3/3/2005
terry: 2/25/2005
alopez: 9/6/2004
terry: 9/1/2004
alopez: 4/27/2004
terry: 4/26/2004
mgross: 4/16/2004
terry: 4/1/2004
tkritzer: 1/13/2004
ckniffin: 1/5/2004
alopez: 12/19/2003
tkritzer: 7/15/2003
joanna: 7/11/2003
tkritzer: 4/16/2003
terry: 4/10/2003
cwells: 2/13/2003
cwells: 2/12/2003
cwells: 12/3/2002
mgross: 5/8/2002
terry: 3/11/2002
mgross: 3/4/2002
mgross: 2/20/2002
carol: 2/5/2002
carol: 1/20/2002
mcapotos: 1/10/2002
terry: 1/7/2002
cwells: 12/5/2001
cwells: 11/29/2001
cwells: 11/9/2001
cwells: 11/5/2001
cwells: 10/31/2001
alopez: 10/3/2001
terry: 10/2/2001
cwells: 6/20/2001
cwells: 6/15/2001
terry: 6/13/2001
mgross: 5/22/2001
cwells: 5/22/2001
cwells: 5/17/2001
mgross: 3/27/2001
carol: 2/16/2001
cwells: 2/13/2001
cwells: 2/12/2001
alopez: 6/15/2000
carol: 2/11/2000
carol: 11/23/1999
terry: 11/22/1999
jlewis: 9/16/1999
terry: 9/8/1999
carol: 4/14/1999
terry: 4/12/1999
mgross: 3/16/1999
carol: 3/7/1999
terry: 2/24/1999
carol: 7/17/1998
terry: 7/14/1998
terry: 11/11/1997
mark: 7/16/1997
mark: 6/24/1997
jenny: 4/15/1997
mark: 3/26/1997
jamie: 12/4/1996
mark: 11/18/1996
terry: 10/22/1996
mark: 10/5/1996
terry: 10/1/1996
terry: 9/17/1996
mark: 9/10/1996
mark: 8/30/1996
marlene: 8/15/1996
terry: 3/29/1996
mark: 2/29/1996
mark: 2/28/1996
terry: 2/28/1996
mark: 2/23/1996
carol: 1/13/1995
mimadm: 3/12/1994
carol: 9/8/1993
supermim: 3/17/1992
carol: 1/22/1991
carol: 9/25/1990

MIM 605956
*RECORD*
*FIELD* NO
605956
*FIELD* TI
*605956 NUCLEOTIDE-BINDING OLIGOMERIZATION DOMAIN PROTEIN 2; NOD2
;;CASPASE RECRUITMENT DOMAIN-CONTAINING PROTEIN 15; CARD15
read more*FIELD* TX

DESCRIPTION

APAF1 (602233) and NOD1 (605980), also called CARD4, are members of a
family of intracellular proteins that contain an N-terminal caspase
recruitment domain (CARD), a centrally located nucleotide-binding domain
(NBD), and a C-terminal regulatory domain. In the case of APAF1, the
C-terminal regulatory domain consists of WD40 repeats, whereas NOD1 has
leucine-rich repeats (LRRs). The APAF1 WD40 repeats act as recognition
domains for mitochondrial damage, which leads to APAF1 oligomerization
and eventual apoptosis. NOD1 also promotes apoptosis, but unlike APAF1,
it does so through nuclear factor kappa-B (NFKB; see 164011) activation.
Also, NOD1 has striking structural similarity to a class of
disease-resistance genes in plants that induce localized cell death at
the site of pathogen invasion (Ogura et al., 2001).

CLONING

By searching a genomic database for NOD1 homologs, followed by 5-prime
RACE and RT-PCR, Ogura et al. (2001) obtained cDNAs encoding NOD2.
Sequence analysis predicted that the 1,040-amino acid NOD2 protein,
which is 34% identical to NOD1, contains 2 N-terminal CARDs fused to a
central NBD domain followed by 10 tandem LRRs. Ogura et al. (2001) also
identified a NOD2 variant encoding a 1,013-amino acid protein, which
they called NOD2B. Northern blot analysis detected 7.0- and 5.5-kb NOD2
transcripts in peripheral blood leukocytes, with little or no expression
found in other tissues. RT-PCR analysis revealed expression primarily in
monocytes. In contrast, NOD1 and APAF1 are broadly expressed. Expression
of NOD2 or NOD2B resulted in NFKB activation, and mutants lacking the
LRRs had enhanced NFKB activation. The authors determined that both
intact CARD domains are necessary and sufficient for IKK-gamma (IKBKG;
300248)- and RICK (RIPK2; 603455)-dependent NFKB activation.
Coimmunoprecipitation analysis showed that the CARD domain of RICK
interacts with the CARD domains of NOD2.

By 5-prime RACE and semiquantitative RT-PCR, King et al. (2007) showed
that most human NOD2 transcripts in blood leukocytes and colon are
products of an alternative first exon. They concluded that the principal
NOD2 protein product lacks 27 previously reported N-terminal amino
acids.

GENE STRUCTURE

King et al. (2007) identified an alternative first exon that lies within
a strong CpG island about 3.5 kb upstream of the canonical first exon of
the NOD2 gene.

MAPPING

By analysis of BAC clones, Ogura et al. (2001) determined that the NOD2
gene maps to 16q12 and contains 12 coding exons.

GENE FUNCTION

Ogura et al. (2001) proposed that NOD2 serves as an intracellular
receptor for bacterial products in monocytes and transduces signals
leading to NFKB activation.

Cooney et al. (2010) showed that activation of NOD2 with
muramyldipeptide induced autophagy in dendritic cells (DCs) that
required RIPK2, PI3K (see 601232), ATG5 (604261), ATG7 (608760), and
ATG16L1 (610767), but not NALP3 (NLRP3; 606416). DCs from Crohn disease
(CD; 266600) patients with susceptibility variants in NOD2 (e.g.,
1007fs; 605956.0001) or ATG16L1 (T300A; 610767.0001) were deficient in
autophagy induction. DCs from CD patients with NOD2 variants also showed
reduced localization of bacteria in autophagolysosomes, which could be
reversed by treatment with rapamycin. Cooney et al. (2010) concluded
that NOD2 influences bacterial degradation and interacts with the major
histocompatibility complex class II antigen presentation machinery
within DCs, and that ATG16L1 and NOD2 are linked within 1 functional
pathway.

MOLECULAR GENETICS

- Susceptibility to Inflammatory Bowel Disease

Ogura et al. (2001) and Hugot et al. (2001) identified mutations in the
NOD2 gene (see, e.g., 605956.0001-605956.0003) that were associated with
susceptibility to Crohn disease (IBD1; 266600).

Lesage et al. (2002) reported mutation analysis of the CARD15 gene in
453 patients with Crohn disease, including 166 sporadic and 287 familial
cases, 159 patients with ulcerative colitis (IBD1; 266600), and 103
healthy control subjects. Although no mutations were found to be
associated with ulcerative colitis, 50% of patients with Crohn disease
carried at least 1 potential disease-causing mutation, including 17% who
had a double mutation. There were 27 rare additional mutations. Each of
3 polymorphisms (R702W, 605956.0003; G908R, 605956.0002; and 1007fs,
605956.0001) were confirmed to be intermittently associated with
susceptibility to Crohn disease. These 3 main variants represented 32%,
18%, and 31%, respectively, of the total Crohn disease mutations,
whereas the total of the 27 rare mutations represented 19% of
disease-causing mutations. Altogether, 93% of the mutations were located
in the distal third of the gene. These observations confirmed the
gene-dosage effect in Crohn disease. Patients with double-dose mutations
were characterized by a younger age at onset, a more frequent
stricturing phenotype, and a less frequent colonic involvement than were
seen in those patients who had no mutation. The severity of the disease
and extraintestinal manifestations were not different for any of the
CARD15 genotypes. The proportion of familial and sporadic cases and the
proportion of patients with smoking habits were similar in the groups of
Crohn disease patients with or without mutation.

Crohn disease exhibits a 2- to 4-fold increased frequency in Jews as
compared with other ethnic/racial groups. Sugimura et al. (2003) sought
additional NOD2 mutations in patients with CD, since the 3 coding
variants that had been reported were found in only 30 to 40% of patients
and could not account for all the linkage between CD and IBD1 locus
(266600). They studied 64 Ashkenazi Jewish and 147 non-Jewish white
families. After excluding the influence of the 3 independent
disease-predisposing mutations (1007fs, G908R, and R702W), significant
linkage of the IBD1 locus on chromosome 16 to Crohn disease was found in
Jews, with 2 peaks at D16S403 (mean allele sharing (MAS) = 0.70) and
D16S411 (MAS = 0.59). They observed an increased frequency of a
haplotype carrying only the 268S variant in Jewish patients but not in
non-Jews, suggesting the existence of a Jewish-specific additional
disease-predisposing factor on this haplotype. Sequencing of this
haplotype revealed a new variant: IVS8+158 (referred to as JW1;
605956.0007). The 268S-JW1 combination exhibited a further increased
risk (odds ratio = 5.75, p = 0.0005) and the highest
population-attributable risk (15.1%) for CD among reported
disease-predisposing mutations in Jews. Thus, in Ashkenazi Jews,
unrecognized population-specific predisposing factor(s) existed on the
268S-JW1 haplotype at the IBD1 locus. This factor may contribute to the
higher risk for CD in Ashkenazi Jews as compared with non-Jews.

Among 483 Japanese patients with Crohn disease, Yamazaki et al. (2002)
tested for the 3 mutations found to be independent risk factors for
Crohn disease in Caucasian patients (R702W, G908R, and 1007fs). None of
these mutations was identified; only an R702Q substitution was found in
a single patient. Direct sequencing of DNA from 96 of these patients in
the regions containing the 3 reported major mutations detected no
sequence alterations of consequence. Yamazaki et al. (2002) therefore
concluded that NOD2/CARD15 is not a major contributor to Crohn disease
susceptibility in the Japanese.

By using assays based on NFKB activation, Chamaillard et al. (2003)
showed that cytosolic CARD15 efficiently detects bacterial peptidoglycan
(PGN), reminiscent of the PGN recognition protein surveillance mechanism
in Drosophila. The 3 variants that are associated with Crohn disease and
13 additional variants carried by Crohn disease patients demonstrated
impaired PGN-dependent response revealing null, hypomorphic, or
dominant-negative properties. Quantitative parametrization of this
response, computed from the patients' CARD15 genotypes, was predictive
of several variable manifestations of Crohn disease. In contrast, CARD15
alleles associated with Blau syndrome (186580) promoted PGN-independent
NFKB activation, an observation that accounts for the minimal microbial
input in the etiology of this dominant, monogenic inflammatory disorder
affecting solely aseptic sites.

Croucher et al. (2003) examined 23 SNPs in and around the CARD15 gene in
large northern European and Korean samples of patients with CD and
normal controls. In the European patients, they confirmed that the 3
disease-associated SNPs in CARD15 (R702W, G908R, and 1007fs) occur
independently, but noted that they share a common background haplotype,
suggesting a common origin and the possibility of an undiscovered, more
strongly predisposing mutation. Korean CD patients have a phenotype
identical to the European patients, but had not previously been screened
for CARD15. The 3 disease-associated SNPs were absent and there was no
evidence of association between CARD15 and CD. Croucher et al. (2003)
concluded that the disease-associated mutations in Europeans, which are
rare, arose after the Asian-European split.

Van Heel et al. (2003) performed a genomewide scan of 137 Crohn disease
affected relative pairs from 112 families. The authors verified linkage
of Crohn disease to regions on chromosome 3 (IBD9; 608448; p = 0.0009)
and X (p = 0.001) in their cohort. Linkage to chromosome 16 (IBD1;
266600) was observed in Crohn disease pairs not possessing common CARD15
mutations (p = 0.0007), 25 cM q telomeric of CARD15. Evidence for
linkage to chromosome 19 (IBD6; 606674) was observed in Crohn disease
pairs not possessing CARD15 mutations (p = 0.0001), and in pairs
possessing 1 or 2 copies of the IBD5 (606348) risk haplotype (p =
0.0005), with significant evidence for genetic heterogeneity and
epistasis, respectively. These analyses demonstrated the complex genetic
basis to Crohn disease, and that the discovery of disease-causing
variants may be used to aid identification of further susceptibility
loci in complex diseases.

Stoll et al. (2004) identified variants in the DLG5 gene (604090)
associated with inflammatory bowel disease. One of the risk-associated
DLG5 haplotypes was distinguished from the common haplotype by a
nonsynonymous single-nucleotide polymorphism (SNP) 113G-A, resulting in
the amino acid substitution arg30-to-gln (R30Q) in the DUF622 domain of
DLG5 (604090.0001). The mutation was predicted to impede scaffolding of
DLG5. They stratified the study sample according to the presence of
risk-associated variants of CARD15 (1007fs, also known as 3020insC,
605956.0001; G908R, 605956.0002; R702W, 605956.0003) to study potential
gene-gene interaction. They found a significant difference in
association of the 113A variant of DLG5 with Crohn disease in affected
individuals carrying the risk-associated CARD15 alleles versus those
carrying non-risk-associated CARD15 alleles. This suggested a complex
pattern of gene-gene interaction between DLG5 and CARD15, reflecting the
complex nature of polygenic diseases.

Li et al. (2004) defined cytokine regulation in mononuclear cells, with
muramyl dipeptide (MDP), the minimal NOD2/CARD15 activating component of
peptidoglycan. MDP induced a broad array of transcripts, including
interleukin-1-beta (IL1B; 147720) and interleukin-8 (IL8; 146930).
Leu1007fsinsC homozygotes demonstrated decreased transcriptional
response to MDP. Modest induction of IL8 protein was observed in G908R
and R702W homozygotes, indicating varying MDP sensitivity of the
CD-associated mutations. With MDP plus TNF-alpha (TNFA; 191160), there
was a synergistic induction of IL1B secretion. In leu1007fsinsC
homozygotes, there was a profound defect in IL1B secretion despite
marked induction of IL1B mRNA. Li et al. (2004) concluded that there is
posttranscriptional dependency on the CARD15 pathway for IL1B secretion
with MDP and TNF-alpha treatment and suggested that a signaling defect
of innate immunity to MDP may be an essential underlying defect in the
pathogenesis of some CD patients.

Van Heel et al. (2005) analyzed the cytokine response of peripheral
blood mononuclear cells to MDP. MDP induced strong IL8 secretion and
substantially upregulated the secretion of TNF-alpha and IL1B induced by
Toll-like receptor (see 601194) ligands. At low nanomolar MDP
concentrations, these effects were abolished by the most common Crohn
disease NOD2/CARD15 double-mutant genotypes (702W/1007fs, 702W/702W,
1007fs/1007fs, and 908R/1007fs). Van Heel et al. (2005) suggested that
NOD2 activation provides a priming signal to condition a broad early
immune response to pathogens, and that the absence of this priming
signal in NOD2-associated CD causes failure of early immune pathogen
clearance and explains the abnormal adaptive immune responses to
microbial antigens in CD patients.

Netea et al. (2005) investigated the responses of mononuclear cells from
Crohn disease patients to MDP and other muramyl peptides and found that
patients homozygous for the NOD2fs mutation were totally unresponsive to
a diaminopimelic acid-containing muramyl tripeptide, the specific
agonist for NOD1, and to gram-negative bacterial peptidoglycan. In
contrast, a Crohn disease patient with the R702W mutation had normal
responses to peptidoglycan. RT-PCR analysis indicated that patients with
Nod2fs expressed significantly higher levels of peptidoglycan
recognition protein S (PGLYRP1; 604963), which may have contributed to
the downregulation of NOD1-dependent responses. Netea et al. (2005)
concluded that there is unexpected cross-talk between the NOD1 and NOD2
signaling pathways and proposed that NOD1 functional defects may
participate in the development of Crohn disease.

In summarizing previous findings, King et al. (2006) stated that 3
common mutations in the CARD15 gene are associated with susceptibility
to CD, and genetic data suggested a gene dosage model with an increased
risk of 2- to 4-fold in heterozygotes and 20- to 40-fold in homozygotes.
However, the discovery of numerous rare variants of CARD15 indicated
that some heterozygotes with the common mutation have a rare mutation on
the other CARD15 allele, which would support a recessive model for CD.
King et al. (2006) screened CARD15 for mutations in 100 CD patients who
were heterozygous for 1 of those 3 common mutations. They developed a
strategy for evaluating potential disease susceptibility alleles that
involved assessing the degree of evolutionary conservation of involved
residues, predicted effects on protein structure and function, and
genotyping in a large sample of cases and controls. The evolutionary
analysis was aided by sequencing the entire coding region of CARD15 in 3
primates (chimp, gibbon, and tamarin) and aligning the human sequence
with these and orthologs from other species. They found that 11 of the
100 CD patients screened had a second potential pathogenic mutation
within the exonic and periexonic sequences examined. Assuming that there
are no additional pathogenic mutations in noncoding regions, the study
of King et al. (2006) suggested that most carriers of the common disease
susceptibility alleles are true heterozygotes, and supported evidence
for a gene dosage model. Four novel nonsynonymous mutations were
detected.

Medici et al. (2006) studied 23 CARD15 SNPs in a Norwegian population of
476 unrelated IBD patients and 236 controls in comparison to a
well-studied German population of IBD patients and controls. They found
significantly lower frequencies of the predisposing CARD15 SNPs (1007fs,
G908R, and R702W) and no significant associations with CD in the
Norwegian samples. The population-attributable risk percentage of the 3
CARD15 variants in the Norwegian cohort was one of the lowest reported
for a European population (1.88%). Medici et al. (2006) stated that
these results are consistent with a low frequency of the CARD15 variants
in the northern European countries where the prevalence of IBD is
greatest.

MacArthur et al. (2012) performed a systematic survey of
loss-of-function variants in human protein-coding genes from the 1000
Genomes Study and imputed 417 loss-of-function single-nucleotide
variants and indels into a total of 13,241 patients representing 7
complex diseases, such as Crohn disease and rheumatory arthritis, along
with 2,938 shared controls, who had previously been subjected to
genomewide SNP genotyping (45:Wellcome Trust Case Control Consortium,
2007). MacArthur et al. (2012) confirmed a previously known frameshift
indel in the NOD2 gene (dbSNP rs2066847, 605956.0012) associated with
Crohn disease with a genomewide-significant imputed P value of 1.78 x
10(-14) (2 orders of magnitude more significant than the best tag SNP).
However, no other loss-of-function variants achieved genomewide
significance, suggesting that common gene-disrupting variants play a
minor role in complex disease predisposition.

Rivas et al. (2011) used pooled next-generation sequencing to study 56
genes from regions associated with Crohn disease in 350 cases and 350
controls. Through follow-up genotyping of 70 rare and low-frequency
protein-altering variants in 9 independent case-control series (16,054
Crohn disease cases, 12,153 ulcerative colitis cases, and 17,575 healthy
controls), they identified 4 additional independent risk factors in
NOD2: R311W, S431L, R703C, and N852S. N852S occurred only in Ashkenazi
Jewish individuals.

- Blau Syndrome and Early-Onset Sarcoidosis

Blau syndrome (186580) is a rare autosomal dominant disorder
characterized by early-onset granulomatous arthritis, uveitis, and skin
rash with camptodactyly. In affected members of 4 families with Blau
syndrome, Miceli-Richard et al. (2001) identified 3 different
heterozygous mutations in the CARD15 gene (R334Q; 605956.0004, L469F;
605956.0005, and R334W; 605956.0006). All mutations were located in the
region encoding the nucleotide binding domain of CARD15; mutations
identified patients with Crohn disease were located in the leucine-rich
repeat domain of CARD15.

Because Blau syndrome shows phenotypic overlap with early-onset
sarcoidosis (EOS; 609464), Miceli-Richard et al. (2001) also screened 2
patients with EOS for mutations in the CARD15 gene, but found none.
However, Kanazawa et al. (2004) described a sporadic case of systemic
granulomatosis syndrome with clinical features of EOS that showed one of
the same CARD15 mutations (605956.0007) as detected in BS. Kanazawa et
al. (2005) collected Japanese EOS cases retrospectively and searched for
CARD15 mutations. Among 10 such cases, heterozygous missense mutations
were found in 9; 4 showed an arg334-to-trp mutation (605956.0006) that
had been reported in BS, 4 showed novel missense mutations, and 1 showed
compound heterozygosity for 2 different missense mutations. All 6 of
these variants of CARD15 showed increased basal NFKB activity. Kanazawa
et al. (2005) concluded that the majority of early-onset sarcoidosis and
Blau syndrome cases share a common genetic etiology of CARD15 mutations
that cause constitutive NFKB activation.

Goyal et al. (2007) reported an unusual case of a 12-year-old girl who
presented with persistent focal seizures and MRI signal abnormalities.
Brain biopsies showed marked dural granulomatous inflammation with focal
extension into the brain parenchyma. Studies for systemic sarcoidosis
were negative. Treatment with infliximab, a TNF-alpha inhibitor,
resulted in clinical improvement. Family history revealed a paternal
uncle and grandfather with Crohn disease, and molecular analysis
identified 3 missense mutations in the NOD2 gene in the proband.

GENOTYPE/PHENOTYPE CORRELATIONS

Hampe et al. (2002) investigated the relationship between specific NOD2
genotypes and phenotypic characteristics of patients with Crohn disease.
Hypotheses were generated retrospectively from a group of 446 German
patients with this disorder. Positive findings (p less than 0.100) were
verified in prospectively established cohorts of 106 German and 55
Norwegian patients with Crohn disease. All patients were genotyped for
the main coding mutations in NOD2, denoted SNP8 (R702W), SNP12 (G908R),
and SNP13 (1007fs). In the retrospective cohort, 6 clinical
characteristics showed noteworthy haplotype association: fistulizing,
disease of the ileum and left and right colon, stenosis, and resection.
In the German prospective cohort, these haplotype associations could be
replicated for ileal disease (p = 0.006) and right colonic disease (p
less than 0.001). A similar trend was noted in the Norwegian patients.

Vermeire et al. (2002) collected a cohort of 231 patients with Crohn
disease and 71 healthy control individuals from the Canadian province of
Quebec to determine the prevalence of 3 sequence variants: leu1007fsinsC
(605956.0001), gly908 to arg (G908R; 605956.0002), and arg702 to trp
(R702W; 605956.0003). In this cohort, 45.0% of patients with Crohn
disease carried at least 1 variant in the CARD15 gene, compared with
9.0% of control individuals. Allele frequencies of R702W, G908R, and
leu1007fsinsC were 12.9%, 5.2%, and 10.3% in patients with Crohn
disease, compared with 4.2%, 0.7%, and 0.7% in control individuals,
respectively. Analysis of the relationship between genotype and
phenotype convincingly demonstrated that CARD15 variants are
significantly associated with ileal disease involvement, as opposed to
strictly colonic disease (P less than 0.001). Moreover, Vermeire et al.
(2002) determined the haplotype structure surrounding this disease gene
by genotyping 45 SNPs in the 177-kb region that contains the CARD15
gene. The structure helped clarify the history of these causal
mutations. Their analysis showed that CARD15 involvement with Crohn
disease is detectable by use of publicly available SNPs alone.

Murillo et al. (2002) studied 130 Dutch patients with Crohn disease,
with a median follow-up of 9.2 years, and 152 ethnically matched healthy
controls. They confirmed reports that the CARD15 3020insC mutation
increases susceptibility to Crohn disease, but could not confirm the
relationship for the CARD15 low frequency G2722C missense mutation
reported by Ogura et al. (2001).

Van Heel et al. (2002) discussed difficulties facing microsatellite
linkage and linkage disequilibrium mapping methods for identifying
disease genes in complex traits. They used 27 microsatellite markers
encompassing the IBD1 susceptibility locus in 131 sib pairs affected
with Crohn disease and in a simplex family cohort. No evidence of
linkage was observed, and microsatellite markers close to NOD2 did not
show association. However, significant association was confirmed in 294
Crohn disease trios (2 parents and affected offspring) for the NOD2
variants R702W and leu1007fsinsC.

Fidder et al. (2003) studied the frequency of 2 missense and 1
frameshift variant of CARD15 in Israeli Jewish Crohn disease and
ulcerative colitis patients. The 2 missense mutations were R675W
(605956.0003) and G881R (605956.0002); the frameshift mutation was
980FS981X (605956.0001). Mutations in CARD15 were observed with
significantly greater frequency in Crohn disease patients (46/170, 27%)
than in ulcerative colitis patients (7/68, 10%) (p = 0.005).
Homozygosity and compound heterozygosity was found only in 7 (4%)
patients with Crohn disease as compared to none of the ulcerative
colitis patients. Similar rates were observed in Ashkenazi and
non-Ashkenazi Jewish patients. Age of onset of disease was lower in
Ashkenazi mutation carriers as compared to noncarriers of Ashkenazi
origin (18.7 vs 25.8 years, respectively). No other phenotypic
characteristics could distinguish mutation carriers from noncarriers.

Karason et al. (2003) performed a genomewide linkage scan in psoriatic
arthritis in a group of 178 patients from 39 Icelandic families and
found a lod score of 2.17 on 16q (607507). Further analysis, conditional
on paternal transmission to affected individuals, resulted in a lod
score of 4.19. The peak of this lod score was within 20 Mb of the CARD15
gene. The region overlapping CARD15 had been implicated by a genomewide
scan in psoriasis by Nair et al. (1997). The possibility of a common
susceptibility gene shared by psoriasis/psoriatic arthritis and Crohn
disease was further supported by epidemiologic studies that noted an
increased incidence of psoriasis and psoriatic arthritis in subjects
with Crohn disease (Lee et al., 1990). See psoriasis susceptibility-1
(PSORS1; 177900).

In Newfoundland, Rahman et al. (2003) screened 187 patients with
psoriatic arthritis and 136 healthy controls for the 3 common,
independent sequence variants of CARD15: R702W (605956.0003),
leu1007fsinsC (605956.0001), and G908R (605956.0002). In total, 53 of
187 (28.3%) probands with psoriatic arthritis had at least 1 variant of
the CARD15 gene, compared with 16 of 136 (11.8%) controls; odds ratio =
2.97, p = 0.0005. Allele frequencies of R702W, leu1007fsinsC, and G908R
were 10.43%, 3.21%, and 1.61%, respectively, in patients with psoriatic
arthritis, compared with 3.31%, 2.57%, and 0.37%, respectively, in the
control patients. CARD15 conferred susceptibility to psoriatic arthritis
independent of HLA-Cw*0602 (see HLA-C, 142840), which of the HLA types
shows the strongest association with psoriasis (Gladman, 2002). Rahman
et al. (2003) stated that CARD15 was the first candidate gene identified
in psoriatic arthritis that resides outside the major histocompatibility
complex. They referred to CARD15 as a pleiotropic autoimmune gene, since
it confers susceptibility to Crohn disease, Blau syndrome, and psoriatic
arthritis.

To determine whether CARD15 mutations account for the higher prevalence
of Crohn disease in Ashkenazi Jews, Tukel et al. (2004) assessed the
haplotypes and allele frequencies of the common mutations and variants
in 219 members of 50 Ashkenazi Jewish and 53 members of 10
Sephardi/Oriental Jewish multiplex families with CD, in 36 Ashkenazi
Jewish patients with sporadic CD, and in 246 Ashkenazi and 82
Sephardi/Oriental Jewish controls. A higher frequency of CARD15
mutations was found in Ashkenazi Jewish patients from multiplex families
with CD from central (44%) versus eastern (24%) Europe, especially for
the G908R and 1007fs mutations, and in Sephardi/Oriental Jewish patients
(34.5%) compared with Ashkenazi (10.1%) or Sephardi/Oriental (5.4%)
Jewish controls.

Giachino et al. (2004) analyzed the 3 recurrent CARD15 variants (R702W,
G908R, and 1007fs) in 184 CD and 92 UC Italian patients and in 177
healthy controls. They found significant associations for G908R and
L1007fs with CD only. Analysis of mutation-phenotype correlations
revealed an increased chance of mutation positivity in patients with
strictures (OR, 2.76; 95% CI, 1.2-6.3) and fistulas (OR, 2.59; 95% CI
1.0-6.6), and a weaker association with ileal location of disease (OR,
3.03; 95% CI, 0.9-9.8). Giachino et al. (2004) concluded that the CARD15
genotype can serve as an explanatory variable for predicting the pattern
of IBD presentation and progression.

Kanazawa et al. (2005) retrospectively collected Japanese early-onset
sarcoidosis (EOS; 609464) cases in search of CARD15 mutations. Among 10
EOS cases, missense mutations were found in 9: 4 showed the R334W
mutation (605956.0006) that had been reported in Blau syndrome; 4 showed
different novel missense mutations; and 1 patient showed compound
heterozygosity for 2 missense mutations (605956.0009-605956.0010). All 6
of these variants of CARD15 showed increased basal NFKB activity.
Kanazawa et al. (2005) concluded that most EOS and Blau syndrome cases
share a common genetic etiology of CARD15 mutations that cause
constitutive NFKB activation.

The Wellcome Trust Case Control Consortium (2007) described a joint
genomewide association study using the Affymetrix GeneChip 500K Mapping
Array Set, undertaken in the British population, which examined
approximately 2,000 individuals for each of 7 major diseases and a
shared set of approximately 3,000 controls. This analysis identified 9
associations with Crohn disease including CARD15, which was represented
by dbSNP rs17221417 (p = 9.4 x 10(-12)).

EVOLUTION

Analysis of the evolution of CARD15 revealed strong conservation of the
encoded protein, with identity to the human sequence ranging from 99.1%
in the chimp to 44.5% in fugu (King et al., 2006).

ANIMAL MODEL

The mouse Nod2 locus is situated on chromosome 8 and comprises 12 exons,
11 of which encode the Nod2 protein. Ogura et al. (2003) performed
sequence analysis of the mouse Nod2 gene from 45 different strains and
identified extensive polymorphisms involving all exons of the gene.
Studies of the polymorphisms demonstrated a conserved role for Nod2 in
the response to bacterial components and suggested that selective
evolutionary pressure exerted by pathogens may have contributed to the
high level of variability of Nod2 sequences in both humans and mice.

Pauleau and Murray (2003) generated mice lacking Nod2. Nod2 -/- mice
were indistinguishable from wildtype mice and manifested no symptoms or
pathology consistent with human Crohn disease. Macrophages of Nod2 -/-
mice had nearly normal responses to TLR stimulation and to Ifng (147570)
and Il10 (124092), which activate and deactivate macrophages,
respectively. However, Nod2 -/- weanling mice better survived a lethal
lipopolysaccharide (LPS) challenge than did wildtype weanling mice.

Kobayashi et al. (2005) generated mice deficient in Nod2 by targeted
disruption. Nod2-null mice were outwardly healthy and displayed normal
lymphoid and myeloid cellular composition in the thymus and spleen. The
mice also displayed no overt symptoms of intestinal inflammation when
observed for up to 6 months. Kobayashi et al. (2005) showed that
protective immunity mediated by Nod2 recognition of bacterial muramyl
dipeptide is abolished in Nod2-deficient mice. The mice were susceptible
to bacterial infection through oral delivery but not through intravenous
or peritoneal delivery. Nod2 is required for the expression of a
subgroup of intestinal antimicrobial peptides known as cryptdins.
Kobayashi et al. (2005) concluded that the NOD2 protein is a critical
mediator of bacterial immunity within the intestine, providing a
possible mechanism for NOD2 mutations in Crohn disease.

Watanabe et al. (2004) studied Nod2 -/- mice and determined that intact
Nod2 signaling inhibits Tlr2 (603028)-driven activation of Nfkb (see
164011), particularly its Rel subunit (164910). Nod2 deficiency or the
presence of a Crohn disease-like Nod2 mutation increased Tlr2-mediated
activation of Nfkb-Rel in association with enhanced Th1 responses.
Watanabe et al. (2004) concluded that NOD2 signaling normally inhibits
TLR2-driven Th1 responses by regulating NFKB signaling.

Maeda et al. (2005) generated mice whose Nod2 locus harbors the homolog
of the most common Crohn disease susceptibility allele, 3020insC
(605956.0001), which encodes a truncated protein lacking the last 33
amino acids. Homozygous Nod2 mutant mice were obtained at the expected
mendelian ratio, were healthy, and showed no abnormalities of the
gastrointestinal tract or other organs. The mutation had no effect on
Nod2 mRNA or protein amounts in bone marrow-derived macrophages. Mutant
mice exhibited elevated NFKB activation in response to bacteria-derived
muramyl dipeptide and more efficient processing and secretion of the
cytokine interleukin-1-beta (IL1B; 147720). These effects were linked to
increased susceptibility to bacteria-induced intestinal inflammation and
identified NOD2 as a positive regulator of NFKB activation and IL1B
secretion.

By histopathologic analysis, Divangahi et al. (2008) showed that
Nod2-deficient mice had reduced inflammatory responses but similar
bacterial counts compared with wildtype mice in the first 2 months after
infection with Mycobacterium tuberculosis. Nod2-deficient mice infected
with the M. bovis BCG vaccine had decreased production of Tnf, Ifng, and
Il12p40 (IL12B; 161561) and reduced recruitment of Cd4 (186940)-positive
and Cd8 (see 186910)-positive T cells. After 6 months, the bacterial
burden was increased in the Nod2-deficient mice and their survival was
significantly reduced. Divangahi et al. (2008) concluded that NOD2
mediates resistance to mycobacterial infection via both innate and
adaptive immunity.

Hruz et al. (2009) found that Nod2-deficient mice exhibited a delayed
but ultimately exacerbated response to subcutaneous Staphylococcus
aureus infection. Nod2 action was dependent on Il1b-amplified production
of Il6 (147620), which promoted rapid bacterial killing by neutrophils.
Hruz et al. (2009) concluded that NOD2 is not only involved in
recognition of organisms in cytoplasm, but that it also contributes to
recognition of pathogenic bacteria in the extracellular compartment that
elaborate pore-forming toxins.

T helper-17 (Th17) cells are a subset of CD4-positive helper T cells
characterized by secretion of IL17 (603149) and IL22 (605330). Geddes et
al. (2011) infected mice with Citrobacter rodentium or Salmonella
typhimurium species and observed triggering of early Il17 production
that was crucial for host defense mediated by Cd4-positive helper T
cells. Th17 responses occurred principally in the cecum and were
mediated by innate Th17 cells that were regulated by Nod1 and Nod2. Mice
lacking both Nod1 and Nod2 were unable to induce early Th17 responses
due to insufficient Il6 production. Geddes et al. (2011) concluded that
the NOD-innate Th17 axis, which is dependent on IL6 expression and
requires intestinal microbiota for induction, is a key element of
mucosal immunity against bacterial pathogens.

*FIELD* AV
.0001
INFLAMMATORY BOWEL DISEASE 1, SUSCEPTIBILITY TO
NOD2, 1-BP INS, 3020C

Ogura et al. (2001) sequenced all coding exons and flanking introns of
the NOD2 gene in 12 affected individuals from pure Crohn disease (IBD1;
266600) families with increased linkage scores at D16S3396, which is
tightly linked to NOD2, as well as in 4 case controls. In 3 Crohn
disease patients, they identified a 1-bp insertion (C) at nucleotide
3020 (3020insC) in exon 11 of the NOD2 gene, resulting in a frameshift
at the second nucleotide of codon 1007 and a leu1007-to-pro substitution
in the tenth LRR, followed by a premature stop codon. The predicted
truncated NOD2 protein contained 1,007 amino acids instead of the 1,040
amino acids of the wildtype protein. Ogura et al. (2001) observed
preferential transmission from heterozygous parents to affected children
of the 3020insC mutation (P of 0.0046). There was no preferential
transmission of this mutation in families with ulcerative colitis. The
frequency of the 3020insC mutation was 8.4% among Jewish Caucasians and
8.1% among non-Jewish Caucasians. The frequency among control Caucasians
was 4.0%. The allele frequency of this mutation from 182 unrelated
ulcerative colitis patients was 3.0%. The genotype frequencies of the
3020insC mutation in unrelated Crohn disease individuals was 11
homozygotes, 46 heterozygotes, and 359 wildtype homozygotes. The
genotype-relative risk for heterozygous and homozygous 3020insC was 1.5
and 17.6, respectively, as compared with wildtype controls.
Lipopolysaccharide (LPS) from various bacteria induced nuclear factor
kappa-B (NFKB; see 164011) activation in cells expressing wildtype NOD2,
but not in cells transfected with control plasmid. Cells transfected
with NOD2 carrying the 3020insC mutation had greatly diminished response
to LPS, with the most significant reduction in response to Salmonella,
Shigella, Klebsiella, Campylobacter, and Neisseria gonorrhea.

Hugot et al. (2001) independently identified this mutation in
association with Crohn disease; however, because they used the
1,013-amino acid NOD2B sequence, they reported the mutation as a
frameshift at codon 980.

Hampe et al. (2001) studied the association between this mutation and
inflammatory bowel disease in 512 affected individuals from 309 German
or British families, 369 German trios (patients with sporadic
inflammatory bowel disease and their unaffected parents), and 272 normal
controls. Family-based association analyses were consistently positive
in 95 British and 99 German affected sib pairs with Crohn disease; the
association was confirmed in 304 German trios with Crohn disease. No
association was seen in the 115 sib pairs and 65 trios with ulcerative
colitis. The genotype-specific disease risks conferred by heterozygous
and homozygous mutant genotypes were 2.6 and 42.1, respectively.

A genetically impaired intestinal barrier function has long been
suspected to be a predisposing factor for Crohn disease. To test the
association of CARD15 with intestinal permeability, Buhner et al. (2006)
studied 128 patients with quiescent CD, 129 first-degree relatives, 66
nonrelated household members, and 96 healthy controls. There were 3 main
findings. Healthy first-degree relatives of patients with CD showed
increased permeability in contrast with unrelated household members and
controls. Secondly, the prevalence of the CARD15 3020insC mutation was
similar in first-degree relatives and CD patients and higher compared
with controls. Thirdly, in healthy first-degree relatives, high mucosal
permeability and the presence of a CARD15 3020insC mutation were
significantly associated.

.0002
INFLAMMATORY BOWEL DISEASE 1, SUSCEPTIBILITY TO
NOD2, GLY908ARG

Hugot et al. (2001) identified a mutation leading to a gly881-to-arg
(GLY881ARG) substitution in the NOD2 gene that was associated with an
increased susceptibility to Crohn disease (IBD1; 266600). The allele
frequency of this mutation was 0.11 among Crohn disease patients, 0.03
among ulcerative colitis (IBD1; 266600) patients, and 0.04 among
unaffected controls.

This mutation was designated GLY908ARG in the study of Vermeire et al.
(2002).

.0003
INFLAMMATORY BOWEL DISEASE 1, SUSCEPTIBILITY TO
NOD2, ARG702TRP

Hugot et al. (2001) identified a mutation leading to an arg675-to-trp
(ARG675TRP) substitution in the NOD2 gene that was associated with
increased susceptibility to Crohn disease (IBD1; 266600). The allele
frequency of this mutation was 0.06 among Crohn disease patients, 0.01
among unaffected controls, and it was not present among ulcerative
colitis patients.

This mutation was designated ARG702TRP in the study of Vermeire et al.
(2002).

.0004
BLAU SYNDROME
NOD2, ARG334GLN

In affected members of 2 families with Blau syndrome (186580),
Miceli-Richard et al. (2001) found a 1001G-A transition in the NOD2
gene, resulting in an arg334-to-gln (R334Q) amino acid change.

.0005
BLAU SYNDROME
NOD2, LEU469PHE

In a proband and his father with Blau syndrome (186580), Miceli-Richard
et al. (2001) found a 1405C-T transition in the NOD2 gene, resulting in
a leu469-to-phe (L469F) amino acid change.

.0006
BLAU SYNDROME
SARCOIDOSIS, EARLY-ONSET, INCLUDED
NOD2, ARG334TRP

In affected members of a family with Blau syndrome (186580),
Miceli-Richard et al. (2001) found a 1000C-T transition in the NOD2
gene, resulting in an arg334-to-trp (R334W) amino acid change.

In a study of 10 early-onset sarcoidosis (609464) cases in Japan,
Kanazawa et al. (2005) found that 4 had the 1000C-T transition (R334W)
in the CARD15 gene.

Dhondt et al. (2008) identified heterozygosity for the R334W mutation in
a patient with Blau syndrome. The mutation occurred in the central
nucleotide-binding oligomerization domain.

.0007
INFLAMMATORY BOWEL DISEASE 1, SUSCEPTIBILITY TO
NOD2, IVS8+158

In Jewish patients with Crohn disease (IBD1; 266600), Sugimura et al.
(2003) found a novel disease-predisposing variant, IVS8+158, which is a
C-to-T mutation in the palindrome sequence in the intron 8 splicing
region.

.0008
SARCOIDOSIS, EARLY-ONSET
NOD2, HIS496LEU

Among 10 cases of early-onset sarcoidosis (609464) studied
retrospectively in Japan, Kanazawa et al. (2005) found that 4 had
different novel missense mutations in the CARD15 gene, one of which was
a 1487A-T transversion resulting in a his496-to leu (H496L)
substitution.

.0009
SARCOIDOSIS, EARLY-ONSET
NOD2, ASP382GLU

Among 10 cases of early-onset sarcoidosis (609464) studied
retrospectively in Japan, Kanazawa et al. (2005) found that 1 was
compound heterozygous for 2 missense mutations in the CARD15 gene: a
1146C-G transversion resulting in an asp382-to-glu (D382E) substitution
and a 1834G-A transition resulting in an ala612-to-thr (A612T)
substitution (605956.0010).

.0010
SARCOIDOSIS, EARLY-ONSET
CARD15, ALA612THR

See 605956.0009 and Kanazawa et al. (2005).

.0011
BLAU SYNDROME
NOD2, GLU383LYS

In a mother and daughter with Blau syndrome (186580), van Duist et al.
(2005) identified a heterozygous 1147G-A transition in exon 4 of the
CARD15 gene, resulting in a glu383-to-lys (E383K) substitution. The
mutation is in a highly conserved region in the central
nucleotide-binding NACHT domain and may result in increased signaling.

.0012
INFLAMMATORY BOWEL DISEASE 1, SUSCEPTIBILITY TO
NOD2, 1-BP INS, 3016C (dbSNP rs2066847)

MacArthur et al. (2012) reported a single-basepair insertion of a
cytosine between nucleotides 3016 and 3017 of the NOD2 gene, leading to
a frameshift that was associated with Crohn disease (IBD1; 266600), with
a genomewide-significant imputed P value of 1.78 x 10(-14), just 2
orders of magnitude more significant than the best tag SNP.

*FIELD* RF
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*FIELD* CN
Ada Hamosh - updated: 7/23/2012
Ada Hamosh - updated: 2/27/2012
Paul J. Converse - updated: 8/5/2011
Paul J. Converse - updated: 9/28/2010
Paul J. Converse - updated: 2/4/2010
Paul J. Converse - updated: 1/7/2010
Cassandra L. Kniffin - updated: 6/2/2009
Cassandra L. Kniffin - updated: 11/30/2007
Patricia A. Hartz - updated: 10/31/2007
Ada Hamosh - updated: 7/24/2007
Victor A. McKusick - updated: 5/31/2007
George E. Tiller - updated: 1/16/2007
Marla J. F. O'Neill - updated: 5/24/2006
Victor A. McKusick - updated: 1/20/2006
Paul J. Converse - updated: 10/27/2005
Marla J. F. O'Neill - updated: 9/1/2005
Cassandra L. Kniffin - updated: 7/11/2005
Victor A. McKusick - updated: 3/21/2005
Victor A. McKusick - updated: 3/15/2005
Ada Hamosh - updated: 2/25/2005
Marla J. F. O'Neill - updated: 5/3/2004
George E. Tiller - updated: 4/28/2004
Victor A. McKusick - updated: 4/27/2004
Victor A. McKusick - updated: 4/21/2004
Marla J. F. O'Neill - updated: 4/2/2004
Victor A. McKusick - updated: 10/8/2003
Victor A. McKusick - updated: 9/5/2003
Victor A. McKusick - updated: 5/2/2003
Victor A. McKusick - updated: 4/25/2003
Victor A. McKusick - updated: 3/3/2003
Victor A. McKusick - updated: 2/26/2003
Victor A. McKusick - updated: 10/1/2002
Victor A. McKusick - updated: 9/24/2002
Victor A. McKusick - updated: 9/12/2002
Victor A. McKusick - updated: 7/17/2002
Victor A. McKusick - updated: 6/26/2002
Victor A. McKusick - updated: 4/12/2002
Victor A. McKusick - updated: 3/1/2002
Victor A. McKusick - updated: 8/23/2001
Ada Hamosh - updated: 5/22/2001

*FIELD* CD
Paul J. Converse: 5/22/2001

*FIELD* ED
alopez: 03/14/2013
alopez: 7/24/2012
terry: 7/23/2012
terry: 6/8/2012
alopez: 5/1/2012
alopez: 2/28/2012
terry: 2/27/2012
mgross: 8/9/2011
terry: 8/5/2011
mgross: 9/30/2010
terry: 9/28/2010
mgross: 2/15/2010
terry: 2/4/2010
mgross: 1/8/2010
terry: 1/7/2010
wwang: 6/22/2009
ckniffin: 6/2/2009
alopez: 10/31/2008
carol: 8/28/2008
carol: 8/14/2008
wwang: 12/7/2007
ckniffin: 11/30/2007
ckniffin: 11/29/2007
mgross: 11/1/2007
terry: 10/31/2007
alopez: 7/24/2007
alopez: 6/4/2007
terry: 5/31/2007
alopez: 5/16/2007
wwang: 1/26/2007
wwang: 1/23/2007
terry: 1/16/2007
wwang: 6/1/2006
terry: 5/24/2006
alopez: 2/15/2006
terry: 1/20/2006
mgross: 11/7/2005
terry: 10/27/2005
wwang: 9/1/2005
wwang: 7/26/2005
ckniffin: 7/11/2005
carol: 7/5/2005
wwang: 3/23/2005
terry: 3/21/2005
terry: 3/15/2005
wwang: 3/3/2005
terry: 2/25/2005
terry: 6/28/2004
alopez: 5/28/2004
carol: 5/5/2004
terry: 5/3/2004
alopez: 4/28/2004
alopez: 4/27/2004
tkritzer: 4/22/2004
terry: 4/21/2004
terry: 4/9/2004
tkritzer: 4/7/2004
tkritzer: 4/5/2004
terry: 4/2/2004
alopez: 10/8/2003
alopez: 9/8/2003
terry: 9/5/2003
tkritzer: 5/9/2003
tkritzer: 5/7/2003
terry: 5/2/2003
terry: 4/25/2003
carol: 3/10/2003
tkritzer: 3/6/2003
terry: 3/3/2003
alopez: 2/26/2003
terry: 2/26/2003
carol: 10/2/2002
tkritzer: 10/1/2002
tkritzer: 9/24/2002
tkritzer: 9/12/2002
tkritzer: 7/30/2002
tkritzer: 7/29/2002
tkritzer: 7/26/2002
terry: 7/17/2002
cwells: 7/9/2002
terry: 6/26/2002
carol: 5/8/2002
alopez: 4/25/2002
cwells: 4/17/2002
terry: 4/12/2002
carol: 3/1/2002
terry: 3/1/2002
alopez: 11/5/2001
alopez: 8/27/2001
terry: 8/23/2001
joanna: 7/3/2001
joanna: 7/2/2001
mgross: 5/30/2001
mgross: 5/22/2001

MIM 609464
*RECORD*
*FIELD* NO
609464
*FIELD* TI
#609464 SARCOIDOSIS, EARLY-ONSET
;;EOS
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
read moreearly-onset sarcoidosis is caused by mutation in the NOD2/CARD15 gene
(605956) on chromosome 16.

CLINICAL FEATURES

In childhood, 2 distinct types of sarcoidosis have been described
(Shetty and Gedalia, 1998). Usually the disease is detected in older
children by chest radiography, and the clinical manifestations are
characterized by a classic triad of lung, lymph node, and eye
involvement, similar to those in adults with sarcoidosis (181000). In
contrast, early-onset sarcoidosis (EOS), which usually appears in those
younger than 4 years of age, is rare and has a distinct triad of skin,
joint, and eye disorders, without apparent pulmonary involvement.
Compared with an asymptomatic and sometimes naturally disappearing
course of the disease in older children, EOS is progressive and in many
cases causes severe complications, such as blindness, joint destruction,
and visceral involvement.

MOLECULAR GENETICS

Blau syndrome (BS; 186580), which also shows early-onset granulomatous
arthritis, uveitis, and skin rash, is a rare familial disorder
transmitted in an autosomal dominant manner. By linkage analysis, the
responsible locus was mapped to chromosome 16, and the CARD15 gene was
identified as the susceptibility gene. Since the first report of Blau
syndrome, there has been discussion of whether EOS and BS are the same
disease. In the first paper describing mutations in the CARD15 gene in
patients with BS, Miceli-Richard et al. (2001) found no CARD15 mutation
in 2 EOS patients. However, Kanazawa et al. (2004) described a sporadic
case of systemic granulomatosis syndrome with clinical features of EOS
that showed the same CARD15 mutation as detected in BS. Kanazawa et al.
(2005) collected Japanese EOS cases retrospectively and searched for
CARD15 mutations. Among 10 such cases, heterozygous missense mutations
were found in 9; 4 showed an arg334-to-trp mutation (605956.0006) that
had been reported in BS, 4 showed novel missense mutations, and 1 showed
compound heterozygosity for 2 different missense mutations. All 6 of
these variants of CARD15 showed increased basal NF-kappa-B (see NFKB1;
164011) activity. Kanazawa et al. (2005) concluded that the majority of
early-onset sarcoidosis and Blau syndrome cases share a common genetic
etiology of CARD15 mutations that cause constitutive NF-kappa-B
activation.

*FIELD* RF
1. Kanazawa, N.; Matsushima, S.; Kambe, N.; Tachibana, T.; Nagai,
S.; Miyachi, Y.: Presence of a sporadic case of systemic granulomatosis
syndrome with a CARD15 mutation. J. Invest. Derm. 122: 851-852,
2004.

2. Kanazawa, N.; Okafuji, I.; Kambe, N.; Nishikomori, R.; Nakata-Hizume,
M.; Nagai, S.; Fuji, A.; Yuasa, T.; Manki, A.; Sakurai, Y.; Nakajima,
M.; Kobayashi, H.; Fujiwara, I.; Tsutsumi, H.; Utani, A.; Nishigori,
C.; Heike, T.; Nakahata, T.; Miyachi, Y.: Early-onset sarcoidosis
and CARD15 mutations with constitutive nuclear factor-kappa-B activation:
common genetic etiology with Blau syndrome. Blood 105: 1195-1197,
2005.

3. Miceli-Richard, C.; Lesage, S.; Rybojad, M.; Prieur, A.-M.; Manouvrier-Hanu,
S.; Hafner, R.; Chamaillard, M.; Zouali, H.; Thomas, G.; Hugot, J.-P.
: CARD15 mutations in Blau syndrome. Nature Genet. 29: 19-20, 2001.

4. Shetty, A. K.; Gedalia, A.: Sarcoidosis: a pediatric perspective. Clin.
Pediat. 37: 707-717, 1998.

*FIELD* CD
Victor A. McKusick: 7/5/2005

*FIELD* ED
wwang: 01/23/2007
carol: 9/2/2005
carol: 7/7/2005
carol: 7/5/2005