Complement receptor 1: Difference between revisions

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{{GNF_Protein_box
| image = PBB_Protein_CR1_image.jpg
| image_source = [[Protein Data Bank|PDB]] rendering based on 1gkg.
| Name = Complement component (3b/4b) receptor 1 (Knops blood group)
| HGNCid = 2334
| Symbol = CR1
| AltSymbols =; C3BR; CD35; KN
| OMIM = 120620
| ECnumber = 
| Homologene = 55474
| MGIid = 
| GeneAtlas_image1 = PBB_GE_CR1_206244_at_tn.png
| GeneAtlas_image2 = PBB_GE_CR1_208488_s_at_tn.png
| GeneAtlas_image3 = PBB_GE_CR1_217552_x_at_tn.png
| Function = {{GNF_GO|id=GO:0004872 |text = receptor activity}} {{GNF_GO|id=GO:0004877 |text = complement component C3b receptor activity}}
| Component = {{GNF_GO|id=GO:0005887 |text = integral to plasma membrane}} {{GNF_GO|id=GO:0016020 |text = membrane}}
| Process = {{GNF_GO|id=GO:0006958 |text = complement activation, classical pathway}} {{GNF_GO|id=GO:0045087 |text = innate immune response}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 1378
    | Hs_Ensembl = ENSG00000203710
    | Hs_RefseqProtein = XP_001126036
    | Hs_RefseqmRNA = XM_001126036
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 1
    | Hs_GenLoc_start = 205736125
    | Hs_GenLoc_end = 205880615
    | Hs_Uniprot = P17927
    | Mm_EntrezGene = 
    | Mm_Ensembl = 
    | Mm_RefseqmRNA = 
    | Mm_RefseqProtein = 
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 
    | Mm_GenLoc_start = 
    | Mm_GenLoc_end =
    | Mm_Uniprot = 
  }}
}}
{{SI}}
{{CMG}}


'''Complement receptor type 1''' ('''CR1''') also known as '''C3b/C4b receptor''' or '''CD35''' (cluster of differentiation 35) is a [[protein]] that in humans is encoded by the '''CR1''' [[gene]].<ref name = "entrez_ 1378">{{cite web | title = Entrez Gene: CR1 complement component (3b/4b) receptor 1 (Knops blood group)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1378| accessdate = }}</ref><ref name="pmid1708809">{{cite journal |vauthors=Moulds JM, Nickells MW, Moulds JJ, Brown MC, Atkinson JP | title = The C3b/C4b receptor is recognized by the Knops, McCoy, Swain-langley, and York blood group antisera | journal = J. Exp. Med. | volume = 173 | issue = 5 | pages = 1159–63 | date = May 1991 | pmid = 1708809 | pmc = 2118866 | doi = 10.1084/jem.173.5.1159 | url =  }}</ref>


This gene is a member of the [[regulators of complement activation]] (RCA) family and is located in the 'cluster RCA' region of chromosome 1. The gene encodes a monomeric single-pass type I membrane [[glycoprotein]] found on [[erythrocyte]]s, [[leukocyte]]s, glomerular [[podocyte]]s, [[hyalocytes]], and splenic follicular [[dendritic cell]]s. The Knops blood group system is a system of antigens located on this protein. The protein mediates cellular binding to particles and immune complexes that have activated complement. Decreases in expression of this protein and/or mutations in its gene have been associated with gallbladder carcinomas, [[mesangiocapillary glomerulonephritis]], [[systemic lupus erythematosus]] and [[sarcoidosis]]. Mutations in this gene have also been associated with a reduction in ''[[Plasmodium falciparum]]'' rosetting, conferring protection against severe malaria. Alternate allele-specific splice variants, encoding different isoforms, have been characterized. Additional allele specific isoforms, including a secreted form, have been described but have not been fully characterized.<ref name = "entrez_ 1378"/>


==Overview==
In primates,  CR1 serves as the main system for processing and clearance of complement [[opsonized]] [[immune complexes]]. It has been shown that CR1 can act as a negative regulator of the [[Complement system|complement]] cascade, mediate [[immune adherence]] and [[phagocytosis]] and inhibit both the classic and alternative pathways. The number of CR1 molecules decreases with aging of [[erythrocyte]]s in normal individuals and is also decreased in pathological conditions such as [[systemic lupus erythematosus]] (SLE), [[HIV]] infection, some {{SWL|target=haemolytic anaemia|type=decrease_associated_with_disease}}s and other conditions featuring [[immune complex]]es.<ref  name="pmid19004497 ">{{cite journal |vauthors=Khera R, Das N | title = Complement Receptor 1: Disease associations and therapeutic implications | journal = Molecular Immunology | volume = 46 | issue = 5 | pages = 761–772 | date = February 2009 | pmid = 19004497 | doi = 10.1016/j.molimm.2008.09.026 }}</ref>  In mice, CR1 is an alternatively spliced variant of the complement receptor 2 (CR2) gene.


In primates, '''erythrocyte complement receptor 1''' ('''CR1''', also known as '''[[cluster of differentiation|CD35]]''', '''C3b/C4b receptor''' and '''immune adherence receptor''') serves as the main system for processing and clearance of complement [[opsonized]] [[immune complexes]]. It has been shown that CR1 can act as a negative regulator of the [[Complement system|complement]] cascade, mediate immune adherence and [[phagocytosis]] and inhibit both the classic and alternative pathways. The number of CR1 molecules decreases with aging of [[erythrocyte]]s in normal individuals and is also decreased in pathological conditions such as [[systemic lupus erythematosus]] (SLE), [[HIV]] infection, some [[haemolytic anaemia]]s and other conditions featuring immune complexes.
Certain [[alleles]] of this gene have been statistically associated with an increased risk of developing late-onset [[Alzheimer's disease]].<ref name="pmid19734903">{{cite journal |vauthors=Lambert JC, Heath S, Even G, Campion D, Sleegers K, Hiltunen M, Combarros O, Zelenika D, Bullido MJ, Tavernier B, Letenneur L, Bettens K, Berr C, Pasquier F, Fiévet N, Barberger-Gateau P, Engelborghs S, De Deyn P, Mateo I, Franck A, Helisalmi S, Porcellini E, Hanon O, de Pancorbo MM, Lendon C, Dufouil C, Jaillard C, Leveillard T, Alvarez V, Bosco P, Mancuso M, Panza F, Nacmias B, Bossù P, Piccardi P, Annoni G, Seripa D, Galimberti D, Hannequin D, Licastro F, Soininen H, Ritchie K, Blanché H, Dartigues JF, Tzourio C, Gut I, Van Broeckhoven C, Alpérovitch A, Lathrop M, Amouyel P | title = Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease | journal = Nat. Genet. | volume = 41 | issue = 10 | pages = 1094–9 | date = September 2009 | pmid = 19734903 | doi = 10.1038/ng.439 | url =  | laysummary = http://www.time.com/time/health/article/0,8599,1920745,00.html | laydate = 2009-09-06 | laysource = TIME Magazine }}</ref>


==1q32 region==
==1q32 region==
In humans, the ''CR1'' gene is located at on the long arm of chromosome 1 at band 32 (1q32) and lies within a complex of immunoregulatory genes. In 5’-3’ order the genes in this region are: membrane cofactor protein - CR1- complement receptor type 2 - decay-accelerating factor - C4-binding protein.  
In humans, the ''CR1'' gene is located at on the long arm of chromosome 1 at band 32 (1q32) and lies within a complex of immunoregulatory genes. In 5’-3’ order the genes in this region are: membrane cofactor protein - CR1- complement receptor type 2 - decay-accelerating factor - C4-binding protein.


* [[Membrane cofactor protein]] is a widely distributed C3b/C4b binding regulatory [[glycoprotein]] of the complement system;  
* [[Membrane cofactor protein]] is a widely distributed C3b/C4b binding regulatory [[glycoprotein]] of the complement system;  
* [[decay-accelerating factor]] (DAF: CD55: Cromer antigen) protects host cells from complement-mediated damage by regulating the activation of C3 convertases on host cell surfaces;  
* [[decay-accelerating factor]] (DAF: CD55: Cromer antigen) protects host cells from complement-mediated damage by regulating the activation of C3 convertases on host cell surfaces;  
* [[complement receptor 2]] is the C3d receptor.  
* [[complement receptor 2]] is the C3d receptor.


[[Factor H]], another immunoregulatory protein, also maps to this location.  
[[Factor H]], another immunoregulatory protein, also maps to this location.<ref>{{cite journal|last1=Das|first1=N|last2=Biswas|first2=B|last3=Khera|first3=R|title=Membrane-bound complement regulatory proteins as biomarkers and potential therapeutic targets for SLE.|journal=Advances in experimental medicine and biology|date=2013|volume=735|pages=55–81|pmid=23402019|doi=10.1007/978-1-4614-4118-2_4}}</ref>


==Forms==
==Gene structure and isoforms==
The most common form of the CR1 gene (CR1*1) is composed of 38 [[exon]]s spanning 133kb encoding a [[protein]] of 2039 [[amino acid]]s and has a predicted molecular weight of 220 kDa. Large [[insertion (genetics)|insertion]]s and [[deletion]]s have given rise to four structurally variant [[gene]]s and some alleles may extend up to 160 kb and 9 additional exons. The [[Transcription (genetics)|transcription]] start site has been mapped to 111 bp upstream of the [[translation]] initiation codon ATG and there is another possible start site 29 bp further upstream. The [[promoter]] region lacks a distinct [[TATA box]] sequence. The gene is expressed principally on [[erythrocytes]], [[monocytes]], [[neutrophils]] and [[B cells]] but is also present on some [[T lymphocytes]], [[mast cells]] and [[glomerular podocytes]].


The mean number of complement receptor 1 (CR1) molecules on erythrocytes in normal individuals lies within the range of 100-1000 molecules per cell. Two [[codominant]] [[allele]]s exist - one controlling high and the other low expression. [[Zygosity|Homozygote]]s differ by a factor of 10-20: [[Zygosity|heterozygotes]] typically have 500-600 copies per erythrocyte. These two alleles appear to have originated before the divergence of the European and African populations.  
The canonical Cr2/CD21 gene of subprimate mammals produces two types of complement receptor (CR1, ca. 200 kDa; CR2, ca. 145 kDa) via alternative mRNA splicing. The murine Cr2 gene contains 25 exons; a common first exon is spliced to exon 2 and to exon 9 in transcripts encoding CR1 and CR2, respectively. A transcript with an [[open reading frame]] of 4,224 nucleotides encodes the long isoform, CR1; this is predicted to be a protein of 1,408 amino acids that includes 21 short consensus repeats (SCR) of ca. 60 amino acids each, plus transmembrane and cytoplasmic regions. Isoform CR2 (1,032 amino acids) is encoded by a shorter transcript (3,096 coding nucleotides) that lacks exons 2-8 encoding SCR1-6. CR1 and CR2 on murine B cells form complexes with a co-accessory activation complex containing CD19, CD81, and the fragilis/Ifitm (murine equivalents of LEU13) proteins.<ref name=pmid18713965>{{cite journal |vauthors=Jacobson AC, Weis JH | title = Comparative functional evolution of human and mouse CR1 and CR2 | journal = J. Immunol. | volume = 181 | issue = 5 | pages = 2953–9 | date = Sep 2008 | pmid = 18713965 | pmc = 3366432 | doi = 10.4049/jimmunol.181.5.2953 | publisher =  | issn =  | location = UNITED STATES }}</ref>
 
The [[complement receptor 2]] (CR2) gene of primates produces only the smaller isoform, CR2; primate CR1, which recapitulates many of the structural domains and presumed functions of Cr2-derived CR1 in subprimates, is encoded by a distinct CR1 gene (apparently derived from the gene Crry of subprimates).
 
Isoforms CR1 and CR2 derived from the Cr2 gene possess the same C-terminal sequence, such that association with and activation through CD19 should be equivalent. CR1 can bind to C4b and C3b complexes, whereas CR2 (murine and human) binds to C3dg-bound complexes. CR1, a surface protein produced primarily by [[follicular dendritic cell]]s, appears to be critical for generation of appropriately activated B cells of the germinal centre and for mature antibody responses to bacterial infection.<ref name=pmid23733878>{{cite journal |vauthors=Donius LR, Handy JM, Weis JJ, Weis JH | title = Optimal Germinal Center B Cell Activation and T-Dependent Antibody Responses Require Expression of the Mouse Complement Receptor Cr1 | language =  | journal = J. Immunol. | volume = 191 | issue = 1 | pages = 434–47 | date = Jul 2013 | pmid = 23733878 | doi = 10.4049/jimmunol.1203176 | pmc=3707406}}</ref>
 
The most common allelic variant of the human CR1 gene (CR1*1) is composed of 38 [[exon]]s spanning 133kb encoding a [[protein]] of 2,039 [[amino acid]]s with a predicted molecular weight of 220 kDa. Large [[insertion (genetics)|insertion]]s and [[deletion (genetics)|deletion]]s have given rise to four structurally variant [[gene]]s and some alleles may extend up to 160 kb and 9 additional exons. The [[Transcription (genetics)|transcription]] start site has been mapped to 111 bp upstream of the [[Translation (biology)|translation]] initiation codon ATG and there is another possible start site 29 bp further upstream. The [[Promoter (biology)|promoter]] region lacks a distinct [[TATA box]] sequence. The gene is expressed principally on [[erythrocytes]], [[monocytes]], [[neutrophils]] and [[B cells]] but is also present on some [[T lymphocytes]], [[mast cells]] and [[glomerular podocytes]].


==Structure==
==Structure==
The encoded protein has a 47 amino acid [[signal peptide]], an extracellular domain of 1930 residues, a 25 residue transmembrane domain and a 43 amino acid C terminal cytoplasmic region. The [[leader sequence]] and 5'-untranslated region are contained in one exon. The large extracellular domain of CR1, which has 25 potential [[N-glycosylation]] sites, can be divided into 30 short consensus repeats (SCRs) (also known as [[complement control protein]] repeats (CCPs) or sushi domains), each having 60 to 70 amino acids. The sequence homology between SCRs ranges between 60 to 99 percent. The transmembrane region is encoded by 2 exons and the cytoplasmic domain and the 3'-untranslated regions are coded for by two separate exons.
The encoded protein has a 47 amino acid [[signal peptide]], an extracellular domain of 1930 residues, a 25 residue transmembrane domain and a 43 amino acid C terminal cytoplasmic region. The [[Five prime untranslated region|leader sequence and 5'-untranslated region]] are contained in one exon. The large extracellular domain of CR1, which has 25 potential [[N-glycosylation]] sites, can be divided into 30 short consensus repeats (SCRs) (also known as [[complement control protein]] repeats (CCPs) or sushi domains), each having 60 to 70 amino acids. The sequence homology between SCRs ranges between 60 and 99 percent. The transmembrane region is encoded by 2 exons and the cytoplasmic domain and the 3'-untranslated regions are coded for by two separate exons.


The 30 or so SCRs are further grouped into four longer regions termed long homologous repeats (LHRs) each encoding approximately 45 kDa of protein and designated LHR-A, -B, -C, and -D. The first three have seven SCRs while LHR-D has 9 or more. Each LHR is composed of 8 exons and within an LHR, SCR 1, 5, and 7 are each encoded by a single exon, SCR 2 and 6 are each encoded by 2 exons, and a single exon codes for SCR 3 and 4. The LHR seem to have arisen as a result of unequal crossing over and the event that gave rise to LHR-B seems to have occurred within the fourth exon of either LHR-A or –C.  To date the atomic structure have been solved for SCRs 15-16, 16 & 16-17.
The 30 or so SCRs are further grouped into four longer regions termed long homologous repeats (LHRs) each encoding approximately 45 kDa of protein and designated LHR-A, -B, -C, and -D. The first three have seven SCRs while LHR-D has 9 or more. Each LHR is composed of 8 exons and within an LHR, SCR 1, 5, and 7 are each encoded by a single exon, SCR 2 and 6 are each encoded by 2 exons, and a single exon codes for SCR 3 and 4. The LHR seem to have arisen as a result of unequal crossing over and the event that gave rise to LHR-B seems to have occurred within the fourth exon of either LHR-A or –C.  To date the atomic structure have been solved for SCRs 15-16, 16 & 16-17.


==Alleles==
==Alleles==
Four alleles are known with predicted protein molecular weights of 190 kDa, 220 kDa, 250 kDa and 280kDa are known. Multiple size variants (55kDa-220kDa) are also found among non-human [[primate]]s and a partial amino-terminal duplication (CR1-like gene) that encodes the short (55kDa-70kDa) forms expressed on non human erythrocytes. These short CR1 forms, some of which are [[glycosylphosphatidylinositol]] (GPI) anchored, are expressed on erythrocytes and the 220kDa molecular weight CR1 form is expressed on monocytes. The gene including the repeats is highly conserved in primates possibly because of the ability of the repeats to bind complement. LHR-A binds preferentially to the complement component C4b: LHR-B and LHR-C bind to C3b and also, albeit with a lower affinity, to C4b. Curiously the human CR1 gene appears to have an unusual protein conformation but the significance of this finding is not clear.  
Four known human alleles encode proteins with predicted molecular weights of 190 kDa, 220 kDa, 250 kDa and 280 kDa.<ref name=pmid19004497 /> Multiple size variants (55-220 kDa) are also found among non-human [[primate]]s and a partial amino-terminal duplication (CR1-like gene) that encodes the short (55-70 kDa) forms expressed on non human erythrocytes. These short CR1 forms, some of which are [[glycosylphosphatidylinositol]] (GPI) anchored, are expressed on erythrocytes and the 220-kDa CR1 form is expressed on monocytes. The gene including the repeats is highly conserved in primates possibly because of the ability of the repeats to bind complement. LHR-A binds preferentially to the complement component C4b: LHR-B and LHR-C bind to C3b and also, albeit with a lower affinity, to C4b. Curiously the human CR1 gene appears to have an unusual protein conformation but the significance of this finding is not clear.
 
The mean number of complement receptor 1 (CR1) molecules on erythrocytes in normal individuals lies within the range of 100-1000 molecules per cell. Two [[codominant]] [[allele]]s exist - one controlling high and the other low expression. [[Zygosity|Homozygote]]s differ by a factor of 10-20: [[Zygosity|heterozygotes]] typically have 500-600 copies per erythrocyte. These two alleles appear to have originated before the divergence of the European and African populations.


==Rosetting==
==Rosetting==
<i>[[Plasmodium falciparum]]</i> erythrocyte membrane protein 1 (PfEMP1) interacts with uninfected erythrocytes. This 'stickiness', known as [[rosetting]], is believed to be a strategy used by the [[parasite]] to remain sequestered in the [[microvasculature]] to avoid destruction in the [[spleen]] and [[liver]]. Erythrocyte rosetting causes obstruction of the [[blood]] flow in microcapillaries. There is a direct interaction between PfEMP1 and a functional site of complement receptor type 1 on uninfected erythrocytes.
[[Plasmodium falciparum erythrocyte membrane protein 1|''Plasmodium falciparum'' erythrocyte membrane protein 1]] (PfEMP1) interacts with uninfected erythrocytes. This 'stickiness', known as [[rosetting]], is believed to be a strategy used by the [[parasite]] to remain sequestered in the [[Microcirculation|microvasculature]] to avoid destruction in the [[spleen]] and [[liver]]. Erythrocyte rosetting causes obstruction of the [[blood]] flow in [[microcapillaries]]. There is a direct interaction between PfEMP1 and a functional site of complement receptor type 1 on uninfected erythrocytes.<ref name=pmid19004497 />


==Role in blood Groups==
==Role in blood groups==
The Knops antigen was the 25th blood group system recognized and consists of the single [[antigen]] York (Yk) a with the following allelic pairs:  
The [[Knops antigen]] was the 25th blood group system recognized and consists of the single [[antigen]] [[York]] (Yk) a with the following allelic pairs:  
* Knops (Kn) a and b
* Knops (Kn) a and b
* McCoy (McC) a and b
* [[McCoy (allelic pair)|McCoy]] (McC) a and b
* Swain-Langley (Sl) 1 and 2
* [[Swain-Langley]] (Sl) 1 and 2


The antigen is known to lie within the CR1 protein repeats and was first described in 1970 in a 37-year-old Caucasian woman. Racial differences exist in the frequency of these antigens: 98.5% and 96.7% of American Caucasians and Africans respectively are positive for McC(a). 36% of a Mali population were Kn(a) and 14% of exhibited the null (or Helgeson) phenotype compared with only 1% in the American population. The frequencies of McC (b) and Sl (2) are higher in Africans compared with Europeans and while the frequency of McC (b) was similar between Africans from the USA or Mali, the Sl (b) phenotype is significantly more common in Mali - 39% and 65% respectively. In Gambia the Sl (2)/McC(b) phenotype appears to have been positively selected - presumably due to malaria. 80% of Papua New Guineans have the Helgeson [[phenotype]] and [[case control studies]] suggest this phenotype has a protective effect against severe [[malaria]].
The antigen is known to lie within the CR1 protein repeats and was first described in 1970 in a 37-year-old [[whites|Caucasian]] woman. Racial differences exist in the frequency of these antigens: 98.5% and 96.7% of [[United States|American]] Caucasians and [[Africa]]ns respectively are positive for McC(a). 36% of a Mali population were Kn(a) and 14% of exhibited the null (or Helgeson) phenotype compared with only 1% in the American population. The frequencies of McC (b) and Sl (2) are higher in Africans compared with [[Europe]]ans and while the frequency of McC (b) was similar between Africans from the United States or [[Mali]], the Sl (b) phenotype is significantly more common in Mali - 39% and 65% respectively. In Gambia the Sl (2)/McC(b) phenotype appears to have been positively selected - presumably due to malaria. 80% of [[Papua New Guinea]]ns have the [[Helgeson]] [[phenotype]] and [[case control studies]] suggest this phenotype has a protective effect against severe [[malaria]].


==References==
==References==
{{reflist|2}}
{{reflist|30em}}


==Further reading==
==Further reading==
{{refbegin | 2}}
{{refbegin | 2}}
{{PBB_Further_reading
*{{cite journal |vauthors=Ahearn JM, Fearon DT | title = Structure and function of the complement receptors, CR1 (CD35) and CR2 (CD21) | journal = Adv. Immunol. | volume = 46 | issue =  | pages = 183–219 | year = 1989 | pmid = 2551147 | doi = 10.1016/S0065-2776(08)60654-9 }}
| citations =
*{{cite journal |vauthors=Wong WW, Farrell SA | title = Proposed structure of the F' allotype of human CR1. Loss of a C3b binding site may be associated with altered function | journal = J. Immunol. | volume = 146 | issue = 2 | pages = 656–62 | year = 1991 | pmid = 1670949 | doi =  }}
*{{cite journal | author=Ahearn JM, Fearon DT |title=Structure and function of the complement receptors, CR1 (CD35) and CR2 (CD21). |journal=Adv. Immunol. |volume=46 |issue=  |pages= 183-219 |year= 1989 |pmid= 2551147 |doi= }}
*{{cite journal |vauthors=Tuveson DA, Ahearn JM, Matsumoto AK, Fearon DT | title = Molecular interactions of complement receptors on B lymphocytes: a CR1/CR2 complex distinct from the CR2/CD19 complex | journal = J. Exp. Med. | volume = 173 | issue = 5 | pages = 1083–9 | year = 1991 | pmid = 1708808 | pmc = 2118840 | doi = 10.1084/jem.173.5.1083 }}
*{{cite journal | author=Wong WW, Farrell SA |title=Proposed structure of the F' allotype of human CR1. Loss of a C3b binding site may be associated with altered function. |journal=J. Immunol. |volume=146 |issue= 2 |pages= 656-62 |year= 1991 |pmid= 1670949 |doi=  }}
*{{cite journal |vauthors=Moulds JM, Nickells MW, Moulds JJ, Brown MC, Atkinson JP | title = The C3b/C4b receptor is recognized by the Knops, McCoy, Swain-langley, and York blood group antisera | journal = J. Exp. Med. | volume = 173 | issue = 5 | pages = 1159–63 | year = 1991 | pmid = 1708809 | pmc = 2118866 | doi = 10.1084/jem.173.5.1159 }}
*{{cite journal | author=Tuveson DA, Ahearn JM, Matsumoto AK, Fearon DT |title=Molecular interactions of complement receptors on B lymphocytes: a CR1/CR2 complex distinct from the CR2/CD19 complex. |journal=J. Exp. Med. |volume=173 |issue= 5 |pages= 1083-9 |year= 1991 |pmid= 1708808 |doi= 10.1084/jem.173.5.1083}}
*{{cite journal |vauthors=Rao N, Ferguson DJ, Lee SF, Telen MJ | title = Identification of human erythrocyte blood group antigens on the C3b/C4b receptor | journal = J. Immunol. | volume = 146 | issue = 10 | pages = 3502–7 | year = 1991 | pmid = 1827486 | doi =  }}
*{{cite journal | author=Moulds JM, Nickells MW, Moulds JJ, ''et al.'' |title=The C3b/C4b receptor is recognized by the Knops, McCoy, Swain-langley, and York blood group antisera. |journal=J. Exp. Med. |volume=173 |issue= 5 |pages= 1159-63 |year= 1991 |pmid= 1708809 |doi= 10.1084/jem.173.5.1159}}
*{{cite journal |vauthors=Hourcade D, Miesner DR, Bee C, Zeldes W, Atkinson JP | title = Duplication and divergence of the amino-terminal coding region of the complement receptor 1 (CR1) gene. An example of concerted (horizontal) evolution within a gene | journal = J. Biol. Chem. | volume = 265 | issue = 2 | pages = 974–80 | year = 1990 | pmid = 2295627 | doi =  }}
*{{cite journal | author=Rao N, Ferguson DJ, Lee SF, Telen MJ |title=Identification of human erythrocyte blood group antigens on the C3b/C4b receptor. |journal=J. Immunol. |volume=146 |issue= 10 |pages= 3502-7 |year= 1991 |pmid= 1827486 |doi=  }}
*{{cite journal |vauthors=Reynes M, Aubert JP, Cohen JH, Audouin J, Tricottet V, Diebold J, Kazatchkine MD | title = Human follicular dendritic cells express CR1, CR2, and CR3 complement receptor antigens | journal = J. Immunol. | volume = 135 | issue = 4 | pages = 2687–94 | year = 1985 | pmid = 2411809 | doi =  }}
*{{cite journal | author=Hourcade D, Miesner DR, Bee C, ''et al.'' |title=Duplication and divergence of the amino-terminal coding region of the complement receptor 1 (CR1) gene. An example of concerted (horizontal) evolution within a gene. |journal=J. Biol. Chem. |volume=265 |issue= 2 |pages= 974-80 |year= 1990 |pmid= 2295627 |doi=  }}
*{{cite journal |vauthors=Hinglais N, Kazatchkine MD, Mandet C, Appay MD, Bariety J | title = Human liver Kupffer cells express CR1, CR3, and CR4 complement receptor antigens. An immunohistochemical study | journal = Lab. Invest. | volume = 61 | issue = 5 | pages = 509–14 | year = 1989 | pmid = 2478758 | doi =  }}
*{{cite journal | author=Reynes M, Aubert JP, Cohen JH, ''et al.'' |title=Human follicular dendritic cells express CR1, CR2, and CR3 complement receptor antigens. |journal=J. Immunol. |volume=135 |issue= 4 |pages= 2687-94 |year= 1985 |pmid= 2411809 |doi=  }}
*{{cite journal |vauthors=Fearon DT, Klickstein LB, Wong WW, Wilson JG, Moore FD, Weis JJ, Weis JH, Jack RM, Carter RH, Ahearn JA | title = Immunoregulatory functions of complement: structural and functional studies of complement receptor type 1 (CR1; CD35) and type 2 (CR2; CD21) | journal = Prog. Clin. Biol. Res. | volume = 297 | issue =  | pages = 211–20 | year = 1989 | pmid = 2531419 | doi =  }}
*{{cite journal | author=Hinglais N, Kazatchkine MD, Mandet C, ''et al.'' |title=Human liver Kupffer cells express CR1, CR3, and CR4 complement receptor antigens. An immunohistochemical study. |journal=Lab. Invest. |volume=61 |issue= 5 |pages= 509-14 |year= 1989 |pmid= 2478758 |doi=  }}
*{{cite journal |vauthors=Wong WW, Cahill JM, Rosen MD, Kennedy CA, Bonaccio ET, Morris MJ, Wilson JG, Klickstein LB, Fearon DT | title = Structure of the human CR1 gene. Molecular basis of the structural and quantitative polymorphisms and identification of a new CR1-like allele | journal = J. Exp. Med. | volume = 169 | issue = 3 | pages = 847–63 | year = 1989 | pmid = 2564414 | pmc = 2189269 | doi = 10.1084/jem.169.3.847 }}
*{{cite journal | author=Fearon DT, Klickstein LB, Wong WW, ''et al.'' |title=Immunoregulatory functions of complement: structural and functional studies of complement receptor type 1 (CR1; CD35) and type 2 (CR2; CD21). |journal=Prog. Clin. Biol. Res. |volume=297 |issue=  |pages= 211-20 |year= 1989 |pmid= 2531419 |doi=  }}
*{{cite journal |vauthors=Wong WW, Kennedy CA, Bonaccio ET, Wilson JG, Klickstein LB, Weis JH, Fearon DT | title = Analysis of multiple restriction fragment length polymorphisms of the gene for the human complement receptor type I. Duplication of genomic sequences occurs in association with a high molecular mass receptor allotype | journal = J. Exp. Med. | volume = 164 | issue = 5 | pages = 1531–46 | year = 1986 | pmid = 2877046 | pmc = 2188435 | doi = 10.1084/jem.164.5.1531 }}
*{{cite journal | author=Wong WW, Cahill JM, Rosen MD, ''et al.'' |title=Structure of the human CR1 gene. Molecular basis of the structural and quantitative polymorphisms and identification of a new CR1-like allele. |journal=J. Exp. Med. |volume=169 |issue= 3 |pages= 847-63 |year= 1989 |pmid= 2564414 |doi= 10.1084/jem.169.3.847}}
*{{cite journal |vauthors=Wong WW, Klickstein LB, Smith JA, Weis JH, Fearon DT | title = Identification of a partial cDNA clone for the human receptor for complement fragments C3b/C4b | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 82 | issue = 22 | pages = 7711–5 | year = 1985 | pmid = 2933745 | pmc = 391403 | doi = 10.1073/pnas.82.22.7711 }}
*{{cite journal | author=Wong WW, Kennedy CA, Bonaccio ET, ''et al.'' |title=Analysis of multiple restriction fragment length polymorphisms of the gene for the human complement receptor type I. Duplication of genomic sequences occurs in association with a high molecular mass receptor allotype. |journal=J. Exp. Med. |volume=164 |issue= 5 |pages= 1531-46 |year= 1986 |pmid= 2877046 |doi= 10.1084/jem.164.5.1531}}
*{{cite journal |vauthors=Klickstein LB, Wong WW, Smith JA, Weis JH, Wilson JG, Fearon DT | title = Human C3b/C4b receptor (CR1). Demonstration of long homologous repeating domains that are composed of the short consensus repeats characteristics of C3/C4 binding proteins | journal = J. Exp. Med. | volume = 165 | issue = 4 | pages = 1095–112 | year = 1987 | pmid = 2951479 | pmc = 2188588 | doi = 10.1084/jem.165.4.1095 }}
*{{cite journal | author=Wong WW, Klickstein LB, Smith JA, ''et al.'' |title=Identification of a partial cDNA clone for the human receptor for complement fragments C3b/C4b. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=82 |issue= 22 |pages= 7711-5 |year= 1985 |pmid= 2933745 |doi= 10.1073/pnas.82.22.7711}}
*{{cite journal |vauthors=Moldenhauer F, David J, Fielder AH, Lachmann PJ, Walport MJ | title = Inherited deficiency of erythrocyte complement receptor type 1 does not cause susceptibility to systemic lupus erythematosus | journal = Arthritis Rheum. | volume = 30 | issue = 9 | pages = 961–6 | year = 1987 | pmid = 2959289 | doi = 10.1002/art.1780300901 }}
*{{cite journal | author=Klickstein LB, Wong WW, Smith JA, ''et al.'' |title=Human C3b/C4b receptor (CR1). Demonstration of long homologous repeating domains that are composed of the short consensus repeats characteristics of C3/C4 binding proteins. |journal=J. Exp. Med. |volume=165 |issue= 4 |pages= 1095-112 |year= 1987 |pmid= 2951479 |doi= 10.1084/jem.165.4.1095}}
*{{cite journal |vauthors=Hourcade D, Miesner DR, Atkinson JP, Holers VM | title = Identification of an alternative polyadenylation site in the human C3b/C4b receptor (complement receptor type 1) transcriptional unit and prediction of a secreted form of complement receptor type 1 | journal = J. Exp. Med. | volume = 168 | issue = 4 | pages = 1255–70 | year = 1988 | pmid = 2971757 | pmc = 2189081 | doi = 10.1084/jem.168.4.1255 }}
*{{cite journal | author=Moldenhauer F, David J, Fielder AH, ''et al.'' |title=Inherited deficiency of erythrocyte complement receptor type 1 does not cause susceptibility to systemic lupus erythematosus. |journal=Arthritis Rheum. |volume=30 |issue= 9 |pages= 961-6 |year= 1987 |pmid= 2959289 |doi= 10.1002/art.1780300901}}
*{{cite journal |vauthors=Klickstein LB, Bartow TJ, Miletic V, Rabson LD, Smith JA, Fearon DT | title = Identification of distinct C3b and C4b recognition sites in the human C3b/C4b receptor (CR1, CD35) by deletion mutagenesis | journal = J. Exp. Med. | volume = 168 | issue = 5 | pages = 1699–717 | year = 1988 | pmid = 2972794 | pmc = 2189104 | doi = 10.1084/jem.168.5.1699 }}
*{{cite journal | author=Hourcade D, Miesner DR, Atkinson JP, Holers VM |title=Identification of an alternative polyadenylation site in the human C3b/C4b receptor (complement receptor type 1) transcriptional unit and prediction of a secreted form of complement receptor type 1. |journal=J. Exp. Med. |volume=168 |issue= 4 |pages= 1255-70 |year= 1988 |pmid= 2971757 |doi= 10.1084/jem.168.4.1255}}
*{{cite journal |vauthors=Hing S, Day AJ, Linton SJ, Ripoche J, Sim RB, Reid KB, Solomon E | title = Assignment of complement components C4 binding protein (C4BP) and factor H (FH) to human chromosome 1q, using cDNA probes | journal = Ann. Hum. Genet. | volume = 52 | issue = Pt 2 | pages = 117–22 | year = 1989 | pmid = 2977721 | doi = 10.1111/j.1469-1809.1988.tb01086.x }}
*{{cite journal | author=Klickstein LB, Bartow TJ, Miletic V, ''et al.'' |title=Identification of distinct C3b and C4b recognition sites in the human C3b/C4b receptor (CR1, CD35) by deletion mutagenesis. |journal=J. Exp. Med. |volume=168 |issue= 5 |pages= 1699-717 |year= 1988 |pmid= 2972794 |doi= 10.1084/jem.168.5.1699}}
*{{cite journal | author = Fearon DT | title = Human complement receptors for C3b (CR1) and C3d (CR2) | journal = J. Invest. Dermatol. | volume = 85 | issue = 1 Suppl | pages = 53s–57s | year = 1985 | pmid = 2989379 | doi = 10.1111/1523-1747.ep12275473 }}
*{{cite journal | author=Hing S, Day AJ, Linton SJ, ''et al.'' |title=Assignment of complement components C4 binding protein (C4BP) and factor H (FH) to human chromosome 1q, using cDNA probes. |journal=Ann. Hum. Genet. |volume=52 |issue= Pt 2 |pages= 117-22 |year= 1989 |pmid= 2977721 |doi= }}
*{{cite journal |vauthors=Wilson JG, Murphy EE, Wong WW, Klickstein LB, Weis JH, Fearon DT | title = Identification of a restriction fragment length polymorphism by a CR1 cDNA that correlates with the number of CR1 on erythrocytes | journal = J. Exp. Med. | volume = 164 | issue = 1 | pages = 50–9 | year = 1986 | pmid = 3014040 | pmc = 2188187 | doi = 10.1084/jem.164.1.50 }}
*{{cite journal | author=Fearon DT |title=Human complement receptors for C3b (CR1) and C3d (CR2). |journal=J. Invest. Dermatol. |volume=85 |issue= 1 Suppl |pages= 53s-57s |year= 1985 |pmid= 2989379 |doi= 10.1111/1523-1747.ep12275473}}
*{{cite journal | author=Wilson JG, Murphy EE, Wong WW, ''et al.'' |title=Identification of a restriction fragment length polymorphism by a CR1 cDNA that correlates with the number of CR1 on erythrocytes. |journal=J. Exp. Med. |volume=164 |issue= 1 |pages= 50-9 |year= 1986 |pmid= 3014040 |doi= 10.1084/jem.164.1.50}}
}}
{{refend}}
{{refend}}


==External links==
==External links==
* {{MeshName|CR1+protein,+human}}
* {{MeshName|Receptors,+Complement+3b}}
* [https://www.ncbi.nlm.nih.gov/projects/mhc/xslcgi.fcgi?cmd=bgmut/systems_info&system=knops Knops blood group system] at [[BGMUT]] Blood Group Antigen Gene Mutation Database at [[National Center for Biotechnology Information|NCBI]], [[NIH]]


* [http://www.ncbi.nlm.nih.gov/projects/mhc/xslcgi.fcgi?cmd=bgmut/systems_info&system=knops Knops blood group system at BGMUT] Blood Group Antigen Gene Mutation Database at [[NCBI]], [[NIH]]
{{PDB Gallery|geneid=1378}}
 
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{{Clusters of differentiation}}
{{Complement_system}}
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[[Category:Complement system]]
[[Category:Complement system]]
[[Category:Clusters of differentiation]]
[[Category:Clusters of differentiation]]
[[Category:Blood]]
[[Category:Transfusion medicine]]
[[Category:Transfusion medicine]]
[[Category:Hematology]]
[[Category:Blood antigen systems]]
[[Category:Blood antigen systems]]
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Revision as of 20:02, 26 October 2017

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Complement receptor type 1 (CR1) also known as C3b/C4b receptor or CD35 (cluster of differentiation 35) is a protein that in humans is encoded by the CR1 gene.[1][2]

This gene is a member of the regulators of complement activation (RCA) family and is located in the 'cluster RCA' region of chromosome 1. The gene encodes a monomeric single-pass type I membrane glycoprotein found on erythrocytes, leukocytes, glomerular podocytes, hyalocytes, and splenic follicular dendritic cells. The Knops blood group system is a system of antigens located on this protein. The protein mediates cellular binding to particles and immune complexes that have activated complement. Decreases in expression of this protein and/or mutations in its gene have been associated with gallbladder carcinomas, mesangiocapillary glomerulonephritis, systemic lupus erythematosus and sarcoidosis. Mutations in this gene have also been associated with a reduction in Plasmodium falciparum rosetting, conferring protection against severe malaria. Alternate allele-specific splice variants, encoding different isoforms, have been characterized. Additional allele specific isoforms, including a secreted form, have been described but have not been fully characterized.[1]

In primates, CR1 serves as the main system for processing and clearance of complement opsonized immune complexes. It has been shown that CR1 can act as a negative regulator of the complement cascade, mediate immune adherence and phagocytosis and inhibit both the classic and alternative pathways. The number of CR1 molecules decreases with aging of erythrocytes in normal individuals and is also decreased in pathological conditions such as systemic lupus erythematosus (SLE), HIV infection, some haemolytic anaemia s and other conditions featuring immune complexes.[3] In mice, CR1 is an alternatively spliced variant of the complement receptor 2 (CR2) gene.

Certain alleles of this gene have been statistically associated with an increased risk of developing late-onset Alzheimer's disease.[4]

1q32 region

In humans, the CR1 gene is located at on the long arm of chromosome 1 at band 32 (1q32) and lies within a complex of immunoregulatory genes. In 5’-3’ order the genes in this region are: membrane cofactor protein - CR1- complement receptor type 2 - decay-accelerating factor - C4-binding protein.

Factor H, another immunoregulatory protein, also maps to this location.[5]

Gene structure and isoforms

The canonical Cr2/CD21 gene of subprimate mammals produces two types of complement receptor (CR1, ca. 200 kDa; CR2, ca. 145 kDa) via alternative mRNA splicing. The murine Cr2 gene contains 25 exons; a common first exon is spliced to exon 2 and to exon 9 in transcripts encoding CR1 and CR2, respectively. A transcript with an open reading frame of 4,224 nucleotides encodes the long isoform, CR1; this is predicted to be a protein of 1,408 amino acids that includes 21 short consensus repeats (SCR) of ca. 60 amino acids each, plus transmembrane and cytoplasmic regions. Isoform CR2 (1,032 amino acids) is encoded by a shorter transcript (3,096 coding nucleotides) that lacks exons 2-8 encoding SCR1-6. CR1 and CR2 on murine B cells form complexes with a co-accessory activation complex containing CD19, CD81, and the fragilis/Ifitm (murine equivalents of LEU13) proteins.[6]

The complement receptor 2 (CR2) gene of primates produces only the smaller isoform, CR2; primate CR1, which recapitulates many of the structural domains and presumed functions of Cr2-derived CR1 in subprimates, is encoded by a distinct CR1 gene (apparently derived from the gene Crry of subprimates).

Isoforms CR1 and CR2 derived from the Cr2 gene possess the same C-terminal sequence, such that association with and activation through CD19 should be equivalent. CR1 can bind to C4b and C3b complexes, whereas CR2 (murine and human) binds to C3dg-bound complexes. CR1, a surface protein produced primarily by follicular dendritic cells, appears to be critical for generation of appropriately activated B cells of the germinal centre and for mature antibody responses to bacterial infection.[7]

The most common allelic variant of the human CR1 gene (CR1*1) is composed of 38 exons spanning 133kb encoding a protein of 2,039 amino acids with a predicted molecular weight of 220 kDa. Large insertions and deletions have given rise to four structurally variant genes and some alleles may extend up to 160 kb and 9 additional exons. The transcription start site has been mapped to 111 bp upstream of the translation initiation codon ATG and there is another possible start site 29 bp further upstream. The promoter region lacks a distinct TATA box sequence. The gene is expressed principally on erythrocytes, monocytes, neutrophils and B cells but is also present on some T lymphocytes, mast cells and glomerular podocytes.

Structure

The encoded protein has a 47 amino acid signal peptide, an extracellular domain of 1930 residues, a 25 residue transmembrane domain and a 43 amino acid C terminal cytoplasmic region. The leader sequence and 5'-untranslated region are contained in one exon. The large extracellular domain of CR1, which has 25 potential N-glycosylation sites, can be divided into 30 short consensus repeats (SCRs) (also known as complement control protein repeats (CCPs) or sushi domains), each having 60 to 70 amino acids. The sequence homology between SCRs ranges between 60 and 99 percent. The transmembrane region is encoded by 2 exons and the cytoplasmic domain and the 3'-untranslated regions are coded for by two separate exons.

The 30 or so SCRs are further grouped into four longer regions termed long homologous repeats (LHRs) each encoding approximately 45 kDa of protein and designated LHR-A, -B, -C, and -D. The first three have seven SCRs while LHR-D has 9 or more. Each LHR is composed of 8 exons and within an LHR, SCR 1, 5, and 7 are each encoded by a single exon, SCR 2 and 6 are each encoded by 2 exons, and a single exon codes for SCR 3 and 4. The LHR seem to have arisen as a result of unequal crossing over and the event that gave rise to LHR-B seems to have occurred within the fourth exon of either LHR-A or –C. To date the atomic structure have been solved for SCRs 15-16, 16 & 16-17.

Alleles

Four known human alleles encode proteins with predicted molecular weights of 190 kDa, 220 kDa, 250 kDa and 280 kDa.[3] Multiple size variants (55-220 kDa) are also found among non-human primates and a partial amino-terminal duplication (CR1-like gene) that encodes the short (55-70 kDa) forms expressed on non human erythrocytes. These short CR1 forms, some of which are glycosylphosphatidylinositol (GPI) anchored, are expressed on erythrocytes and the 220-kDa CR1 form is expressed on monocytes. The gene including the repeats is highly conserved in primates possibly because of the ability of the repeats to bind complement. LHR-A binds preferentially to the complement component C4b: LHR-B and LHR-C bind to C3b and also, albeit with a lower affinity, to C4b. Curiously the human CR1 gene appears to have an unusual protein conformation but the significance of this finding is not clear.

The mean number of complement receptor 1 (CR1) molecules on erythrocytes in normal individuals lies within the range of 100-1000 molecules per cell. Two codominant alleles exist - one controlling high and the other low expression. Homozygotes differ by a factor of 10-20: heterozygotes typically have 500-600 copies per erythrocyte. These two alleles appear to have originated before the divergence of the European and African populations.

Rosetting

Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) interacts with uninfected erythrocytes. This 'stickiness', known as rosetting, is believed to be a strategy used by the parasite to remain sequestered in the microvasculature to avoid destruction in the spleen and liver. Erythrocyte rosetting causes obstruction of the blood flow in microcapillaries. There is a direct interaction between PfEMP1 and a functional site of complement receptor type 1 on uninfected erythrocytes.[3]

Role in blood groups

The Knops antigen was the 25th blood group system recognized and consists of the single antigen York (Yk) a with the following allelic pairs:

The antigen is known to lie within the CR1 protein repeats and was first described in 1970 in a 37-year-old Caucasian woman. Racial differences exist in the frequency of these antigens: 98.5% and 96.7% of American Caucasians and Africans respectively are positive for McC(a). 36% of a Mali population were Kn(a) and 14% of exhibited the null (or Helgeson) phenotype compared with only 1% in the American population. The frequencies of McC (b) and Sl (2) are higher in Africans compared with Europeans and while the frequency of McC (b) was similar between Africans from the United States or Mali, the Sl (b) phenotype is significantly more common in Mali - 39% and 65% respectively. In Gambia the Sl (2)/McC(b) phenotype appears to have been positively selected - presumably due to malaria. 80% of Papua New Guineans have the Helgeson phenotype and case control studies suggest this phenotype has a protective effect against severe malaria.

References

  1. ↑ 1.0 1.1 "Entrez Gene: CR1 complement component (3b/4b) receptor 1 (Knops blood group)".
  2. ↑ Moulds JM, Nickells MW, Moulds JJ, Brown MC, Atkinson JP (May 1991). "The C3b/C4b receptor is recognized by the Knops, McCoy, Swain-langley, and York blood group antisera". J. Exp. Med. 173 (5): 1159–63. doi:10.1084/jem.173.5.1159. PMC 2118866. PMID 1708809.
  3. ↑ 3.0 3.1 3.2 Khera R, Das N (February 2009). "Complement Receptor 1: Disease associations and therapeutic implications". Molecular Immunology. 46 (5): 761–772. doi:10.1016/j.molimm.2008.09.026. PMID 19004497.
  4. ↑ Lambert JC, Heath S, Even G, Campion D, Sleegers K, Hiltunen M, Combarros O, Zelenika D, Bullido MJ, Tavernier B, Letenneur L, Bettens K, Berr C, Pasquier F, Fiévet N, Barberger-Gateau P, Engelborghs S, De Deyn P, Mateo I, Franck A, Helisalmi S, Porcellini E, Hanon O, de Pancorbo MM, Lendon C, Dufouil C, Jaillard C, Leveillard T, Alvarez V, Bosco P, Mancuso M, Panza F, Nacmias B, Bossù P, Piccardi P, Annoni G, Seripa D, Galimberti D, Hannequin D, Licastro F, Soininen H, Ritchie K, Blanché H, Dartigues JF, Tzourio C, Gut I, Van Broeckhoven C, Alpérovitch A, Lathrop M, Amouyel P (September 2009). "Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease". Nat. Genet. 41 (10): 1094–9. doi:10.1038/ng.439. PMID 19734903. Lay summary – TIME Magazine (2009-09-06).
  5. ↑ Das, N; Biswas, B; Khera, R (2013). "Membrane-bound complement regulatory proteins as biomarkers and potential therapeutic targets for SLE". Advances in experimental medicine and biology. 735: 55–81. doi:10.1007/978-1-4614-4118-2_4. PMID 23402019.
  6. ↑ Jacobson AC, Weis JH (Sep 2008). "Comparative functional evolution of human and mouse CR1 and CR2". J. Immunol. UNITED STATES. 181 (5): 2953–9. doi:10.4049/jimmunol.181.5.2953. PMC 3366432. PMID 18713965.
  7. ↑ Donius LR, Handy JM, Weis JJ, Weis JH (Jul 2013). "Optimal Germinal Center B Cell Activation and T-Dependent Antibody Responses Require Expression of the Mouse Complement Receptor Cr1". J. Immunol. 191 (1): 434–47. doi:10.4049/jimmunol.1203176. PMC 3707406. PMID 23733878.

Further reading

External links

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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