CD59 (CD59 molecule, complement regulatory protein)
2012-12-01 Rossen M Donev , Martin V Kolev AffiliationInstitute of Life Science, College of Medicine, Swansea University, Swansea, UK (RMD); MRC Centre for Transplantation, Kings College London, Guys Hospital, London, UK (MVK)
Identity
HGNC
LOCATION
11p13
IMAGE
LEGEND
Red line marks the position of the CD59 gene in chromosome 11, p13.
LOCUSID
ALIAS
16.3A5,1F5,EJ16,EJ30,EL32,G344,HRF-20,HRF20,MAC-IP,MACIF,MEM43,MIC11,MIN1,MIN2,MIN3,MIRL,MSK21,p18-20
FUSION GENES
DNA/RNA
CD59 gene consists of 7 exons and 6 introns spanning 1 to 33470bp of DNA (NCBI Reference Sequence: NG_008057.1) from 11p13 and includes a 5-/3- non-coding regions. The position of exons is: 1..98 (exon 1), 2870..2985 (exon 2), 5012..5056 (exon 3), 13528..13563 (exon 4), 13753..13844 (exon 5a), 13753..13909 (exon 5b), 13753..14101 (exon 5c), 14017..14101 (exon 5d), 19009..19110 (exon 6), and 26137..33470 (exon 7). Highlighted in red is the protein coding sequence from exons 5c/5d, 6 and 7 (14035..26354).
Description
NCBI Reference Sequence: NG_008057.1.
Transcription
- Total range: NG_008057.1
- exon 1: (1..98); total length: 98; strand: plus
- exon 2: (2870..2985); total length: 116; strand: plus
- exon 3: (5012..5056); total length: 45; strand: plus
- exon 4: (13528..13563); total length: 36; strand: plus
- exon 5a: (13753..13844); total length: 92; strand: plus
- exon 5b :(13753..13909); total length: 157; strand: plus
- exon 5c: (13753..14101); total length: 349; strand: plus
- exon 5d: (14017..14101); total length: 85; strand: plus
- exon 6: (19009..19110); total length: 102; strand: plus
- exon 7: (26137..33470); total length: 7,334; strand: plus.
Transcription results in 22 different mRNAs (20 alternatively spliced variants and 2 unspliced forms). Despite the very high number of different CD59 transcripts, most of them vary at their 5 and/or 3 ends and encode a unique CD59 protein. However, different splicing variants have alternative promoters and stabilising sequences which is likely to affect the expression level of the protein.
- exon 1: (1..98); total length: 98; strand: plus
- exon 2: (2870..2985); total length: 116; strand: plus
- exon 3: (5012..5056); total length: 45; strand: plus
- exon 4: (13528..13563); total length: 36; strand: plus
- exon 5a: (13753..13844); total length: 92; strand: plus
- exon 5b :(13753..13909); total length: 157; strand: plus
- exon 5c: (13753..14101); total length: 349; strand: plus
- exon 5d: (14017..14101); total length: 85; strand: plus
- exon 6: (19009..19110); total length: 102; strand: plus
- exon 7: (26137..33470); total length: 7,334; strand: plus.
Transcription results in 22 different mRNAs (20 alternatively spliced variants and 2 unspliced forms). Despite the very high number of different CD59 transcripts, most of them vary at their 5 and/or 3 ends and encode a unique CD59 protein. However, different splicing variants have alternative promoters and stabilising sequences which is likely to affect the expression level of the protein.
Proteins
Sequence of CD59 protein. CD59 contains 10 cystein residues involved in 5 disulphide bonds creating 5 loop structures. First three helical loops at the N-terminus form the hydrophobic core of CD59. Detailed information on CD59 protein structure can be obtained in works published by Bubeck et al. (Bubeck et al., 2011) and Huang et al. (Huang et al., 2007).
Description
CD59 is a 128aa-long protein. No polymorphisms have been described in the protein coding sequence of the CD59 gene. All transcription variants of CD59 result in the synthesis of a single CD59 protein with molecular mass between 18 and 22 kDa, depending on the level of glycosylation. CD59 has sites for both N- and O-glycosylation.
Expression
CD59 is expressed in all organs and in almost all cell types. It is essential to protect cells from self-destruction by complement-mediated lysis. The highest expression in humans has been detected in cardiomyocytes and smooth muscles (Su et al., 2004). Some nucleated blood cells (CD14 monocytes, T cells) either lack CD59 expression or express it very low which makes them highly susceptible to complement lysis.
Localisation
CD59 is expressed on the surface of cells. It is attached to the cellular membrane via a glycosylphosphatidylinositol tail (GPI-anchored molecule). In urine, CD59 can be found as soluble protein.
Function
The major and well-studied role of CD59 protein is to protect cells from self-destruction by our complement system. CD59 is the only membrane-bound inhibitor of the terminal pathway of complement cascade. However, in more recent years, some other functions of CD59 were described. CD59 was found to attenuate angiogenesis by preventing the complement-mediated lysis of newly grown blood vessels (Ekdahl et al., 2006). In addition, it was found that via CD59, the LPS signal is transduced into the nucleus via NF-kappaB activation inducing cytokine generation (Yamamoto et al., 2003).
Homology
CD59 protein does not show significant homology with other proteins. However, there is a high cross-primates homology for CD59. Human CD59 has 84% homology with CD59 in Macaca fascicularis and 91% homology in Pongo abelii (BLAST search). Homology between human CD59 protein and CD59 in rodents, however, is less than 50% (BLAST analysis).
Mutations
Somatic
No polymorphisms have been described for CD59 gene which affect the protein sequence. However, analysis of the sequence of the human CD59 gene revealed the presence of a (GT)19 dinucleotide repeat ~800bp upstream from exon 1 (Nöthen and Dewald, 1995). This polymorphism might affect expression and/or stability of CD59 transcripts, however, there is no experimental information on this matter.
A mutation in another gene, PIGA gene, however, indirectly results in lack of CD59 on red blood cells (RBCs). This condition is called paroxysmal nocturnal haemoglobinuria (PNH) and is a clonal disorder of RBCs. As a result of defective PIGA function, affected RBCs lack all GPI-linked membrane proteins, including CD59. The lack of CD59 renders PNH-RBCs susceptible to autologous complement lysis (Botto et al., 2009).
A mutation in another gene, PIGA gene, however, indirectly results in lack of CD59 on red blood cells (RBCs). This condition is called paroxysmal nocturnal haemoglobinuria (PNH) and is a clonal disorder of RBCs. As a result of defective PIGA function, affected RBCs lack all GPI-linked membrane proteins, including CD59. The lack of CD59 renders PNH-RBCs susceptible to autologous complement lysis (Botto et al., 2009).
Implicated in
Entity name
Paroxysmal nocturnal hemoglobinuria (PNH)
Note
Decrease or absence of glycosylphosphatidylinositol-anchored molecules from the surface of the affected cells, such as CD59 (and CD55), resulting in chronic intravascular hemolysis, cytopenia and increased tendency to thrombosis, venous thrombosis, deficient hematopoiesis and, rarely, leukemic conversion.
Disease
PNH involves the defective synthesis of a glycosylphosphatidylinositol (GPI) anchor that is used by certain surface proteins for tethering to the cell membrane, such as CD59 (Meri and Jarva, 1998).
Somatic mutations in the X-linked gene PIGA (GPI complementation group A) which encodes a protein required in the biosynthesis of GPI molecules, have been strongly implicated in the pathogenesis of PNH (Rosti, 2000).
Somatic mutations in the X-linked gene PIGA (GPI complementation group A) which encodes a protein required in the biosynthesis of GPI molecules, have been strongly implicated in the pathogenesis of PNH (Rosti, 2000).
Prognosis
Poor.
Oncogenesis
Possible association between paroxysmal nocturnal hemoglobinuria phenotype and lymphoproliferative syndromes (Meletis et al., 2001).
Entity name
Alzheimers disease (AD)
Note
It was demonstrated at both protein and mRNA levels that CD59 expression in frontal cortex and hippocampus in AD brains was significantly decreased when compared with normal age matched non-demented individuals, supporting the hypothesis that AD brains are particularly vulnerable to complement-mediated neuronal death (Yang et al., 2000).
Disease
AD is a neurodegenerative disease that causes changes in brain function. AD usually affects people over the age of 65 years, with a progressive decline in memory, thinking, language and learning capacity. Age is the strongest predictor for the development and progression of AD (Tanna, 2004).
Prognosis
AD is incurable. It leads to death within an average of eight years after diagnosis, the last three of which are typically spent in an institution.
Cytogenetics
The molecular mechanisms and hypotheses of AD can be incredibly complex. One of the key events leading to AD appears to be the formation of a peptide (protein) known as amyloid beta (beta amyloid, Aβ), which clusters into amyloid plaques (senile plaques) on the blood vessels and on the outside surface of neurons of the brain. This plaques have been shown to activate the complement system (Kolev et al., 2009).
Entity name
Breast cancer
Disease
Human breast cancer cells are protected from complement-dependent lysis (CDC) by overexpression of CD59 (Yu et al., 1999). It has been shown in numerous studies that inhibition/neutralization of CD59 on breast tumour cells increases tumour killing by complement system both in vivo and in vitro.
Prognosis
A recent comparative proteomics study provided novel insights into key proteins associated with the metastatic potential of breast cancer cells and identified CD59 as a marker for breast cancer aggressiveness (Terp et al., 2012).
Oncogenesis
Overexpression of CD59 on the surface of tumour cells confers resistance to CDC which has been suggested to result in tumour growth (Chen et al., 2000; Donev et al., 2006).
Entity name
Ovarian cancer
Disease
CD59 is strongly expressed in the ovarian tumor tissues and their associated cell lines cells in all 28 benign and malignant tumors examined (Bjørge et al., 1997). Neutralization of CD59 with an anti-CD59 monoclonal antibody or inhibition of cd59 expression by siRNA significantly enhances CDC of the ovarian cell lines (Kolev et al., 2011).
Prognosis
Significant reduced levels of CD59 were detected in the urine of patients with ovarian carcinoma compared to the control subjects (Abdullah-Soheimi et al., 2010). Thus, CD59 can be used as a biomarker in the development of noninvasive assays for diagnosis and screening for ovarian carcinoma.
Oncogenesis
It has been demonstrated that overexpression of CD59 on cancer cell surface promotes tumour growth in vitro and in vivo by protecting them from complement lysis (Chen et al., 2000; Donev et al., 2006).
Entity name
Various cancers
Note
Complement is one of the main mediators of antibody-based cancer therapy via the CDC effect. Tumour cells overexpress CD59 which plays a critical role in resistance to CDC and monoclonal antibody-therapy for treatment of cancer (Juhl et al., 1997; Yan et al., 2008).
Disease
CD59 is overexpress on the surface of different tumour types and their associated cell lines - colorectal cancer (Thorsteinsson et al., 1998), B-cell leukemias (Treon et al., 2001), neuroblastoma (Donev et al., 2008), prostate cancer (Jarvis et al., 1997), malignant melanoma (Weichenthal et al., 1999), lung carcinoma (Varsano et al., 1998), etc.
Prognosis
In general, overexpression of CD59 on tumour surface is associated with poor prognosis.
Oncogenesis
It has been demonstrated that overexpression of CD59 on cell surface promotes tumour growth in vitro and in vivo by protecting them from complement lysis (Chen et al., 2000; Donev et al., 2006).
Entity name
Diabetes
Note
Glycation was shown to inhibit CD59 function. In presence of glycation on CD59 it loses its MAC-inhibitory function and results in vascular proliferavative complications like diabetes (Davies et al., 2005). Loss of functional CD59 in hyperglycaemics contributes to their susceptibility to lysis by complement. Thus, it was suggested that glycation-induced inactivation of CD59 is a factor contributing to anaemia in type I diabetes. It is hypothesized that glycation near residue K41 and W40, two highly conserved amino acids essential for the CD59 function, inhibits CD59 function (Davies et al., 2005).
Disease
Diabetes is a disease due to an increased level in glucose, which results in glycation and impairment of protein function. Glycation is when a sugar molecule binds a protein or a lipid molecule without the control of an enzyme.
Entity name
Age-related macular degeneration (AMD)
Note
Immunohistochemical studies have localized activated complement components, including the membrane attack complex (MAC) in retinal pigment epithelium (RPE) and drusen in the eyes of patients with AMD (Johnson et al., 2000). CD59 protects autologous cell killing by preventing the formation of lytic MAC on the cell membrane (Meri et al., 1990). The expression of CD59 was found to be significantly lower on CD14(+) monocytes in patients with neovascular AMD compared with controls (Singh et al., 2012). Introduction of human CD59 using adenoviral vectors as a possible therapeutic strategy has been proposed (Ramo et al., 2008).
Disease
Molecular basis for AMD is not well understood, a growing body of evidence has recently implicated inflammatory processes, specifically the complement system, in the pathogenesis of this disease (Johnson et al., 2000).
Prognosis
AMD is the leading cause of blindness among the elderly in industrialized nations (Klein et al., 2008).
Entity name
Major depression
Note
Expression of CD59 has been found significantly inhibited in an animal model of major depression (Pajer et al., 2012). This suggests that neurons become more susceptible to complement-mediated damage.
Disease
Early-onset major depressive disorder (MDD) is a serious psychiatric condition occurring in people under 25 years of age. Early onset of MDD predicts greater familial risk, suggesting a substantial genetic etiology. Approximately 1% of the population of 12 years has MDD, but rates increase to 17-25% by late adolescence and young adulthood (Pajer et al., 2012).
Breakpoints
Note
Chromosomal in situ hybridization and pulsed field gel electrophoresis mapped the CD59 gene to 11p13, distal to the breakpoint of acute TCL2 (T-Cell Leukemia) and proximal to the Wilms tumor gene (WT1) (Heckl-Ostreicher et al., 1993).
Article Bibliography
| Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|
| 21083881 | 2010 | Patients with ovarian carcinoma excrete different altered levels of urine CD59, kininogen-1 and fragments of inter-alpha-trypsin inhibitor heavy chain H4 and albumin. | Abdullah-Soheimi SS et al |
| 8985085 | 1997 | Complement-regulatory proteins in ovarian malignancies. | Bjørge L et al |
| 19481265 | 2009 | Complement in human diseases: Lessons from complement deficiencies. | Botto M et al |
| 21073882 | 2011 | Structure of human complement C8, a precursor to membrane attack. | Bubeck D et al |
| 10850450 | 2000 | CD59 expressed on a tumor cell surface modulates decay-accelerating factor expression and enhances tumor growth in a rat model of human neuroblastoma. | Chen S et al |
| 15667573 | 2005 | Glycation of CD59 impairs complement regulation on erythrocytes from diabetic subjects. | Davies CS et al |
| 16489052 | 2006 | p53 regulates cellular resistance to complement lysis through enhanced expression of CD59. | Donev RM et al |
| 18632654 | 2008 | Modulation of CD59 expression by restrictive silencer factor-derived peptides in cancer immunotherapy for neuroblastoma. | Donev RM et al |
| 16893068 | 2006 | Possible immunoprotective and angiogenesis-promoting roles for malignant cell-derived prostasomes: a new paradigm for prostatic cancer? | Ekdahl KN et al |
| 7683594 | 1993 | Localization of the human CD59 gene by fluorescence in situ hybridization and pulsed-field gel electrophoresis. | Heckl-Ostreicher B et al |
| 17505110 | 2007 | Crystal structure of CD59: implications for molecular recognition of the complement proteins C8 and C9 in the membrane-attack complex. | Huang Y et al |
| 9185710 | 1997 | Expression and function of the complement membrane attack complex inhibitor protectin (CD59) in human prostate cancer. | Jarvis GA et al |
| 10865992 | 2000 | A potential role for immune complex pathogenesis in drusen formation. | Johnson LV et al |
| 9121154 | 1997 | Frequent expression of complement resistance factors CD46, CD55, and CD59 on gastrointestinal cancer cells limits the therapeutic potential of monoclonal antibody 17-1A. | Juhl H et al |
| 18045568 | 2008 | The epidemiology of retinal reticular drusen. | Klein R et al |
| 21960413 | 2011 | Complement in cancer and cancer immunotherapy. | Kolev M et al |
| 19721814 | 2009 | Implication of complement system and its regulators in Alzheimer's disease. | Kolev MV et al |
| 11920231 | 2001 | Detection of CD55- and/or CD59-deficient red cell populations in patients with lymphoproliferative syndromes. | Meletis J et al |
| 9704459 | 1998 | Complement regulation. | Meri S et al |
| 1698710 | 1990 | Human protectin (CD59), an 18,000-20,000 MW complement lysis restricting factor, inhibits C5b-8 catalysed insertion of C9 into lipid bilayers. | Meri S et al |
| 7543386 | 1995 | Dinucleotide repeat polymorphism at the human CD59 locus. | Nöthen MM et al |
| 18487376 | 2008 | Evaluation of adenovirus-delivered human CD59 as a potential therapy for AMD in a model of human membrane attack complex formation on murine RPE. | Ramo K et al |
| 10629597 | 2000 | The molecular basis of paroxysmal nocturnal hemoglobinuria. | Rosti V et al |
| 22541656 | 2012 | Altered expression of CD46 and CD59 on leukocytes in neovascular age-related macular degeneration. | Singh A et al |
| 15075390 | 2004 | A gene atlas of the mouse and human protein-encoding transcriptomes. | Su AI et al |
| 22990106 | 2012 | Identification of markers associated with highly aggressive metastatic phenotypes using quantitative comparative proteomics. | Terp MG et al |
| 9808413 | 1998 | The complement regulatory proteins CD46 and CD59, but not CD55, are highly expressed by glandular epithelium of human breast and colorectal tumour tissues. | Thorsteinsson L et al |
| 11394505 | 2001 | Tumor cell expression of CD59 is associated with resistance to CD20 serotherapy in patients with B-cell malignancies. | Treon SP et al |
| 9717965 | 1998 | Human lung cancer cell lines express cell membrane complement inhibitory proteins and are extremely resistant to complement-mediated lysis; a comparison with normal human respiratory epithelium in vitro, and an insight into mechanism(s) of resistance. | Varsano S et al |
| 11287977 | 2001 | Complement. First of two parts. | Walport MJ et al |
| 10408345 | 1999 | Expression of complement regulator proteins in primary and metastatic malignant melanoma. | Weichenthal M et al |
| 12834811 | 2003 | Lipopolysaccharide signal transduction in oral keratinocytes--involvement of CD59 but not CD14. | Yamamoto T et al |
| 19025121 | 2008 | The role of membrane complement regulatory proteins in cancer immunotherapy. | Yan J et al |
| 11027207 | 2000 | Deficiency of complement defense protein CD59 may contribute to neurodegeneration in Alzheimer's disease. | Yang LB et al |
| 9933415 | 1999 | Protection of human breast cancer cells from complement-mediated lysis by expression of heterologous CD59. | Yu J et al |
Other Information
Locus ID:
NCBI: 966
MIM: 107271
HGNC: 1689
Ensembl: ENSG00000085063
Variants:
dbSNP: 966
ClinVar: 966
TCGA: ENSG00000085063
COSMIC: CD59
RNA/Proteins
Expression (GTEx)
Pathways
Protein levels (Protein atlas)
References
| Pubmed ID | Year | Title | Citations |
|---|---|---|---|
| 36396448 | 2023 | CD59 Expression in Skeletal Muscles and Its Role in Myasthenia Gravis. | 1 |
| 37050931 | 2023 | Multiple CD59 Polymorphisms in Chinese Patients with Mycobacterium tuberculosis Infection. | 0 |
| 37522198 | 2023 | The bioinformatics analysis of CD59 in Helicobacter pylori infected gastric cancer. | 0 |
| 36396448 | 2023 | CD59 Expression in Skeletal Muscles and Its Role in Myasthenia Gravis. | 1 |
| 37050931 | 2023 | Multiple CD59 Polymorphisms in Chinese Patients with Mycobacterium tuberculosis Infection. | 0 |
| 37522198 | 2023 | The bioinformatics analysis of CD59 in Helicobacter pylori infected gastric cancer. | 0 |
| 35443950 | 2022 | Plasma-glycated CD59 as an early biomarker for gestational diabetes mellitus: prospective cohort study protocol. | 1 |
| 35666870 | 2022 | Alternative splicing encodes functional intracellular CD59 isoforms that mediate insulin secretion and are down-regulated in diabetic islets. | 10 |
| 35907507 | 2022 | The utility of first trimester plasma glycated CD59 (pGCD59) in predicting gestational diabetes mellitus: A prospective study of non-diabetic pregnant women in Ireland. | 1 |
| 35443950 | 2022 | Plasma-glycated CD59 as an early biomarker for gestational diabetes mellitus: prospective cohort study protocol. | 1 |
| 35666870 | 2022 | Alternative splicing encodes functional intracellular CD59 isoforms that mediate insulin secretion and are down-regulated in diabetic islets. | 10 |
| 35907507 | 2022 | The utility of first trimester plasma glycated CD59 (pGCD59) in predicting gestational diabetes mellitus: A prospective study of non-diabetic pregnant women in Ireland. | 1 |
| 32290641 | 2021 | Serum CD59: a novel biomarker of idiopathic pulmonary fibrosis? | 3 |
| 32940116 | 2021 | The value of p16 and HPV DNA in non-tonsillar, non-base of tongue oropharyngeal cancer. | 5 |
| 33529836 | 2021 | The expression of membrane-bound complement regulatory proteins CD46, CD55 and CD59 in oral lichen planus. | 0 |
Citation
Rossen M Donev ; Martin V Kolev
CD59 (CD59 molecule, complement regulatory protein)
Atlas Genet Cytogenet Oncol Haematol. 2012-12-01
Online version: http://atlasgeneticsoncology.org/gene/985/cd59-(cd59-molecule-complement-regulatory-protein)
