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MICA (MHC class I polypeptide-related sequence A)

Written2014-07Zain Ahmed, Medhat Askar
Cleveland Clinic/, Cleveland, OH;

Abstract Human Major Histocompatibility Complex (MHC) Class I Chain-Related gene A (MICA) is located 46 Kb centromeric to the HLA-B locus on the short arm of human chromosome 6 and encodes for a 62-kda cell surface glycoprotein. It is expressed on endothelial cells, dendritic cells, fibroblasts, epithelial cells, and many tumours and serves as target for both cellular and humoral immune responses in transformed cells. MICA protein at normal states has a low level of expression in epithelial tissues but is upregulated in response to various stimuli of cellular stress. MICA also functions as a ligand recognized by the activating receptor NKG2D that is expressed on the surface of NK, NKT, CD8+ and TCRγδ+ T cells. Allelic variants of MICA due to a single amino acid substitution at position 129 in the α2 domain have been reported to result in large differences in NKG2D binding. These variable affinities have been suggested to affect thresholds of NK cell triggering and T cell modulation in autoimmune diseases and malignancies. MICA molecules exist also in soluble forms (sMICA) and altered serum levels of sMICA have been reported in multiple states of health and disease.

Keywords MICA, MHC, Malignancy, Autoimmunity, NK cells; Transplantation; Rejection; GVHD

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Alias (NCBI)MHC (Human Major Histocompatibility Complex)
Class I Chain-Related Gene A,
MHC Class I Chain-related Protein A,
MHC class I-related chain A,
HGNC Alias symbPERB11.1
LocusID (NCBI) 100507436
Atlas_Id 41364
Location 6p21.33  [Link to chromosome band 6p21]
Location_base_pair Starts at 31400711 and ends at 31415315 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping MICA.png]
  Figure 1: Chromosomal location of MICA genes shown on a map of the MHC on chromosome 6p21.3 (not to scale). Chromosome 6 [Drawing modified from the National Library of Medicine, the National Center for Biotechnology Information public website (2013)]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
CSNK2B (6p21.33)::MICA (6p21.33)MICA (6p21.33)::ASXL2 (2p23.3)PLOD3 (7q22.1)::MICA (6p21.33)


  Figure 2: The MICA gene spans a 11,720-bp stretch of DNA was located 46,445 bp centromeric of the HLA-B locus on the short arm of human chromosome 6 (Mizuki et al., 1997).
Description The MICA gene was described in 1994 among a group of genes within the MHC class I region (Bahram et al., 1994). It is a member of the MIC gene family, which consists of 7 members (MICA-MICG). MICA is classified as a non-classical MHC class I gene as opposed to classical MHC class I genes encoding the commonly known Human Leukocyte Antigen (HLA) proteins. Similar to the HLA genes, the MICA gene is highly polymorphic. One hundred alleles have been reported (according to IMGT Release 3.17.0, 2014-07-14), with new alleles being continuously described and added to the database. As such it is significantly less polymorphic than HLA loci A (2,884 alleles), B (3,589), C (2,375), DRB1 (1,540), DQB1 (664), and DPB1 (422). However, MICA is more polymorphic than HLA loci G (50), DRB3 (58), DRB4 (15), DRB5 (20), DRA (7), DQA1 (52), DPA1 (38), and its closely related MICB gene (40) (Robinson et al., 2013).
MICA gene is organized into 7 exons of which exon 5 encodes the transmembrane (TM) region of the MICA molecule. TM encodes the repeat polymorphism (GCT/Ala) and eight types of repeats have been described as A4, A5, A5.1, A6, A7, A8, A9, and A10 (Gambelunghe et al., 2006; Zou et al., 2006). The combinations of extracellular and TM types facilitates the identification of the MICA alleles and reduces the number of potential ambiguous typings in heterozygous individuals. This combination identifies MICA alleles based on polymorphisms in the TM region as well as elsewhere, e.g., MICA*007:01/A4, MICA*008:01/A5.1, etc.
Transcription MICA gene encodes 383 amino acids polypeptide. MICA is up-regulated on human endothelial cells by the pro-inflammatory cytokine TNFα. This up-regulation is controlled at the transcriptional level by a master regulatory control element positioned 130-base pair (bp) upstream of the MICA transcription start site integrating input from the NF-kB and heat shock pathways (Lin et al., 2012).
Pseudogene Of the MIC gene family, only MICA and MICB are true genes with protein products while the remaining (MICC-MICG) are pseudogenes.


Note Due to synonymous substitutions being the only differences among some of the MICA alleles, the 100 MICA alleles encode for only 79 distinct proteins. Two of the MICA alleles are null alleles with no expressed protein products. MICA molecules are considered non-classical MHC class I molecules rather than human leukocyte antigens (HLA) since they are not expressed on the surface of human leukocytes. Nevertheless they are expressed on endothelial cells, dendritic cells, fibroblasts, epithelial cells, and many tumors and serve as targets for both cellular and humoral immune responses (Bahram et al., 1994; Zou and Stastny, 2010). MICA protein at normal states has a low level of expression in epithelial tissues but is upregulated in many tumors and under various stimuli of cellular stress including heat shock proteins (Groh et al., 1996). Similar to MHC class I, MICA molecules have 3 extracellular immunoglobulin-like domains, a transmembrane domain and intracellular cytoplasmic tail. However, unlike class I, MICA is not covalently bound a monomorphic β2 microglobulin and its peptide binding groove is empty and does not present peptides (Figure 3).
Allelic variants of MICA based on a single amino acid substitution at position 129 in the α2 domain have been reported to result in large differences in the affinity of binding to the activating natural killer group 2, member D (NKG2D) (Steinle et al., 2001). MICA alleles with a methionine (M) or valine (V) have been classified as having strong or weak binding affinity for NKG2D, respectively. These variable affinities have been suggested to affect thresholds of NK cell triggering and T cell modulation and consequently influencing clinical phenotypes in autoimmune disorders and malignancies (Amroun et al., 2005; Douik et al., 2009).
MICA molecules exist also in soluble forms (sMICA) encompassing three extracellular domains (Salih et al., 2002). ADAM, a disintegrin and metalloproteinase, is reported to mediate sMICA generation by cleavage of the molecule in the α3 domain close to the papain cleavage site (Figure X), however the precise location of the cleavage site is still unknown (Waldhauer et al., 2008). sMICA are not normally detected in sera of healthy donors and tumor cells are the major source of sMICA generation (Holdenrieder et al., 2006). In addition to patients with malignancies, sMICA is detected in the sera of patients with autoimmune diseases, acute bacterial infections, renal insufficiency, and cholestasis (Holdenrieder et al., 2007). Unlike the surface-bound form of MICA that stimulates immune responses, the secreted soluble counterpart, sMICA abates immune responses primarily by down regulating NKG2D expression which impairs the cellular cytotoxicity of T cells and NK cells against tumor cells (Groh et al., 2002). This may partly explain why higher levels of sMICA were observed in the serum of chronically infected individuals compared to healthy controls and HIV-1 controllers (Nolting et al., 2010). Similarly CMV infection triggers shedding of sMICA (Andresen et al., 2009).
  Figure 3: Diagram of comparison among HLA-Class I, MICA and sMICA molecules
Description 383 amino acids in length (including the 23 amino acids leader sequence that is lost from the 360 amino acid mature protein), 42,915 Da protein, undergoes N-glycoslation as post-translational modification, although not required to interact with NKG2D. MICA has three external (α1, α2, α3), a transmembrane and an intracytoplasmic domains (figure 4).
  Figure 4: The amino acid sequence of the full length MICA molecule. Source: IMGT/HLA online database (Robinson et al., 2013)
Expression Co-dominantly and constitutively expressed on cell membranes of human epithelial, endothelial, fibroblasts cells, keratinocytes, monocytes, dendritic cells, thymic medulla, and gastrointestinal epithelial cells but not on the surface of other healthy cells (Zwirner et al., 1999). Activated CD4+ and CD8+ T cells are shown to express MICA. Nuclear factor (NF)-kB regulates MICA expression on activated T lymphocytes by binding to a specific sequence in the long intron 1 of the MICA gene (Molinero et al., 2004). MICA expression is also up-regulated on stressed cells, tumour cells, and pathogen-infected cells (Mistry and O'Callaghan, 2007). It's noteworthy that in vitro CMV infection strongly induces expression of MICA (Groh et al., 2001). Similarly, respiratory syncytial virus (RSV) infection of epithelial cells up-regulated cell surface expression of MICA and levels of soluble MICA (Zdrenghea et al., 2012). It is also reported that CMV induced expression on the surface of fibroblasts is skewed towards a common form of MICA (A5.1), which has a nucleotide insertion in exon 5 corresponding to the transmembrane region and no cytoplasmic tail and less activation of the NKG2D pathway (Zou et al., 2005).
  Figure 5: A phylogram of the genetic distance between HLA class I consensus sequence, MICA and MICB reference alleles. This Phylogram considers only amino acid sequence of the 'Mature Protein' excluding the 23 amino acids leader sequence in MICA and MICB reference sequences and 24 amino acids leader sequence in the Class I consensus sequence due to lack of consensus among leader sequences of loci HLA-A, B, and C
Localisation Cell surface as a single-pass type 1 membrane protein
Function Like other MHC Class I molecules, MICA is a highly polymorphic MHC Class I molecule expressed on the cell surface of cells mentioned above. However, unlike other classical MHC Class I molecules, MICA is not involved in antigen presentation because its peptide-binding groove is too narrow to present antigens and is not associated with β2-microglobulin (Groh et al., 1996). MICA is expressed under cellular stress and is a ligand for NKG2D receptor expressed on surface of NK, NKT, CD8+ and TCRγδ T cells (Bauer et al., 1999). NKG2D binding results in up-regulation of MICA and ultimately cytotoxicity and release of IFN? by NKG2D-expressing cells.
  Figure 6: Sequence alignment between MICA (MICA*001) and MICB (MICB*001) reference sequences. This alignment considers the 'Full Length Protein' including the 23 amino acids leader sequence that is lost in the mature protein
Homology Searching the non-redundant protein sequences (nr) database for the protein sequences similar to the MICA reference amino acid sequence (MICA*001) using Blastp (protein-protein BLAST) tool publicly available from the website of The National Center for Biotechnology Information ( showed that the closest protein sequences are MICB followed by MHC class I (Wheeler and Bhagwat, 2007). The phylogenetic distance among these 3 sequences as determined by the online ClustalW2 (version CLUSTAL 2.1) Multiple Sequence Alignments tool publicly available at the website of the European Bioinformatics Institute of the European Molecular Biology Laboratory (EMBL-EBI) ( is shown in figure (5) (McWilliam et al., 2013). Aligning MICA *001 and MICB reference amino acid sequence (MICB *001) using the same ClustalW2 tool yields scores of 83.03% sequence identity (Figure 6). Similarly alignment of MICA*001 and HLA class I consensus amino acid sequence yielded an identity score of 26.47% between (Figure 7).


Note Similar to HLA genes, each allelic variant of MICA is given a distinct name that is officiated by the WHO Nomenclature Committee for Factors of the HLA System. The following are the 100 recognized MICA alleles (according to IMGT Release 3.17.0, 2014-07-14): MICA*001, MICA*002:01, MICA*002:02, MICA*002:03, MICA*002:04, MICA*004, MICA*005, MICA*006, MICA*007:01, MICA*007:02, MICA*007:03, MICA*007:04, MICA*007:05, MICA*007:06, MICA*008:01:01, MICA*008:01:02, MICA*008:02, MICA*008:03, MICA*008:04, MICA*008:05, MICA*009:01, MICA*009:02, MICA*010:01, MICA*010:02, MICA*011, MICA*012:01, MICA*012:02, MICA*012:03, MICA*012:04, MICA*013, MICA*014, MICA*015, MICA*016, MICA*017, MICA*018:01, MICA*018:02, MICA*019, MICA*020, MICA*022, MICA*023, MICA*024, MICA*025, MICA*026, MICA*027, MICA*028, MICA*029, MICA*030, MICA*031, MICA*032, MICA*033, MICA*034, MICA*035, MICA*036, MICA*037, MICA*038, MICA*039, MICA*040, MICA*041, MICA*042, MICA*043, MICA*044, MICA*045, MICA*046, MICA*047, MICA*048, MICA*049, MICA*050, MICA*051, MICA*052, MICA*053, MICA*054, MICA*055, MICA*056, MICA*057, MICA*058, MICA*059, MICA*060, MICA*061, MICA*062, MICA*063N, MICA*064N, MICA*065, MICA*066, MICA*067, MICA*068, MICA*069, MICA*070, MICA*072, MICA*073, MICA*074, MICA*075, MICA*076, MICA*077, MICA*078, MICA*079, MICA*080, MICA*081, MICA*082, MICA*083, MICA*084 (Robinson et al., 2013).

Implicated in

Entity Pregnancy
Note MICA genotypes MICA5.0/5.1 were associated with autoimmune type 1 diabetes with onset during pregnancy (Torn et al., 2004). On the other hand sMIC molecules released from the placenta is considered as a possible immune escape mechanism important for fetal survival (Mincheva-Nilsson et al., 2006). sMIC was also reported as a novel blood biomarker of the chances of a viable baby in infertile women undergoing in vitro fertilization (Porcu-Buisson et al., 2007). Consistent with these reports is the finding of reduced production of sMICA by the aged placenta playing a role in parturition (Huang et al., 2011).
Entity Malignancies
Note MICA 129 M/V dimorphism with variable NKG2D binding affinities has been reported to affect thresholds of NK cell triggering and T cell modulation in malignancies (Douik et al., 2009). In cancer patients, elevated sMICA levels are significantly correlated with cancer stage, differentiation, and metastasis (Holdenrieder et al., 2006). MICA is also expressed in abundance in large granular lymphocyte leukemia cells. Neutrophil counts were inversely correlated with MICA expression and MICA*00801/A5.1 was reported in higher frequency in patients with large granular lymphocyte leukemia (Viny et al., 2010).
Entity Graft versus host disease (GVHD)
Disease GVHD is an immunological disorder that affects many organ systems, including the gastrointestinal tract, liver, skin, and lungs and results from donor-host disparities in major and minor histocompatibility antigens following solid organs and hematopoietic stem cell transplantation (Ferrara et al., 2009; Sharma et al., 2012).
Prognosis GVHD remains a significant hurdle in overcoming the morbidity and mortality associated with hematopoietic stem cell transplantation (Dhir et al., 2014).
Because of its genomic location between MHC Class I and Class II genes, there is strong linkage disequilibrium between many MICA and HLA-B alleles. MICA could also serve as a genetic marker of recombination between MHC classes I and II in otherwise MHC matched individuals where MICA mismatched individuals would be predicted to have mismatched haplotypes whereas the MICA matched pairs may or may not be haplotype matched. This distinction is biologically relevant since MHC haplotype mismatching in otherwise HLA matched donor/recipient pairs was reported in association with a statistically significantly increased risk of severe acute GvHD (Petersdorf et al., 2007). Donor/recipient MICA mismatches were associated with increased risk of severe acute GVHD and were also reported to have a synergistic effect with HLA-DPB1 mismatches on the risk of severe acute GVHD (Askar et al., 2012). MICA-129 genotype, sMICA, and anti-MICA antibodies were reported as biomarkers of chronic GVHD (Boukouaci et al., 2009).
Entity Allograft rejection
Disease MICA mismatch is associated with presence of MICA antibodies in serum of solid organ transplant recipient, which in turn is associated with acute rejection. Anti-MICA sera can bind to endothelial cells from MICA A5.1 donors. Thus, MICA A5.1 can potentially serve as an alloantigen and possibly mediate an alloimmune response. Transplant recipients can also develop donor-specific antibodies to MICA. MICA DSA were associated with decreased graft function.
Prognosis Presensitization of kidney-transplant recipients to MICA antigens was reported in association with an increased frequency of graft loss and was suggested to contribute to allograft loss among recipients who are otherwise well matched for HLA (Zou et al., 2007).
Donor MICA A5.1 mismatch is associated with anti-MICA antibody formation and increased proteinuria in kidney recipients. MICA*001,*004, *007, *009, *012, and *018 are more prevalent in patients with impaired renal function than normal function.
Entity Psoriasis
Disease Psoriasis is a disease of the skin characterized by chronic inflammation leading to scaly plaques.
Prognosis MICA transmembrane (MICA-TM) A9 allele is associated with increased susceptibility to psoriasis in Asian populations (Song et al., 2014).
Entity Psoriatic arthritis
Disease Psoriastic arthritis is a seronegative inflammatory arthritis that develops in a more than 10% of patients with psoriasis. Like other seronegative spondyloarthropathies, psoriastic arthritis is associated with HLA-B27 allele.
Prognosis Psoriastic arthritis tends not to be as serve as rheumatoid arthritis in joint destruction.
MICA-TM A9 allele is associated with a PsA susceptibility in European populations (Amroun H et. al, 2005).
Since MICA is located 46 kb centromeric to the HLA-B gene cluster, its location may explain its association.
Entity Ankylosing spondylitis (AS)
Disease Ankylosing spondylitis is a seronegative spondyloarthropathies associated with HLA-B27 allele. AS is characterized by chronic inflammation of joints typically in the axial skeleton, such as spine and sacroiliac joints, leading to destruction of cartilage and ultimately bony ankylosis causing severe joint immobility. AS is also characterized by extraarticular manifestations including uveitis, aortitis, and amyloidosis.
Prognosis MICA alleles are associated with AS in both HLA-B27-positive and B27-negative AS patients. The MICA*007:01 allele is associated with increased susceptibility to AS in Caucasian and Han Chinese populations. The MICA*019 allele increases the risk for AS in Chinese patients. In a small cohort study of of Algerian patients with AS, MICA-129 allele was associated with an early onset of AS (Tong, 2013).
Entity Systemic lupus erythematosus (SLE)
Prognosis Poor (Susceptibility)
Polymorphisms of MICA TM region have been reported in association with susceptibility to SLE (Yoshida et al., 2011).
Entity Hepatitis B and C
Note There is an association of MICA rs2596542G/A promoter variant and substitutions MICA-129Met/Val, MICA-251Gln/Arg, MICA-175Gly/Ser with HBV-induced hepatocellular carcinoma and HBV persistence (Kumar V, 2012).
Disease Hepatitis B and C are viral infections that can chronically predispose to hepatocellular carcinoma. MICA genetic variations and soluble MICA levels may serve as predictive biomarker for HBV- and HCV-induced HCC. Expression of MICA may be induced by the stress of viral infection and play a role in tumor immune surveillance (Kumar V, 2012).
Prognosis Poor. HBV-induced HCC patients with the high serum level of sMICA have shown to have worse prognosis than those with low serum level of sMICA (?5 pg/ml).5
A single nucleotide polymorphism of MICA rs2596542 located in MICA promotor region is associated with hepatitis C-induced HCC in a Japanese patients and serum levels of soluble MICA (sMICA).


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NF-B regulates MICA gene transcription in endothelial cell through a genetically inhibitable control site
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RSV infection modulates IL-15 production and MICA levels in respiratory epithelial cells
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PMID 15728525
MICA allele-level typing by sequence-based typing with computerized assignment of polymorphic sites and short tandem repeats within the transmembrane region
Zou Y, Han M, Wang Z, Stastny P
Hum Immunol 2006 Mar;67(3):145-51
PMID 16698436
Antibodies against MICA antigens and kidney-transplant rejection
Zou Y, Stastny P, Süsal C, Döhler B, Opelz G
N Engl J Med 2007 Sep 27;357(13):1293-300
PMID 17898098
Differential surface expression of MICA by endothelial cells, fibroblasts, keratinocytes, and monocytes
Zwirner NW, Dole K, Stastny P
Hum Immunol 1999 Apr;60(4):323-30
PMID 10363723


This paper should be referenced as such :
Zain Ahmed, Medhat Askar
MICA (MHC class I polypeptide-related sequence A)
Atlas Genet Cytogenet Oncol Haematol. 2015;19(5):340-348.
Free journal version : [ pdf ]   [ DOI ]

External links

HGNC (Hugo)MICA   7090
Entrez_Gene (NCBI)MICA    MHC class I polypeptide-related sequence A
AliasesMIC-A; PERB11.1
GeneCards (Weizmann)MICA
Ensembl hg19 (Hinxton)ENSG00000204520 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000204520 [Gene_View]  ENSG00000204520 [Sequence]  chr6:31400711-31415315 [Contig_View]  MICA [Vega]
ICGC DataPortalENSG00000204520
Genatlas (Paris)MICA
SOURCE (Princeton)MICA
Genetics Home Reference (NIH)MICA
Genomic and cartography
GoldenPath hg38 (UCSC)MICA  -     chr6:31400711-31415315 +  6p21.33   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)MICA  -     6p21.33   [Description]    (hg19-Feb_2009)
GoldenPathMICA - 6p21.33 [CytoView hg19]  MICA - 6p21.33 [CytoView hg38]
Genome Data Viewer NCBIMICA [Mapview hg19]  
Gene and transcription
Genbank (Entrez)AB506764 AK094237 AK225393 AK299135 AK310028
RefSeq transcript (Entrez)NM_000247 NM_001177519 NM_001289152 NM_001289153 NM_001289154
Consensus coding sequences : CCDS (NCBI)MICA
Gene ExpressionMICA [ NCBI-GEO ]   MICA [ EBI - ARRAY_EXPRESS ]   MICA [ SEEK ]   MICA [ MEM ]
Gene Expression Viewer (FireBrowse)MICA [ Firebrowse - Broad ]
GenevisibleExpression of MICA in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)100507436
GTEX Portal (Tissue expression)MICA
Human Protein AtlasENSG00000204520-MICA [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Conserved Domain (NCBI)MICA
Human Protein Atlas [tissue]ENSG00000204520-MICA [tissue]
Protein Interaction databases
Ontologies - Pathways
PubMed499 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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