CIITA

protein-coding

class II major histocompatibility complex transactivator, the group of NLR family

Gene summary

This gene encodes a protein with an acidic transcriptional activation domain, 4 LRRs (leucine-rich repeats) and a GTP binding domain. The protein is located in the nucleus and acts as a positive regulator of class II major histocompatibility complex gene transcription, and is referred to as the "master control factor" for the expression of these genes. The protein also binds GTP and uses GTP binding to facilitate its own transport into the nucleus. Once in the nucleus it does not bind DNA but rather uses an intrinsic acetyltransferase (AT) activity to act in a coactivator-like fashion. Mutations in this gene have been associated with bare lymphocyte syndrome type II (also known as hereditary MHC class II deficiency or HLA class II-deficient combined immunodeficiency), increased susceptibility to rheumatoid arthritis, multiple sclerosis, and possibly myocardial infarction. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2013]

Previous symbols:

MHC2TA

MANE transcript

NM_000246.4

Inheritance

ClinVar variants

P:106U:617B:761

Top phenotype

MHC class II deficiency 1

gnomAD constraint

pLI —, LoF o/e 0.4

Max pathogenic AF

—

Genomic locus

chr16:10,866,222-10,943,021

External References & Databases

Ensembl (ENSG00000179583)

Transcript & Mutation Effects

hg38 • Region Span ~76.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

MHC class II deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008855

Submitter: Orphanet

MHC class II deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008855

Submitter: Labcorp Genetics (formerly Invitae)

MHC class II deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008855

Submitter: ClinGen

CIITA was first reported in relation to autosomal recessive major histocompatibility complex (MHC) class II deficiency by (Steimle et al., PMID:8402893). MHC class II molecules are essential for the presentation of exogenous peptides to CD4+ helper T cells and thus in the adaptive immune response. Mutations in four trans-acting genes CIITA, RFXANK, RFX5, and RFXAP are responsible for the primary immunodeficiency. 21 total variants, including (nonsense, missense, and splice site) have been reported in 11 probands in 11 publications. Affected individuals typically present in infancy with severe, recurrent infections, failure to thrive, low levels of CD4+ T cells, and undetectable HLA-DR expression on monocytes and B cells. The mechanism of pathogenicity appears to be loss of function. This gene-disease association is supported by experimental evidence including animal models (PMID: 8624807). Mice that are homozygous with loss of function CIITA alleles (-/-) display a lack of MHC class II molecules on B cells and macrophages and low levels of peripheral CD4+ cells. They are also unable to form a proliferative T-cell response following immunization. Further experimental evidence that supports a causative role of CIITA for this disorder includes co-immunoprecipitation (PMID: 10913187), rescue of function in patient and non-patient cells (PMIDs: 8402893, 25940550), expression (PMID:16818750) and biochemical function (PMID: 11332992). In summary, CIITA is definitively associated with autosomal recessive MHC class II deficiency. This has been repeatedly demonstrated in both research and the clinical diagnostic setting and has been upheld over time. Heterozygous carriers of CIITA variants are not clinically reported to have the disease. Classification approved by SCID-CID GCEP on 10/20/2022 (SOP Version 9).

MHC class II deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008855

Submitter: Natera

Clinical Genomic Database (CGD)

MHC class II deficiency 1AR

Manifestation: Allergy/Immunology/Infectious; Gastrointestinal

Intervention: Allergy/Immunology/Infectious

Rationale: Prophylaxis and early and aggressive treatment of infections can be beneficial; BMT has been reported in Bare lymphocyte syndrome, type II

Refs: 8402893; 9099848; 11862382

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CIITA variants in ClinVar

8 Conditions Cataloged

MHC class II deficiencyTotal: 1666

Inborn genetic diseasesTotal: 176

not providedTotal: 110

not specifiedTotal: 100

CIITA-related disorderTotal: 38

Rheumatoid arthritisTotal: 34

MHC class II deficiency 1Total: 32

Hodgkin lymphoma, susceptibility toTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000246.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			25 clinvar	723 clinvar	4 clinvar	752
missense		1 clinvar	588 clinvar	31 clinvar	3 clinvar	623
nonsense	21 clinvar	11 clinvar	1 clinvar			33
start loss			1 clinvar			1
frameshift	31 clinvar	22 clinvar				53
splice donor/acceptor (+/-2bp)		20 clinvar	2 clinvar			22
Total	52	54	617	754	7	1484

Highest pathogenic variant AF is 0.00003531327

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 54 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000246.4	RefSeq	NP_000237.2	19	MANE Select
ENST00000324288.14	Ensembl	ENSP00000316328.8	19	MANE Select
NM_001286402.1	RefSeq	NP_001273331.1	19	Standard
NM_001286403.2	RefSeq	NP_001273332.1	17	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Antigen processing and presentation - Homo sapiens (human)
Primary immunodeficiency - Homo sapiens (human)
Influenza A - Homo sapiens (human)
Tuberculosis - Homo sapiens (human)
Toxoplasmosis - Homo sapiens (human)

Biological Process

negative regulation of transcription by RNA polymerase II
inflammatory response
immune response
phosphorylation
negative regulation of collagen biosynthetic process

Molecular Function

DNA binding
transcription coactivator activity
protein binding
ATP binding
GTP binding

Cellular Component

nucleoplasm
PML body

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000324288
Coding exons: 19
Length: 55025
Individuals with no LoFs: 125700
Homozygous LoFs: 0
Heterozygous LoFs: 48
Defined: 125748
p: 0.000191

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.930	733	665	1.10	0.0000453	7197
Missense (PolyPhen)		134	169.33	0.79137		2055
Synonymous	-3.94	388	301	1.29	0.0000214	2422
Loss of Function	3.97	21	51.9	0.405	0.00000285	559

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00014	0.00014	rare
Ashkenazi Jewish	0.00031	0.00030	rare
East Asian	0.00033	0.00033	rare
Finnish	0.000094	0.000092	rare
European (Non-Finnish)	0.00019	0.00019	rare
South Asian	0.00016	0.00016	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Essential for transcriptional activity of the HLA class II promoter; activation is via the proximal promoter. No DNA binding of in vitro translated CIITA was detected. May act in a coactivator-like fashion through protein-protein interactions by contacting factors binding to the proximal MHC class II promoter, to elements of the transcription machinery, or both. Alternatively it may activate HLA class II transcription by modifying proteins that bind to the MHC class II promoter. Also mediates enhanced MHC class I transcription; the promoter element requirements for CIITA-mediated transcription are distinct from those of constitutive MHC class I transcription, and CIITA can functionally replace TAF1 at these genes. Exhibits intrinsic GTP-stimulated acetyltransferase activity. Exhibits serine/threonine protein kinase activity: can phosphorylate the TFIID component TAF7, the RAP74 subunit of the general transcription factor TFIIF, histone H2B at 'Ser-37' and other histones (in vitro). {ECO:0000269|PubMed:11172716, ECO:0000269|PubMed:16600381, ECO:0000269|PubMed:17493635, ECO:0000269|PubMed:24036077}.;
Disease: DISEASE: Bare lymphocyte syndrome 2 (BLS2) [MIM:209920]: A severe combined immunodeficiency disease with early onset. It is characterized by a profound defect in constitutive and interferon- gamma induced MHC II expression, absence of cellular and humoral T-cell response to antigen challenge, hypogammaglobulinemia and impaired antibody production. The consequence include extreme susceptibility to viral, bacterial and fungal infections. {ECO:0000269|PubMed:10501838, ECO:0000269|PubMed:11466404, ECO:0000269|PubMed:11862382, ECO:0000269|PubMed:7749984, ECO:0000269|PubMed:8402893}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.515

Intolerance Scores

LoFtool: 0.480
RVIS EVS: -0.89
RVIS percentile EVS: 10.19

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.945

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium