CIITA

Chr 16AR

class II major histocompatibility complex transactivator

Also known as: C2TA, CIITAIV, MHC2D1, MHC2TA, NLRA

NCBI Gene: 4261 ENSG00000179583 UniProt: P33076 OMIM: 600005

The CIITA protein functions as the master transcriptional regulator of MHC class II genes, essential for their expression, and exhibits acetyltransferase activity to activate transcription without directly binding DNA. Mutations cause MHC class II deficiency, a severe combined immunodeficiency presenting in early childhood with recurrent infections due to impaired T cell and antigen presentation function. This condition follows autosomal recessive inheritance, and the gene is highly constrained against loss-of-function variants.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 0.582 OMIM phenotypes

Clinical Summary— CIITA

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Gene-Disease Validity (ClinGen)

MHC class II deficiency · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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Clinical Trials

3 active or recruiting trials — potential therapeutic options may be available

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.58LOEUF

pLI 0.000

Z-score 3.97

OE 0.40 (0.29–0.58)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

-0.93Z-score

OE missense 1.10 (1.04–1.17)

733 obs / 665.5 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.40 (0.29–0.58)

0≤0.351.4

Missense OE?1.10 (1.04–1.17)

0≤0.61.4

Synonymous OE?1.29

0≤1.21.6

LoF obs/exp: 21 / 51.9Missense obs/exp: 733 / 665.5Syn Z: -3.94

This gene — mechanism propensity

0.6841th %ile

GOF

0.6444th %ile

LOF

0.2581th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.