RGD Reference Report - Mutation in the class II trans-activator leading to a mild immunodeficiency. - Rat Genome Database

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Mutation in the class II trans-activator leading to a mild immunodeficiency.

Authors: Wiszniewski, W  Fondaneche, MC  Le Deist, F  Kanariou, M  Selz, F  Brousse, N  Steimle, V  Barbieri, G  Alcaide-Loridan, C  Charron, D  Fischer, A  Lisowska-Grospierre, B 
Citation: Wiszniewski W, etal., J Immunol. 2001 Aug 1;167(3):1787-94.
RGD ID: 5491200
Pubmed: PMID:11466404   (View Abstract at PubMed)

The expression of MHC class II molecules is essential for all Ag-dependent immune functions and is regulated at the transcriptional level. Four trans-acting proteins control the coordinate expression of MHC class II molecules: class II trans-activator (CIITA), regulatory factor binding to the X box (RFX)-associated protein; RFX protein containing ankyrin repeats, and RFX5. In humans, defects in these genes result in MHC class II expression deficiency and cause combined immunodeficiency. Most patients with this deficiency suffer from severe recurrent infections that frequently lead to death during early childhood. We investigated three sisters, now ages 21, 22, and 24 years, in whom MHC-II deficiency was detected. Even though the eldest sibling was asymptomatic and the other two had only mild immunodeficiency, none of the three class II isotypes was expressed on T cell blasts, fibroblasts, EBV B cell lines, or epidermal dendritic cells. Residual HLA-II expression was detected in fresh PBMC. Somatic complementation identified the disease as CIITA deficiency. A homozygous T1524C (L469P) substitution was found in the coding region of the CIITA cDNA and was shown to be responsible for the defect in MHC-II expression. This missense mutation prevents the normal functioning of MHC-II but does not lead to the nuclear exclusion of the L469P CIITA. Transfection experiments demonstrated that the CIITA L469P mutant had residual MHC class II trans activation activity, which might explain the unusual clinical course of the patients studied. This study shows that an attenuated clinical phenotype or an asymptomatic clinical course can be observed in patients despite a profound defect in the expression of MHC class II genes. The frequency of the inherited MHC class II deficiency might thus be underestimated.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
MHC class II deficiency severityIAGP 5491200DNA:mutation:CDS:c.1524T>C and p.L469P associated with mild or asymptomatic disease despite absence of MHC-II expression on immune cellsRGD 
MHC class II deficiency severityISOCIITA (Homo sapiens)5491200; 5491200DNA:mutation:CDS:c.1524T>C and p.L469P associated with mild or asymptomatic disease despite absence of MHC-II expression on immune cells (human)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Ciita  (class II, major histocompatibility complex, transactivator)

Genes (Mus musculus)
Ciita  (class II transactivator)

Genes (Homo sapiens)
CIITA  (class II major histocompatibility complex transactivator)


Additional Information