RGD Reference Report - Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations. - Rat Genome Database

Send us a Message
Submit Data |  Help |  Video Tutorials |  News |  Publications |  Download |  REST API |  Citing RGD |  Contact   
Search RGD Grant Resources Citing RGD About Us Contact Us
Genes Variants Community Projects QTLs Strains Markers Genome Information Ontologies Cell Lines References Download Submit Data
OntoMate (Literature Search) JBrowse (Genome Browser) Synteny Browser (VCMap) Variant Visualizer Multi-Ontology Enrichment (MOET) Gene-Ortholog Location Finder (GOLF) InterViewer (Protein-Protein Interactions) PhenoMiner (Quatitative Phenotypes) Gene Annotator OLGA (Gene List Generator) AllianceMine GViewer (Genome Viewer)
Aging & Age-Related Disease Cancer & Neoplastic Disease Cardiovascular Disease Coronavirus Disease Developmental Disease Diabetes Hematologic Disease Immune & Inflammatory Disease Infectious Disease Liver Disease Neurological Disease Obesity & Metabolic Syndrome Renal Disease Respiratory Disease Sensory Organ Disease
Find Models   new Genetic Models Autism Models Rat PhenoMiner (Quantitative Phenotypes) Chinchilla PhenoMiner Expected Ranges (Quantitative Phenotype) PhenoMiner Term Comparison Hybrid Rat Diversity Panel Phenotypes Phenotypes in Other Animal Models Animal Husbandry Strain Medical Records Phylogenetics Strain Availability Calendar Rats 101 Submissions Photo Archive
Pathways
Rat Community Forum Directory of Rat Laboratories Video Tutorials News RGD Publications RGD Presentations Archive Nomenclature Guidelines Resource Links Laboratory Resources Employment Resources

Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations.

Authors: Schubert, D  Bode, C  Kenefeck, R  Hou, TZ  Wing, JB  Kennedy, A  Bulashevska, A  Petersen, BS  Schaffer, AA  Gruning, BA  Unger, S  Frede, N  Baumann, U  Witte, T  Schmidt, RE  Dueckers, G  Niehues, T  Seneviratne, S  Kanariou, M  Speckmann, C  Ehl, S  Rensing-Ehl, A  Warnatz, K  Rakhmanov, M  Thimme, R  Hasselblatt, P  Emmerich, F  Cathomen, T  Backofen, R  Fisch, P  Seidl, M  May, A  Schmitt-Graeff, A  Ikemizu, S  Salzer, U  Franke, A  Sakaguchi, S  Walker, LS  Sansom, DM  Grimbacher, B 
Citation: Schubert D, etal., Nat Med. 2014 Dec;20(12):1410-6. doi: 10.1038/nm.3746. Epub 2014 Oct 20.
RGD ID: 11053601
Pubmed: PMID:25329329   (View Abstract at PubMed)
PMCID: PMC4668597   (View Article at PubMed Central)
DOI: DOI:10.1038/nm.3746   (Journal Full-text)

The protein cytotoxic T lymphocyte antigen-4 (CTLA-4) is an essential negative regulator of immune responses, and its loss causes fatal autoimmunity in mice. We studied a large family in which five individuals presented with a complex, autosomal dominant immune dysregulation syndrome characterized by hypogammaglobulinemia, recurrent infections and multiple autoimmune clinical features. We identified a heterozygous nonsense mutation in exon 1 of CTLA4. Screening of 71 unrelated patients with comparable clinical phenotypes identified five additional families (nine individuals) with previously undescribed splice site and missense mutations in CTLA4. Clinical penetrance was incomplete (eight adults of a total of 19 genetically proven CTLA4 mutation carriers were considered unaffected). However, CTLA-4 protein expression was decreased in regulatory T cells (Treg cells) in both patients and carriers with CTLA4 mutations. Whereas Treg cells were generally present at elevated numbers in these individuals, their suppressive function, CTLA-4 ligand binding and transendocytosis of CD80 were impaired. Mutations in CTLA4 were also associated with decreased circulating B cell numbers. Taken together, mutations in CTLA4 resulting in CTLA-4 haploinsufficiency or impaired ligand binding result in disrupted T and B cell homeostasis and a complex immune dysregulation syndrome.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
primary immunodeficiency disease  IAGP 11053601DNA:splice site more ...RGD 
primary immunodeficiency disease  ISOCTLA4 (Homo sapiens)11053601; 11053601DNA:splice site more ...RGD 

Phenotype Annotations    Click to see Annotation Detail View

Manual Human Phenotype Annotations - RGD

TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Abnormal T cell count  IAGP 11053601DNA:splice site more ...RGD 
Decreased circulating antibody level  IAGP 11053601DNA:splice site more ...RGD 
Decreased proportion of immature B cells  IAGP 11053601DNA:splice site more ...RGD 
Hepatosplenomegaly  IAGP 11053601associated with Immunologic Deficiency Syndromes more ...RGD 
Impaired T cell function  IAGP 11053601DNA:splice site more ...RGD 
Lymphadenopathy  IAGP 11053601associated withImmunologic Deficiency Syndromes more ...RGD 
Objects Annotated

Genes (Rattus norvegicus)
Ctla4  (cytotoxic T-lymphocyte-associated protein 4)

Genes (Mus musculus)
Ctla4  (cytotoxic T-lymphocyte-associated protein 4)

Genes (Homo sapiens)
CTLA4  (cytotoxic T-lymphocyte associated protein 4)


Additional Information