Lopez-Herrera, G;
Tampella, G;
Pan-Hammarström, Q;
Herholz, P;
Trujillo-Vargas, CM;
Phadwal, K;
Simon, AK;
... Grimbacher, B; + view all
(2012)
Deleterious mutations in LRBA are associated with a syndrome of immune deficiency and autoimmunity.
The American Journal of Human Genetics
, 90
(6)
986 - 1001.
10.1016/j.ajhg.2012.04.015.
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Abstract
Most autosomal genetic causes of childhood-onset hypogammaglobulinemia are currently not well understood. Most affected individuals are simplex cases, but both autosomal-dominant and autosomal-recessive inheritance have been described. We performed genetic linkage analysis in consanguineous families affected by hypogammaglobulinemia. Four consanguineous families with childhood-onset humoral immune deficiency and features of autoimmunity shared genotype evidence for a linkage interval on chromosome 4q. Sequencing of positional candidate genes revealed that in each family, affected individuals had a distinct homozygous mutation in LRBA (lipopolysaccharide responsive beige-like anchor protein). All LRBA mutations segregated with the disease because homozygous individuals showed hypogammaglobulinemia and autoimmunity, whereas heterozygous individuals were healthy. These mutations were absent in healthy controls. Individuals with homozygous LRBA mutations had no LRBA, had disturbed B cell development, defective in vitro B cell activation, plasmablast formation, and immunoglobulin secretion, and had low proliferative responses. We conclude that mutations in LRBA cause an immune deficiency characterized by defects in B cell activation and autophagy and by susceptibility to apoptosis, all of which are associated with a clinical phenotype of hypogammaglobulinemia and autoimmunity.
| Type: | Article |
|---|---|
| Title: | Deleterious mutations in LRBA are associated with a syndrome of immune deficiency and autoimmunity. |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.ajhg.2012.04.015 |
| Publisher version: | http://dx.doi.org/10.1016/j.ajhg.2012.04.015 |
| Language: | English |
| Additional information: | This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. PMCID: PMC3370280 |
| Keywords: | Adaptor Proteins, Signal Transducing, Agammaglobulinemia, Apoptosis, Autoimmunity, Autophagy, B-Lymphocytes, Cell Proliferation, Child, Child, Preschool, Chromosome Mapping, Female, Genetic Linkage, Genotype, Homozygote, Humans, Immunologic Deficiency Syndromes, Immunophenotyping, Male, Microscopy, Electron, Transmission, Models, Genetic, Mutation, Pedigree, Phenotype |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1363947 |
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