Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 90, Issue 6, Pages 986-1001Publisher
CELL PRESS
DOI: 10.1016/j.ajhg.2012.04.015
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Funding
- German Federal Ministry of Education and Research [BMBF 01 EO 0803]
- European Community [HEALTH-F2-2008-201549, Health-F5-2008-223292]
- Marie Curie Excellence Grant [MEXT-CT-2006-042316]
- European Research Council [24511-ImmunoSwitch]
- Swedish Research Council
- Swedish Cancer Society
- Glaxo-Smith-Kline
- Fondazione C. Golgi, Brescia
- Associazione Italiana Immunodeficienze Primitive
- National Institutes of Health, National Library of Medicine, USA
- CONACyT, Mexico [93910]
- Leukaemia and Lymphoma Research UK
- Medical Research Council
- National Institute for Health Research Biomedical Research Centre, Oxford, UK
- BBSRC [BB/G021422/1] Funding Source: UKRI
- MRC [G0900950] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/G021422/1] Funding Source: researchfish
- Medical Research Council [G0900950B, G0900950] Funding Source: researchfish
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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.
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