X-linked agammaglobulinemia: lack of mature B lineage cells caused by mutations in the Btk kinase

C. I. Edvard Smith l, z, 3, Carl-Magnus B~ickesj61, 2, Anna Bergl6f 1, 2, Lars J. Brand6n l, 2, Tahmina Islam 1, z, Pekka I'. Mattsson l, 4, Abdalla J. Mohamed 1, z, Susanne Miiller 1, z, Beston Nore 1, 2 Mauno Vihinen 5 Center for BioTechnology, Department of Biosciences at Novum, Karolinska Institute, S-141 57 Huddinge, Sweden 2 Department of Immunology, Microbiology, Pathology and Infectious diseases (IMPI), Huddinge Hospital, Huddinge, Sweden 3 Gene Therapy Center, Clinical Research Center, Huddinge Hospital, S-141 57 Huddinge, Sweden 4 Department of Biochemistry and Food Chemistry, University of Turku, FIN-20014 Turku, Finland Department of Biosciences, Division of Biochemistry, PO Box 56, FIN-00014, Helsinki, Finland Brief introduction In 1946 a boy suffering from recurrent infections was observed. He was later described as having X-linked agammaglobulinemia (XLA), the first primary immunodeficiency in which a molecular defect was identified [12]. In this initial description gammaglob- ulin was reported as undetectable in serum from the affected child using the available technology, hence the name agammaglobulinemia. With the development of more sen- sitive techniques, immunoglobulins became identifiable in patients with XLA, albeit at low levels. However, humoral immune responses are virtually absent, resulting in a propensity for pyogenic bacterial infections, which is the hallmark of primary immu- noglobulin deficiencies. Almost two decades after the original description, the cellular abnormality was recognized by several investigators as a lack of cells carrying surface immunoglobulins, considerably increasing the scientific interest in the underlying de- fect [17, 25, 31, 60, 86]. The differentiation block was later shown to be manifested as early as at the pro-B to Pre-B transition stage, but more dramatically after the Pre-B cell stage [13, 37]. Using different molecular strategies, unrelated to the XLA pheno- type, the defective gene was independently cloned and demonstrated to encode a novel cytoplasmic protein tyrosine kinase (PTK) involved in intracellular signalling [94, 96]. The identification of the disease gene allows mutation detection and a large number of different mutations have been found and collected into a database, BTKbase [47, 88, 100, 102-104, 106]. Correspondence to: C. I. E. Smith