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Bruton's agammaglobulinemia

Written2001-01Niels B Atkin
Department of Cancer Research, Mount Vernon Hospital, Northwood, Middlesex, UK

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Identity

Other namesX-linked agammaglobulinemia (XLA)
Atlas_Id 10023
Genes implicated inBTK  
Inheritance X-linked disorder occurring in males; frequency of XLA is about 0.3-0.6/105.

Clinics

Phenotype and clinics immunological deficiency, first described in 1952, manifest from late infancy and typically resulting in frequent bacterial infections commencing in the second half of the first year of life: tonsils and lymph nodes are very small; marked decrease of serum immunoglobulins of all isotypes (maternal IgG gives some protection in early infancy)
Neoplastic risk probably slight; in a 1963 paper, two patients with lymphoma were reported and reference was made to two adults with hypoglobulinemia who also had lymphomas; recent surveys of XLA patients do not reveal any cases of lymphoma; however, long-term vigilance needs to be maintained; at least seven cases of adenocarcinoma of the gastrointestinal tract in young adults with XLA have been reported; other malignancies have also been reported, but it is not clear whether they occur with an increased frequency
Treatment vigorous antibiotic therapy and regular injections of immunoglobulin
Prognosis good, on survival into early adulthood

Other findings

Note absence of plasma cells in bone marrow and lymph nodes (the latter lack germinal centres) resulting in an almost complete lack of humoral immunity due to a failure of early B-lymphocyte development; normal myeloid and T-cell function: extremely deficient production of antibodies to all antigens

Genes involved and Proteins

Gene NameBTK (Bruton agammaglobulinemia tyrosine kinase)
Location Xq22.1
DNA/RNA
Description encoded in 19 exons spanning 37 kb
Protein
Description Btk is a 659 amino-acid cytoplasmic tyrosine kinase
Expression is expressed at all except the terminally differentiated plasma cell stage of B-cell development
Function it is a member of a small family of src-related hematopoietic kinases and, like them, has several interaction domains that allow it to bind to other components of signal-transduction pathways; unlike other src family members, Btk family members have a pleckstrin homology (PH) domain which is followed by a proline rich region that binds to the SH3 region of several src family members
Mutations
Germinal over 300 different mutations in Btk have been identified; only about 50% of patients with the clinical and laboratory findings of XLA have a family history of immunodeficiency; most of the remaining patients are the first manifestation of a new mutation in Btk; most mutations are single base-pair substitutions that result in premature stop codons, splice defects, or amino-acid substitutions. 5-10% of patients with XLA have gross alterations in the BTK gene (usually deletions) detectable by Southern-blot analysis; most amino-acid substitutions in Btk render the protein unstable and markedly reduced or absent

Bibliography

Agammaglobulinemia.
BRUTON OC
Pediatrics. 1952 ; 9 (6) : 722-728.
PMID 14929630
 
X-linked agammaglobulinemia.
Conley ME, Rohrer J, Minegishi Y
Clinical reviews in allergy & immunology. 2000 ; 19 (2) : 183-204.
PMID 11107501
 
The immunological deficiency diseases of man: consideration of some questions asked by these patients with an attempt at classification.
Good RA, Peterson RDA, Perey DY, Finstad J, Cooper MD
Birth Defects Original Article Series. 1968 ; 4 : 17-39.
 
Identification of Bruton's tyrosine kinase (Btk) gene mutations and characterization of the derived proteins in 35 X-linked agammaglobulinemia families: a nationwide study of Btk deficiency in Japan.
Hashimoto S, Tsukada S, Matsushita M, Miyawaki T, Niida Y, Yachie A, Kobayashi S, Iwata T, Hayakawa H, Matsuoka H, Tsuge I, Yamadori T, Kunikata T, Arai S, Yoshizaki K, Taniguchi N, Kishimoto T
Blood. 1996 ; 88 (2) : 561-573.
PMID 8695804
 
Occurrence of leukemia and lymphoma in patients with agammaglobulinemia.
PAGE AR, HANSEN AE, GOOD RA
Blood. 1963 ; 21 : 197-206.
PMID 13941046
 
Activation of BTK by a phosphorylation mechanism initiated by SRC family kinases.
Rawlings DJ, Scharenberg AM, Park H, Wahl MI, Lin S, Kato RM, Fluckiger AC, Witte ON, Kinet JP
Science (New York, N.Y.). 1996 ; 271 (5250) : 822-825.
PMID 8629002
 
Symposium on gene abnormalities in medical diseases. 1. Immunological diseases: Bruton's agammaglobulinemia.
Tsukada S
Internal medicine (Tokyo, Japan). 1997 ; 36 (2) : 148-150.
PMID 9099606
 

Citation

This paper should be referenced as such :
Atkin, NB
Bruton's agammaglobulinemia
Atlas Genet Cytogenet Oncol Haematol. 2001;5(2):139-140.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Tumors/BrutonAgammaID10023.html


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