KEGG   DISEASE: Agammaglobulinemias
Entry
H00085                      Disease                                
Name
Agammaglobulinemias
  Subgroup
Agammaglobulinaemia, X-linked (AGMX)
  Supergrp
Disorders of adaptive immunity [DS:H02526]
Primary immunodeficiency disease [DS:H01725]
Description
There are three major categories of antibody deficiencies: (a) defects in early B cell development, (b) hyper-IgM syndromes (also called class switch recombination defects), and (c) common variable immunodeficiency (CVID). Category (a) consists of agammaglobulinaemias (AGM). Defects in early B cell development are characterized by the onset of recurrent bacterial infections in the first 5 years of life, profound hypogammaglobulinemia, markedly reduced or absent B cells in the peripheral circulation, and (in the bone marrow) a severe block in B cell differentiation before the production of surface immunoglobulin-positive B cells. Mutations in Btk, the gene responsible for X-linked agammaglobulinemia (XLA), account for approximately 85% of affected patients. Approximately half of the remaining patients have mutations in genes encoding components of the pre-B cell receptor (pre-BCR) or BCR, including mu heavy chain (IGHM); the signal transduction molecules Ig-alpha (CD79A) and Ig-beta (CD79B); and lambda 5 (IGLL1), which forms the surrogate light chain with Vpre-B. A small number of patients with defects in BLNK, a scaffold protein that assembles signal transduction molecules activated by cross-linking of the BCR, have been reported.
Category
Immune system disease
Brite
Human diseases [BR:br08402]
 Immune system diseases
  Primary immunodeficiency
   H00085  Agammaglobulinemias
Human diseases in ICD-11 classification [BR:br08403]
 04 Diseases of the immune system
  Primary immunodeficiencies
   4A01  Primary immunodeficiencies due to disorders of adaptive immunity
    H00085  Agammaglobulinemias
Pathway
hsa04662  B cell receptor signaling pathway
Gene
(AGMX1) BTK [HSA:695] [KO:K07370]
(AGMX2) SH3KBP1 [HSA:30011] [KO:K12470]
(AGM2) IGLL1 [HSA:3543] [KO:K06554]
(AGM3) CD79A [HSA:973] [KO:K06506]
(AGM4) BLNK [HSA:29760] [KO:K07371]
(AGM5) LRRC8A [HSA:56262] [KO:K22038]
(AGM6) CD79B [HSA:974] [KO:K06507]
(AGM7) PIK3R1 [HSA:5295] [KO:K02649]
(AGM8) TCF3 [HSA:6929] [KO:K09063]
(AGM9) SLC39A7 [HSA:7922] [KO:K14713]
(AGM10) SPI1 [HSA:6688] [KO:K09438]
Comment
AGM1 is caused by homozygous or compound heterozygous mutation in the mu heavy-chain gene (IGHM).
Other DBs
ICD-11: 4A01.00
ICD-10: D80
MeSH: D000361
OMIM: 300755 300310 601495 613500 613501 613502 613506 612692 615214 616941 619693 619707
Reference
  Authors
Conley ME, Dobbs AK, Farmer DM, Kilic S, Paris K, Grigoriadou S, Coustan-Smith E, Howard V, Campana D
  Title
Primary B cell immunodeficiencies: comparisons and contrasts.
  Journal
Annu Rev Immunol 27:199-227 (2009)
DOI:10.1146/annurev.immunol.021908.132649
Reference
  Authors
Morra M, Geigenmuller U, Curran J, Rainville IR, Brennan T, Curtis J, Reichert V, Hovhannisyan H, Majzoub J, Miller DT.
  Title
Genetic diagnosis of primary immune deficiencies.
  Journal
Immunol Allergy Clin North Am 28:387-412, x (2008)
DOI:10.1016/j.iac.2008.01.004
Reference
PMID:32552675 (AGMX1)
  Authors
Gao S, Hu S, Duan H, Wang L, Kong X
  Title
Clinical characteristics and prenatal diagnosis for 22 families in Henan Province of China with X-linked agammaglobulinemia (XLA) related to Bruton's tyrosine kinase (BTK) gene mutations.
  Journal
BMC Med Genet 21:131 (2020)
DOI:10.1186/s12881-020-01063-5
Reference
PMID:29636373 (AGMX2)
  Authors
Keller B, Shoukier M, Schulz K, Bhatt A, Heine I, Strohmeier V, Speckmann C, Engels N, Warnatz K, Wienands J
  Title
Germline deletion of CIN85 in humans with X chromosome-linked antibody deficiency.
  Journal
J Exp Med 215:1327-1336 (2018)
DOI:10.1084/jem.20170534
Reference
PMID:8890099 (AGM1)
  Authors
Yel L, Minegishi Y, Coustan-Smith E, Buckley RH, Trubel H, Pachman LM, Kitchingman GR, Campana D, Rohrer J, Conley ME
  Title
Mutations in the mu heavy-chain gene in patients with agammaglobulinemia.
  Journal
N Engl J Med 335:1486-93 (1996)
DOI:10.1056/NEJM199611143352003
Reference
PMID:9419212 (AGM2)
  Authors
Minegishi Y, Coustan-Smith E, Wang YH, Cooper MD, Campana D, Conley ME
  Title
Mutations in the human lambda5/14.1 gene result in B cell deficiency and agammaglobulinemia.
  Journal
J Exp Med 187:71-7 (1998)
DOI:10.1084/jem.187.1.71
Reference
PMID:10525050 (AGM3)
  Authors
Minegishi Y, Coustan-Smith E, Rapalus L, Ersoy F, Campana D, Conley ME
  Title
Mutations in Igalpha (CD79a) result in a complete block in B-cell development.
  Journal
J Clin Invest 104:1115-21 (1999)
DOI:10.1172/JCI7696
Reference
PMID:24582315 (AGM4)
  Authors
Lagresle-Peyrou C, Millili M, Luce S, Boned A, Sadek H, Rouiller J, Frange P, Cros G, Cavazzana M, Andre-Schmutz I, Schiff C
  Title
The BLNK adaptor protein has a nonredundant role in human B-cell differentiation.
  Journal
J Allergy Clin Immunol 134:145-54 (2014)
DOI:10.1016/j.jaci.2013.12.1083
Reference
PMID:14660746 (AGM5)
  Authors
Sawada A, Takihara Y, Kim JY, Matsuda-Hashii Y, Tokimasa S, Fujisaki H, Kubota K, Endo H, Onodera T, Ohta H, Ozono K, Hara J
  Title
A congenital mutation of the novel gene LRRC8 causes agammaglobulinemia in humans.
  Journal
J Clin Invest 112:1707-13 (2003)
DOI:10.1172/JCI18937
Reference
PMID:17675462 (AGM6)
  Authors
Dobbs AK, Yang T, Farmer D, Kager L, Parolini O, Conley ME
  Title
Cutting edge: a hypomorphic mutation in Igbeta (CD79b) in a patient with immunodeficiency and a leaky defect in B cell development.
  Journal
J Immunol 179:2055-9 (2007)
DOI:10.4049/jimmunol.179.4.2055
Reference
PMID:22351933 (AGM7)
  Authors
Conley ME, Dobbs AK, Quintana AM, Bosompem A, Wang YD, Coustan-Smith E, Smith AM, Perez EE, Murray PJ
  Title
Agammaglobulinemia and absent B lineage cells in a patient lacking the p85alpha subunit of PI3K.
  Journal
J Exp Med 209:463-70 (2012)
DOI:10.1084/jem.20112533
Reference
PMID:24216514 (AGM8)
  Authors
Boisson B, Wang YD, Bosompem A, Ma CS, Lim A, Kochetkov T, Tangye SG, Casanova JL, Conley ME
  Title
A recurrent dominant negative E47 mutation causes agammaglobulinemia and BCR(-) B cells.
  Journal
J Clin Invest 123:4781-5 (2013)
DOI:10.1172/JCI71927
Reference
PMID:30718914 (AGM9)
  Authors
Anzilotti C, Swan DJ, Boisson B, Deobagkar-Lele M, Oliveira C, Chabosseau P, Engelhardt KR, Xu X, Chen R, Alvarez L, Berlinguer-Palmini R, Bull KR, Cawthorne E, Cribbs AP, Crockford TL, Dang TS, Fearn A, Fenech EJ, de Jong SJ, Lagerholm BC, Ma CS, Sims D, van den Berg B, Xu Y, Cant AJ, Kleiner G, Leahy TR, de la Morena MT, Puck JM, Shapiro RS, van der Burg M, Chapman JR, Christianson JC, Davies B, McGrath JA, Przyborski S, Santibanez Koref M, Tangye SG, Werner A, Rutter GA, Padilla-Parra S, Casanova JL, Cornall RJ, Conley ME, Hambleton S
  Title
An essential role for the Zn(2+) transporter ZIP7 in B cell development.
  Journal
Nat Immunol 20:350-361 (2019)
DOI:10.1038/s41590-018-0295-8
Reference
PMID:33951726 (AGM10)
  Authors
Le Coz C, Nguyen DN, Su C, Nolan BE, Albrecht AV, Xhani S, Sun D, Demaree B, Pillarisetti P, Khanna C, Wright F, Chen PA, Yoon S, Stiegler AL, Maurer K, Garifallou JP, Rymaszewski A, Kroft SH, Olson TS, Seif AE, Wertheim G, Grant SFA, Vo LT, Puck JM, Sullivan KE, Routes JM, Zakharova V, Shcherbina A, Mukhina A, Rudy NL, Hurst ACE, Atkinson TP, Boggon TJ, Hakonarson H, Abate AR, Hajjar J, Nicholas SK, Lupski JR, Verbsky J, Chinn IK, Gonzalez MV, Wells AD, Marson A, Poon GMK, Romberg N
  Title
Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients.
  Journal
J Exp Med 218:e20201750 (2021)
DOI:10.1084/jem.20201750
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