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Different molecular behavior of CD40 mutants causing hyper-IgM syndrome.

Lanzi, Gaetana; Ferrari, Simona; Vihinen, Mauno LU ; Caraffi, Stefano; Kutukculer, Necil; Schiaffonati, Luisa; Plebani, Alessandro; Notarangelo, Luigi Daniele; Fra, Anna Maria and Giliani, Silvia (2010) In Blood 116(26). p.5867-5874
Abstract
CD40/CD40 ligand (CD40L) cross-talk plays a key role in B-cell terminal maturation in the germinal centers. Genetic defects affecting CD40 cause a rare form of hyper-immunoglobulin M (IgM) syndrome, a disorder characterized by low or absent serum IgG and IgA, associated with recurrent infections. We previously reported on a few patients with homozygous CD40 mutations resulting in lack or severe reduction of CD40 cell surface expression. Here we characterize the 3 CD40 mutants due to missense mutations or small in-frame deletions, and show that the mutated proteins are synthesized but retained in the endoplasmic reticulum (ER), likely due to protein misfolding. Interestingly, the intracellular behavior and fate differ significantly among... (More)
CD40/CD40 ligand (CD40L) cross-talk plays a key role in B-cell terminal maturation in the germinal centers. Genetic defects affecting CD40 cause a rare form of hyper-immunoglobulin M (IgM) syndrome, a disorder characterized by low or absent serum IgG and IgA, associated with recurrent infections. We previously reported on a few patients with homozygous CD40 mutations resulting in lack or severe reduction of CD40 cell surface expression. Here we characterize the 3 CD40 mutants due to missense mutations or small in-frame deletions, and show that the mutated proteins are synthesized but retained in the endoplasmic reticulum (ER), likely due to protein misfolding. Interestingly, the intracellular behavior and fate differ significantly among the mutants: progressive accumulation of the P2 mutant causes endoplasmic reticulum stress and the activation of an unfolded protein response; the mutant P4 is rather efficiently disposed by the ER-associated degradation pathway, while the P5 mutant partially negotiates transport to the plasma membrane, and is competent for CD40L binding. Interestingly, this latter mutant activates downstream signaling elements when overexpressed in transfected cells. These results give new important insights into the molecular pathogenesis of HIGM disease, and suggest that CD40 deficiency can also be regarded as an ER-storage disease. (Less)
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Contribution to journal
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published
subject
keywords
Mutant Proteins: chemistry, Kidney: metabolism, Kidney: cytology, Hyper-IgM Immunodeficiency Syndrome: immunology, Hyper-IgM Immunodeficiency Syndrome: genetics, Frameshift Mutation: genetics, Endoplasmic Reticulum: metabolism, Cell Membrane: metabolism, B-Lymphocytes: metabolism, CD40: metabolism, CD40: chemistry, CD40: genetics, Antigens, Mutant Proteins: genetics, Mutant Proteins: metabolism, Mutation, Missense: genetics, RNA, Messenger: genetics
in
Blood
volume
116
issue
26
pages
5867 - 5874
publisher
American Society of Hematology
external identifiers
  • pmid:20702779
  • scopus:78650664671
ISSN
1528-0020
DOI
10.1182/blood-2010-03-274241
language
English
LU publication?
no
id
22053250-53b7-4260-8eb6-abff57b53397 (old id 3634716)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/20702779?dopt=Abstract
date added to LUP
2013-06-12 20:41:16
date last changed
2018-05-29 12:20:45
@article{22053250-53b7-4260-8eb6-abff57b53397,
  abstract     = {CD40/CD40 ligand (CD40L) cross-talk plays a key role in B-cell terminal maturation in the germinal centers. Genetic defects affecting CD40 cause a rare form of hyper-immunoglobulin M (IgM) syndrome, a disorder characterized by low or absent serum IgG and IgA, associated with recurrent infections. We previously reported on a few patients with homozygous CD40 mutations resulting in lack or severe reduction of CD40 cell surface expression. Here we characterize the 3 CD40 mutants due to missense mutations or small in-frame deletions, and show that the mutated proteins are synthesized but retained in the endoplasmic reticulum (ER), likely due to protein misfolding. Interestingly, the intracellular behavior and fate differ significantly among the mutants: progressive accumulation of the P2 mutant causes endoplasmic reticulum stress and the activation of an unfolded protein response; the mutant P4 is rather efficiently disposed by the ER-associated degradation pathway, while the P5 mutant partially negotiates transport to the plasma membrane, and is competent for CD40L binding. Interestingly, this latter mutant activates downstream signaling elements when overexpressed in transfected cells. These results give new important insights into the molecular pathogenesis of HIGM disease, and suggest that CD40 deficiency can also be regarded as an ER-storage disease.},
  author       = {Lanzi, Gaetana and Ferrari, Simona and Vihinen, Mauno and Caraffi, Stefano and Kutukculer, Necil and Schiaffonati, Luisa and Plebani, Alessandro and Notarangelo, Luigi Daniele and Fra, Anna Maria and Giliani, Silvia},
  issn         = {1528-0020},
  keyword      = {Mutant Proteins: chemistry,Kidney: metabolism,Kidney: cytology,Hyper-IgM Immunodeficiency Syndrome: immunology,Hyper-IgM Immunodeficiency Syndrome: genetics,Frameshift Mutation: genetics,Endoplasmic Reticulum: metabolism,Cell Membrane: metabolism,B-Lymphocytes: metabolism,CD40: metabolism,CD40: chemistry,CD40: genetics,Antigens,Mutant Proteins: genetics,Mutant Proteins: metabolism,Mutation,Missense: genetics,RNA,Messenger: genetics},
  language     = {eng},
  number       = {26},
  pages        = {5867--5874},
  publisher    = {American Society of Hematology},
  series       = {Blood},
  title        = {Different molecular behavior of CD40 mutants causing hyper-IgM syndrome.},
  url          = {http://dx.doi.org/10.1182/blood-2010-03-274241},
  volume       = {116},
  year         = {2010},
}