PMID- 24297891
OWN - NLM
STAT- MEDLINE
DCOM- 20140224
LR  - 20220317
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 110
IP  - 51
DP  - 2013 Dec 17
TI  - MuSK IgG4 autoantibodies cause myasthenia gravis by inhibiting binding between 
      MuSK and Lrp4.
PG  - 20783-8
LID - 10.1073/pnas.1313944110 [doi]
AB  - Myasthenia gravis (MG) is a severely debilitating autoimmune disease that is due 
      to a decrease in the efficiency of synaptic transmission at neuromuscular 
      synapses. MG is caused by antibodies against postsynaptic proteins, including (i) 
      acetylcholine receptors, the neurotransmitter receptor, (ii) muscle-specific 
      kinase (MuSK), a receptor tyrosine kinase essential for the formation and 
      maintenance of neuromuscular synapses, and (iii) low-density lipoprotein 
      receptor-related protein 4 (Lrp4), which responds to neural Agrin by binding and 
      stimulating MuSK. Passive transfer studies in mice have shown that IgG4 
      antibodies from MuSK MG patients cause disease without requiring complement or 
      other immune components, suggesting that these MuSK antibodies cause disease by 
      directly interfering with MuSK function. Here we show that pathogenic IgG4 
      antibodies to MuSK bind to a structural epitope in the first Ig-like domain of 
      MuSK, prevent binding between MuSK and Lrp4, and inhibit Agrin-stimulated MuSK 
      phosphorylation. In contrast, these IgG4 antibodies have no direct effect on MuSK 
      dimerization or MuSK internalization. These results provide insight into the 
      unique pathogenesis of MuSK MG and provide clues toward development of specific 
      treatment options.
FAU - Huijbers, Maartje G
AU  - Huijbers MG
AD  - Department of Neurology, Department of Human Genetics and Department of Molecular 
      Cell Biology, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands.
FAU - Zhang, Wei
AU  - Zhang W
FAU - Klooster, Rinse
AU  - Klooster R
FAU - Niks, Erik H
AU  - Niks EH
FAU - Friese, Matthew B
AU  - Friese MB
FAU - Straasheijm, Kirsten R
AU  - Straasheijm KR
FAU - Thijssen, Peter E
AU  - Thijssen PE
FAU - Vrolijk, Hans
AU  - Vrolijk H
FAU - Plomp, Jaap J
AU  - Plomp JJ
FAU - Vogels, Pauline
AU  - Vogels P
FAU - Losen, Mario
AU  - Losen M
FAU - Van der Maarel, Silvere M
AU  - Van der Maarel SM
FAU - Burden, Steven J
AU  - Burden SJ
FAU - Verschuuren, Jan J
AU  - Verschuuren JJ
LA  - eng
GR  - R01 NS036193/NS/NINDS NIH HHS/United States
GR  - R37 NS036193/NS/NINDS NIH HHS/United States
GR  - T32 GM007592/GM/NIGMS NIH HHS/United States
GR  - NS36193/NS/NINDS NIH HHS/United States
PT  - Clinical Trial
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20131202
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Agrin)
RN  - 0 (Autoantibodies)
RN  - 0 (Epitopes)
RN  - 0 (Immunoglobulin G)
RN  - 0 (LDL-Receptor Related Proteins)
RN  - 0 (LRP4 protein, human)
RN  - 0 (Lrp4 protein, mouse)
RN  - 0 (Receptors, Cholinergic)
RN  - 0 (Receptors, LDL)
RN  - EC 2.7.10.1 (MUSK protein, human)
RN  - EC 2.7.10.1 (MuSK protein, mouse)
RN  - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Agrin/immunology
MH  - Animals
MH  - Autoantibodies/*immunology/pharmacology
MH  - Cell Line
MH  - Child
MH  - Child, Preschool
MH  - Epitopes/immunology
MH  - Female
MH  - Humans
MH  - Immunization, Passive
MH  - Immunoglobulin G/*immunology/pharmacology
MH  - LDL-Receptor Related Proteins/antagonists & inhibitors/*immunology
MH  - Male
MH  - Mice
MH  - Middle Aged
MH  - Myasthenia Gravis/chemically induced/*immunology/pathology
MH  - Phosphorylation/drug effects/immunology
MH  - Protein Multimerization/drug effects/immunology
MH  - Receptor Protein-Tyrosine Kinases/antagonists & inhibitors/*immunology
MH  - Receptors, Cholinergic/*immunology
MH  - Receptors, LDL/antagonists & inhibitors/*immunology
PMC - PMC3870730
OTO - NOTNLM
OT  - Dok7
OT  - Rapsyn
OT  - activation loop
OT  - insulin receptor
OT  - neuromuscular junction
COIS- The authors declare no conflict of interest.
EDAT- 2013/12/04 06:00
MHDA- 2014/02/25 06:00
PMCR- 2013/12/02
CRDT- 2013/12/04 06:00
PHST- 2013/12/04 06:00 [entrez]
PHST- 2013/12/04 06:00 [pubmed]
PHST- 2014/02/25 06:00 [medline]
PHST- 2013/12/02 00:00 [pmc-release]
AID - 1313944110 [pii]
AID - 201313944 [pii]
AID - 10.1073/pnas.1313944110 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2013 Dec 17;110(51):20783-8. doi: 
      10.1073/pnas.1313944110. Epub 2013 Dec 2.