PMID- 21814823
OWN - NLM
STAT- MEDLINE
DCOM- 20120703
LR  - 20220408
IS  - 1432-1459 (Electronic)
IS  - 0340-5354 (Linking)
VI  - 259
IP  - 3
DP  - 2012 Mar
TI  - Anti-LRP4 autoantibodies in AChR- and MuSK-antibody-negative myasthenia gravis.
PG  - 427-35
LID - 10.1007/s00415-011-6194-7 [doi]
AB  - Myasthenia gravis (MG) is an autoimmune disorder characterized by a defect in 
      synaptic transmission at the neuromuscular junction causing fluctuating muscle 
      weakness with a decremental response to repetitive nerve stimulation or altered 
      jitter in single-fiber electromyography (EMG). Approximately 80% of all 
      myasthenia gravis patients have autoantibodies against the nicotinic 
      acetylcholine receptor in their serum. Autoantibodies against the tyrosine kinase 
      muscle-specific kinase (MuSK) are responsible for 5-10% of all myasthenia gravis 
      cases. The autoimmune target in the remaining cases is unknown. Recently, 
      low-density lipoprotein receptor-related protein (LRP4) has been identified as 
      the agrin receptor. LRP4 interacts with agrin, and the binding of agrin activates 
      MuSK, which leads to the formation of most if not all postsynaptic 
      specializations, including aggregates containing acetylcholine receptors (AChRs) 
      in the junctional plasma membrane. In the present study we tested if 
      autoantibodies against LRP4 are detectable in patients with myasthenia gravis. To 
      this end we analyzed 13 sera from patients with generalized myasthenia gravis but 
      without antibodies against AChR or MuSK. The results showed that 12 out of 13 
      antisera from double-seronegative MG patients bound to proteins concentrated at 
      the neuromuscular junction of adult mouse skeletal muscle and that approximately 
      50% of the tested sera specifically bound to HEK293 cells transfected with human 
      LRP4. Moreover, 4 out of these 13 sera inhibited agrin-induced aggregation of 
      AChRs in cultured myotubes by more than 50%, suggesting a pathogenic role 
      regarding the dysfunction of the neuromuscular endplate. These results indicate 
      that LRP4 is a novel target for autoantibodies and is a diagnostic marker in 
      seronegative MG patients.
FAU - Pevzner, Alexandra
AU  - Pevzner A
AD  - Department of Physiological Genomics, Institute for Physiology, 
      Ludwig-Maximilians University, Pettenkoferstrasse 12, 80336, Munich, Germany.
FAU - Schoser, Benedikt
AU  - Schoser B
FAU - Peters, Katja
AU  - Peters K
FAU - Cosma, Nicoleta-Carmen
AU  - Cosma NC
FAU - Karakatsani, Andromachi
AU  - Karakatsani A
FAU - Schalke, Berthold
AU  - Schalke B
FAU - Melms, Arthur
AU  - Melms A
FAU - Kroger, Stephan
AU  - Kroger S
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20110805
PL  - Germany
TA  - J Neurol
JT  - Journal of neurology
JID - 0423161
RN  - 0 (Agrin)
RN  - 0 (Autoantibodies)
RN  - 0 (Bungarotoxins)
RN  - 0 (LDL-Receptor Related Proteins)
RN  - 0 (LRP4 protein, human)
RN  - 0 (Receptors, Nicotinic)
RN  - 0 (enhanced green fluorescent protein)
RN  - 147336-22-9 (Green Fluorescent Proteins)
RN  - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Aged
MH  - Agrin/metabolism
MH  - Animals
MH  - Autoantibodies/*blood/pharmacology
MH  - Bungarotoxins/metabolism
MH  - Cells, Cultured
MH  - Female
MH  - Green Fluorescent Proteins/metabolism
MH  - Humans
MH  - LDL-Receptor Related Proteins/genetics/*immunology/metabolism
MH  - Male
MH  - Mice
MH  - Middle Aged
MH  - Muscle Fibers, Skeletal/cytology/drug effects
MH  - Myasthenia Gravis/*blood/*immunology/pathology
MH  - Neurologic Examination
MH  - Neuromuscular Junction/metabolism/pathology
MH  - Receptor Protein-Tyrosine Kinases/immunology
MH  - Receptors, Nicotinic/immunology/metabolism
MH  - Transfection
MH  - Young Adult
EDAT- 2011/08/05 06:00
MHDA- 2012/07/04 06:00
CRDT- 2011/08/05 06:00
PHST- 2011/05/31 00:00 [received]
PHST- 2011/07/14 00:00 [accepted]
PHST- 2011/06/27 00:00 [revised]
PHST- 2011/08/05 06:00 [entrez]
PHST- 2011/08/05 06:00 [pubmed]
PHST- 2012/07/04 06:00 [medline]
AID - 10.1007/s00415-011-6194-7 [doi]
PST - ppublish
SO  - J Neurol. 2012 Mar;259(3):427-35. doi: 10.1007/s00415-011-6194-7. Epub 2011 Aug 
      5.