Postsynaptic<unk> <unk>  is associated with genetic defects that affect proteins of the neuromuscular junction. Postsynaptic defects are the most frequent cause of<unk>  and often result in abnormalities in the acetylcholine receptor (AChR). In the neuromuscular junction there is a vital pathway that maintains synaptic structure and results in the aggregation and localization of AChR on the postsynaptic folds. This pathway consists of agrin, muscle-specific tyrosine kinase (MuSK), acetylcholine receptors (AChRs) and the AChR-clustering protein rapsyn, encoded by the RAPSN gene. The vast majority of mutations causing<unk>  are found in the AChR subunits and rapsyn genes. Out of all mutations associated with<unk> , more than half are mutations in one of the four genes encoding the adult acetylcholine receptor (AChR) subunits. Mutations of the AChR often result in endplate deficiency. Most of the mutations of the AChR are mutations of the CHRNE gene. The CHRNE gene codes for the epsilon subunit of the AChR. Most mutations are autosomal recessive loss-of-function mutations and as a result there is endplate AChR deficiency. CHRNE is associated with changing the kinetic properties of the AChR. One type of mutation of the epsilon subunit of the AChR introduces an Arginine into the binding site at the α/ε subunit interface of the receptor. The addition of a cationic Arg into the anionic environment of the AChR binding site greatly reduces the kinetic properties of the receptor. The result of the newly introduced Arg is a 30-fold reduction of agonist affinity, 75-fold reduction of gating efficiency, and an extremely weakened channel opening probability. This type of mutation results in an extremely fatal form of<unk> . Another common underlying mechanism of<unk>  is the mutation of the rapsyn protein, coded by the RAPSN gene. Rapsyn interacts directly with the AChRs and plays a vital role in agrin-induced clustering of the AChR. Without rapsyn, functional synapses cannot be created, as the membrane folds do not form properly. Patients with<unk> -related mutations of the rapsyn protein typically are either homozygous for N88K or heterozygous for N88K and a second mutation. The major effect of the mutation N88K in rapsyn is to reduce the stability of AChR clusters. The second mutation can be a determining factor in the severity of the disease. Studies have shown that most patients with<unk>  that have rapsyn mutations carry the common mutation N88K on at least one allele. However, research has revealed that there is a small population of patients who do not carry the N88K mutation on either of their alleles, but instead have different mutations of the RAPSN gene that codes for rapsyn on both of their alleles. Two novel missense mutations that have been found are R164C and L283P; the result is a decrease in co-clustering of AChR with raspyn. A third mutation is the intronic base alteration IVS1-15C>A, which causes abnormal splicing of RAPSN RNA. These results show that diagnostic screening for<unk>  mutations of the RAPSN gene cannot be based exclusively on the detection of N88K mutations Dok-7 is a postsynaptic protein that binds and activates MuSK protein, which then leads to AChR clustering and typical folding of the postsynaptic membrane. Mutations of Dok-7 are yrt another underlying mechanism of postsynaptic<unk> .
Congenital myasthenic syndrome
Limb–girdle muscular dystrophy
Lambert–Eaton myasthenic syndrome
Distal hereditary motor neuronopathies
Neurasthenia
Hereditary sensory and autonomic neuropathy
Hereditary neuralgic amyotrophy
Hereditary sensory and autonomic neuropathy type I