*100710 CHOLINERGIC RECEPTOR, NICOTINIC, BETA POLYPEPTIDE 1; CHRNB1
;;CHRNB;;
ACETYLCHOLINE RECEPTOR, MUSCLE, BETA SUBUNIT; ACHRB
*FIELD* AV
.0001
MYASTHENIC SYNDROME, CONGENITAL, SLOW-CHANNEL
CHRNB1, VAL266MET
In a 19-year-old female with slow-channel congenital myasthenic syndrome
(601462), Engel et al. (1996) identified a heterozygous 796G-A
transition in exon 8 of the CHRNB1 gene, resulting in a val266-to-met
(V266M) substitution in a conserved residue in the M2 transmembrane
domain of the AChR-beta subunit. Functional expression studies showed
that the V266M mutation slowed the rate of AChR channel closure and
increased the apparent affinity for ACh. The mutation also caused
pathologic channel openings even in the absence of ACh, resulting in a
leaky channel. Cationic overload of the postsynaptic region caused an
endplate myopathy.
.0002
MYASTHENIC SYNDROME, CONGENITAL, SLOW-CHANNEL
CHRNB1, LEU263MET
In a 32-year-old male with slow-channel congenital myasthenic syndrome
(601462), Gomez et al. (1996) identified a heterozygous C-to-A
transversion in the CHRNB1 gene, resulting in a leu263-to-met (L263M)
substitution. Functional expression studies showed that the L263M
mutation interrupted the leucine ring of the AChR channel gate, causing
an 8-fold increase in channel open time and resulting in severe endplate
myopathy and extensive remodeling of the postsynaptic membrane. The
pronounced abnormalities in neuromuscular synaptic architecture and
function and the muscle fiber damage and weakness resulting from a
single point mutation were a dramatic example of a mutation having a
dominant gain of function and of hereditary excitotoxicity.
.0003
MYASTHENIC SYNDROME, CONGENITAL, ASSOCIATED WITH ACETYLCHOLINE RECEPTOR
DEFICIENCY
CHRNB1, 9-BP DEL, NT1276 
In 3 sibs with congenital myasthenia and AChR deficiency (608931),
Quiram et al. (1999) identified compound heterozygosity for 2 mutations
in the CHRNB1 gene. One mutation was a 9-bp deletion (1276del9) in exon
10, resulting in a deletion of 3 codons (426-428) in the long
cytoplasmic loop between the M3 and M4 domains of the protein. The
second mutation was a skipping of exon 8 (100710.0004), truncating the
beta subunit before its M1 transmembrane domain and abolishing surface
expression of pentameric AChR. By coexpressing the 3-codon deleted
subunit with combinations of wildtype subunits in HEK293 cells, Quiram
et al. (1999) demonstrated that the mutation impairs AChR assembly by
disrupting a specific interaction between the beta and delta (100720)
subunits. Studies with related deletion and missense mutations indicated
that secondary structure in this region of the beta subunit is crucial
for interaction with the delta subunit. The findings implied that the
mutated residues are positioned at the interface between beta and delta
subunits and demonstrated contribution of this local region of the long
cytoplasmic loop to AChR assembly.
.0004
MYASTHENIC SYNDROME, CONGENITAL, ASSOCIATED WITH ACETYLCHOLINE RECEPTOR
DEFICIENCY
CHRNB1, EX8DEL 
See 100710.0003 and Quiram et al. (1999).
*FIELD* SA
Beeson et al. (1989)
*FIELD* RF