Human Molecular Genetics, Vol 6, 753-766, Copyright © 1997 by Oxford University Press
K Ohno, PA Quiram, M Milone, HL Wang, MC Harper, JN Pruitt 2nd, JM Brengman, L Pao, KH Fischbeck, TO Crawford, SM Sine and AG Engel
We describe and functionally characterize six mutations of the
acetylcholine receptor (AChR) epsilon subunit gene in three congenital
myasthenic syndrome patients. Endplate studies demonstrated severe endplate
AChR deficiency, dispersed endplate regions and well preserved junctional
folds in all three patients. Electrophysiologic studies were consistent
with expression of the fetal gamma-AChR at the endplates in one patient,
prolongation of some channel events in another and gamma- AChR expression
as well as some shorter than normal channel events in still another.
Genetic analysis revealed two recessive and heteroallelic epsilon subunit
gene mutations in each patient. One mutation in each (epsilonC190T [epsilon
R64X], epsilon 127ins5 and epsilon 553del 7) generates a nonsense codon
that predicts truncation of the epsilon subunit in its N-terminal,
extracellular domain; and one mutation in each generates a missense codon
(epsilon R147L, epsilon P245L and epsilon R311W). None of the mutations was
detected in 100 controls. Expression studies in HEK cells indicate that the
three nonsense mutations are null mutations and that surface expression of
AChRs harboring the missense mutations is significantly reduced. Kinetic
analysis of AChRs harboring the missense mutations show that epsilon R147L
is kinetically benign, epsilon P245L prolongs burst open duration 2-fold by
slowing the rate of channel closing and epsilon R311W shortens burst
duration 2-fold by slowing the rate of channel opening and speeding the
rate of ACh dissociation. The modest changes in activation kinetics are
probably overshadowed by reduced expression of the missense mutations. The
consequences of the endplate AChR deficiency are mitigated by persistent
expression of gamma-AChR, changes in the release of transmitter quanta and
appearance of multiple endplate regions on the muscle fiber.
ARTICLES
Congenital myasthenic syndromes due to heteroallelic nonsense/missense mutations in the acetylcholine receptor epsilon subunit gene: identification and functional characterization of six new mutations
Department of Neurology and Neuromuscular Research Laboratory, Mayo Clinic and Foundation, Rochester, MN 55905, USA.
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