Myotonia congenita-associated chloride channelopathies: mutations, function, and structure.

Download File (2.8M)
Publication Type dissertation
School or College School of Medicine
Department Neurology
Author Zhang, Jie.
Title Myotonia congenita-associated chloride channelopathies: mutations, function, and structure.
Date 1999-12
Description Myotonia Congenita (MC) is a genetic muscle disorder manifesting myotonia, a delayed relaxation of muscle after contraction. MC includes two inherited forms: autosomal dominant myotonia congenita (Thomsen's disease) and autosomal recessive myotonia congenita (Becker's disease). Both diseases are characterized electrophysiologically by increased excitability of muscle fibers, and are caused by mutations in the skeletal muscle voltage-gated chloride channel (ClC-1) gene CLCN1 . By genetic screening, we identified several novel and detected many previously identified CLCN1 mutations and polymorphisms in a large number of MC kindreds. Genetic analysis suggested that these mutations are responsible for the symptoms seen in MC patients. Interestingly, we found that the same CLCN1 mutations could be responsible for both Thomsen's and Becker's MC in different families. To understand the molecular basis of these disorders, it is important to determine the physiological consequences of mutations found in MC patients. We used a mammalian cell expression system and whole-cell voltage clamping technique to functionally express and physiologically characterize some CLCN1 mutations. Functional defects caused by these mutations include abolishment of chloride conductance, depolarizing-shifts of voltage-dependence of channel open probabilities, and inversion of voltage-dependent gating of ClC-1 channels. The functional consequences of these mutations are the basis of the physiological argument that these are disease-causing defects and could lead to MC by impairing the ability of the ClC-1 channels to maintain normal muscle excitability. Furthermore, we conducted intensive biophysical analysis of one novel CLCN1 mutation (G499R) identified in our genetic screening. In addition to its hyperpolarization-activated gating behavior, site-directed mutagenesis studies of G499R and other mutations revealed the importance of putative transmembrane domain 10 of ClC-1 in the voltage-gating of these channels. Taken together, mutation identification, functional characterization, and channel structure studies will add to the knowledge about the mechanisms underlying the MC phenotype. These insights will lead to a better understanding of MC pathogenesis and ultimately, to better diagnosis and treatment of myotonia congenita.
Type Text
Publisher University of Utah
Subject Physiology; Mutations
Subject MESH Chloride Channels; Myotonia Congenita
Dissertation Institution University of Utah
Dissertation Name PhD
Language eng
Relation is Version of Digital reproduction of “Myotonia congenita-associated chloride channelopathies : mutations, function, and structure.” Spencer S. Eccles Health Sciences Library. Print version of “Myotonia congenita-associated chloride channelopathies : mutations, function, and structure.” available at J. Willard Marriott Library Special Collection. QP6.5 1999 .Z43.
Rights Management © Jie Zhang.
Format Medium application/pdf
Identifier us-etd2,209
Source Original: University of Utah Spencer S. Eccles Health Sciences Library (no longer available).
ARK ark:/87278/s6668tt5
ID 193522
setname ir_etd
Reference URL
Back to Search Results