Inactivation of muscle chloride channel by transposon insertion in myotonic mice

Abstract

MYOTONIA (stiffness and impaired relaxation of skeletal muscle) is a symptom of several diseases caused by repetitive firing of action potentials in muscle membranes. Purely myotonic human diseases are dominant myotonia congenita (Thomsen) and recessive generalized myotonia (Becker), whereas myotonic dystrophy is a systemic disease. Muscle hyperexcitability was attributed to defects in sodium channels and/or to a decrease in chloride conductance (in Becker's myotonia and in genetic animal models). Experimental blockage of Cl- conductance (normally 70-85% of resting conductance in muscle) in fact elicits myotonia. ADR mice are a realistic animal model for recessive autosomal myotonia. In addition to Cl- conductance, many other parameters are changed in muscles of homozygous animals. We have now cloned the major mammalian skeletal muscle chloride channel (ClC-1). Here we report that in ADR mice a transposon of the ETn family has inserted into the corresponding gene, destroying its coding potential for several membrane-spanning domains. Together with the lack of recombination between the Clc-1 gene and the adr locus, this strongly suggests a lack of functional chloride channels as the primary cause of mouse myotonia.

Myotonia caused by mutations in the muscle chloride channel geneCLCN1

“…A similar reduction of the skeletal muscle Cl conductance was also found in human recessive myotonia [Rüdel et al, 1988]. Goats are not a convenient system for genetic studies and it was in fact a recessive mouse model for myotonia (the adr mouse ) that led to the identification of the CLCN1 gene as being responsible for myotonia [Steinmeyer et al, 1991a].…”

Unusual expression of LINE-1 transposable element in the MRL autoimmune lymphoproliferative syndrome-prone strain

“…Therefore, in MRL/lpr mice, the transposition of the non-autonomous ETn element into the fas gene may have resulted from the trans-acting RT synthesized by the LINE-1 ORF2. Pathogenic insertions of both non-autonomous and autonomous elements have been characterized (Kazazian, 1998) like an Alu insertion in human neurofibromatosis (Wallace et al, 1991) or an ETn insertion in murine myotonia (Steinmeyer et al, 1991). Similarly, LINE-1 insertion has been reported to suppress the expression of clotting factor VIII in a case of haemophilia (Kazazian et al, 1988) or of the dystrophin gene in Duchenne's muscular dystrophy (Holmes et al, 1994), to activate c-myc in tumours (Katzir et al, 1985;Morse et al, 1988), and to disrupt the APC gene in colorectal cancer (Miki et al, 1992).…”

Molecular cloning and characterization of a novel truncated form (ClC‐2β) of ClC‐2α (ClC‐2G) in rabbit heart

“…encoded by a family of genes, a C1C family [13][14][15][16][17][18][19]. Because cardiac C1-currents have been best characterized in rabbits, we made attempts to isolate CI-channel cDNAs belonging to C1C family from rabbit hearts.…”