Proof of a non-functional muscle chloride channel in recessive myotonia congenita (Becker) by detection of a 4 base pair deletion

Abstract

Recessive myotonia congenita (Becker) is genetically linked to HUMCLC, the gene encoding the muscular chloride channel, localized on chromosome 7q35. Three point mutations have so far been reported in HUMCLC, one causing recessive Becker-type myotonia, the others causing the clinically similar Thomsen-type myotonia, which is inherited as a dominant trait. We report a homozygous patient having a 4 base pair deletion in HUMCLC that shifts the reading frame and causes early stop codons, thus destroying the gene's coding potential for several membrane-spanning domains. In addition, we report a patient homozygous for a novel point mutation located at the extracellular side of the first membrane-spanning domain that causes removal of a negative charge (aspartic acid-136-glycine). Both mutations lead to the recessive type of myotonia congenita. Since the patient having the deletion presents less severe clinical myotonia than the patient carrying the missense mutation, it seems that the absence or truncation of the channel protein may disturb muscle fibre function less than the substitution of a single amino acid.

Skeletal muscle channelopathies

“…Both missense mutations (exchange of single amino acid residues) and nonsense mutations (alternative protein splicing or premature truncation) have been identified [21,22,26,39]. While splicing mutations always lead to the recessive phenotype, various truncations and missense mutations are found in the Thomsen and Becker myotonia (Fig.…”

Properties of voltage‐gated chloride channels of the ClC gene family.

“…are caused by mutations in ClC-1 (Koch et al 1992;George et al 1993;Heine et al 1994;Lorenz et al 1994;MeyerKleine et al 1994;kSteinmeyer et al 1994). As mentioned above, a detailed analysis of dominant human mutations came to the conclusion that ClC-1 functions as a multimer, most likely a tetramer .…”

Probing the major skeletal muscle chloride channel with Zn 2+ and other sulfhydryl-reactive compounds

“…This mutant causes a particularly severe form of recessive generalized myotonia [9] because of a drastically altered gating mechanism [3,4]. For instance, when the membrane potential is stepped from zero to negative values, the currents conducted by D136G hClC-1 are slowly activated (Fig.…”