Linkage data suggesting allelic heterogeneity for paramyotonia congenita and hyperkalemic periodic paralysis on chromosome 17

University of Pittsburg School of Medicine
Human Genetics (Impact Factor: 4.82). 01/1991; 88(1):71-74. DOI: 10.1007/BF00204932


Paramyotonia congenita (PC), an autosomal dominant non-progressive muscle disorder, is characterised by cold-induced stiffness followed by muscle weakness. The weakness is caused by a dysfunction of the sodium channel in muscle fibre. Parts of the gene coding for the -subunit of the sodium channel of the adult human skeletal muscle (SCN4A) have been localised on chromosome 17. To investigate the role of this gene in the etiology of PC, a linkage analysis in 17 well-defined families was carried out. The results (z=20.61, =0.001) show that the mutant gene responsible for the disorder is indeed tightly linked to the SCN4A gene. The mutation causing hyperkalemic periodic paralysis (HyperPP) with myotonia has previously been mapped to this gene locus by the same candidate gene approach. Thus, our data suggest that PC and HyperPP are caused by allelic mutations at a single locus on chromosome 17.

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    • "Linkage of hyperkalemic periodic paralysis to SCN4A (Fontaine et al. 1990) provided further evidence for the existence of a sodium channel disease in man. Three groups then showed independently that paramyotonia congenita is also linked to SCN4A (Ebers et al. 1991; Koch et al. 1991; Ptácek et al. 1991b; see Rüdel et al. 1993). Finally, molecular biology revealed that the myotonia in various families that were previously diagnosed as havingàbnormal forms' of myotonia congenita (which is now known to be a chloride channel disease, see below) is in fact the consequence of mutations in SCN4A. "
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    ABSTRACT: In addition to the clarification of the pathology of a whole group of hereditary diseases, the study of the consequences of these mutations at the levels of the whole system (patient), organ and cells (excised muscle specimens), and of the channel proteins has taught us that our current opinions on channel structure-function relations are far from being comprehensive. For instance it had been assumed that as in the potassium channel, also in the sodium and calcium channel proteins, the S4 unit is mainly responsible for channel activation. This notion has to be corrected as mutations in S4 of repeat IV were found to affect mainly channel inactivation. Moreover mutations affecting other channel domains, such as interlinkers or other intramembraneous subunits cause virtually the same alterations, not only when tested with the limited probe of the patch clamp but also on the level of the patient. The lack of mutations in other parts of the genes, in particular those coding for sodium or calcium channels, may indicate that proper function of the corresponding protein domains is essential for life. Thus the knowledge derived from the experiments of Nature, as these diseases may be looked upon by the cell biologist, provides a valuable addition to the results from site-directed mutagenesis. For a final understanding of the pathology of the diseases, for example, triggering effects of cold or potassium, it seems that the regression from the proteins back to the cellular or even systemic levels is unavoidable.
    Reviews of Physiology, Biochemistry and Pharmacology 02/1996; 128:195-268. DOI:10.1007/3-540-61343-9_9 · 6.27 Impact Factor
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    • "For the putative MHS locus on chromosome 17q, which was suggested by cumulating small lod scores from pedigrees typed with different protocol (Levitt et al. 1991), the gene for the muscle sodium channel (SCN4A) has been proposed as a candidate (Olckers et al. 1992). This should be discussed bearing in mind that mutations in this gene have been identified elsewhere as causing hyperkalemic periodic paralysis, paramyotonia congenita, and other forms of nondystrophic myotonias (Fontaine et al. 1990; Koch et al. 1991; Heine et al. 1993; Ricker et al. 1994). The paramount importance of a consistent phenotype in genetic studies of MHS is further emphasized by the observation that anesthesia-related events Table 3 Two-Point Lod Scores "
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    ABSTRACT: Malignant hyperthermia (MH) is a potentially lethal pharmacogenetic disease for which MH susceptibility (MHS) is transmitted as an autosomal dominant trait. A potentially life-threatening MH crisis is triggered by exposure to commonly used inhalational anesthetics and depolarizing muscle relaxants. The first malignant hyperthermia susceptibility locus (MHS1) was identified on human chromosome 19q13.1, and evidence has been obtained that defects in the gene for the calcium-release channel of skeletal muscle sarcoplasmic reticulum (ryanodine receptor; RYR1) can cause some forms of MH. However, MH has been shown to be genetically heterogeneous, and additional loci on chromosomes 17q and 7q have been suggested. In a collaborative search of the human genome with polymorphic microsatellite markers, we now found linkage of the MHS phenotype, as assessed by the European in vitro contracture test protocol, to markers defining a 1-cM interval on chromosome 3q13.1. A maximum multipoint lod score of 3.22 was obtained in a single German pedigree with classical MH, and none of the other pedigrees investigated in this study showed linkage to this region. Linkage to both MHS1/RYR1 and putative loci on chromosome 17q and 7q were excluded. This study supports the view that considerable genetic heterogeneity exists in MH.
    The American Journal of Human Genetics 04/1995; 56(3):684-91. · 10.93 Impact Factor
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    • "and 23 PC families have shown similar results (LOD = 32.96) (Fontaine et al. 1990; Ebers et al. 1991; Koch et al. 1991a, 1991b; Ptacek et al. 1991b, 1991c; McClatchey et al. 1992a; Lehmann-Horn et al., submitted). A HyperPP quarter horse pedigree was used to conduct the first successful disease linkage in the horse species, where the disease was also mapped to the equine sodium-channel gene (Rudolph et al. 1992a). "
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    ABSTRACT: We present a correlation of molecular genetic data (mutations) and genetic data (dinucleotide-repeat polymorphisms) for a cohort of seven hyperkalemic periodic paralysis (HyperPP) and two paramyotonia congenita (PC) families from diverse ethnic backgrounds. We found that each of three previously identified point mutations of the adult skeletal muscle sodium-channel gene occurred on two different dinucleotide-repeat haplotypes. These results indicate that dinucleotide-repeat haplotypes are not predictive of allelic heterogeneity in sodium channelopathies, contrary to previous suggestions. In addition, we identified a HyperPP pedigree in which the dominant disorder was not linked to the sodium-channel gene. Thus, a second locus can give rise to a similar clinical phenotype. Some individuals in this pedigree exhibited a base change causing the nonconservative substitution of an evolutionarily conserved amino acid. Because this change was not present in 240 normal chromosomes and was near another HyperPP mutation, is fulfilled the most commonly used criteria for being a mutation rather than a polymorphism. However, linkage studies using single-strand conformation polymorphism-derived and sequence-derived haplotypes excluded this base change as a causative mutation: these data serve as a cautionary example of potential pitfalls in the delineation of change-of-function point mutations.
    The American Journal of Human Genetics 07/1993; 52(6):1074-84. · 10.93 Impact Factor
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