ORPHA: 423;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1q32.1 | {Malignant hyperthermia susceptibility 5} | 601887 | Autosomal dominant | 3 | CACNA1S | 114208 |
A number sign (#) is used with this entry because of evidence that susceptibility to malignant hyperthermia-5 (MHS5) is conferred by heterozygous mutation in the CACNA1S gene (114208) on chromosome 1q32.
Malignant hyperthermia-5 (MHS5) is a muscle disorder in which an episode is triggered by exposure to volatile anesthetic agents or depolarizing muscle relaxants. A fulminant malignant hyperthermia crisis is characterized by hyperthermia, skeletal muscle rigidity, tachycardia or arrhythmia, respiratory and metabolic acidosis, and rhabdomyolysis (summary by Monnier et al., 1997).
For a general phenotypic description and a discussion of genetic heterogeneity of malignant hyperthermia, see MHS1 (145600).
The transmission pattern of MHS5 in the family studied by Monnier et al. (1997) was consistent with autosomal dominant inheritance.
In a collaborative study in 3 pedigrees in Europe, in which disease status was classified according to the European in vitro contracture test (IVCT), Robinson et al. (1997) performed a genomewide screen and found that at least 2 further loci exist for MH susceptibility. One of these was located on 5p (601888). The other was located on 1q, between markers D1S422 and D1S1660. Between these 2 markers had already been localized a candidate gene, CACNL1A3 (CACNA1S; 114208), assigned to 1q32. This gene had been previously identified as the site of mutations causing hypokalemic periodic paralysis (170400). The MH family linked to 1q was from Grenoble, France.
In affected members of a large French family with MHS, Monnier et al. (1997) identified a heterozygous mutation in the CACNA1S gene (R1086H; 114208.0004).
Stewart et al. (2001) identified heterozygosity for the R1086H mutation in the CACNA1S gene in a North American family with MHS5.
Monnier, N., Procaccio, V., Stieglitz, P., Lunardi, J. Malignant-hyperthermia susceptibility is associated with a mutation of the alpha-1-subunit of the human dihydropyridine-sensitive L-type voltage-dependent calcium-channel receptor in skeletal muscle. Am. J. Hum. Genet. 60: 1316-1325, 1997. [PubMed: 9199552] [Full Text: https://doi.org/10.1086/515454]
Robinson, R. L., Monnier, N., Wolz, W., Jung, M., Reis, A., Nuernberg, G., Curran, J. L., Monsieurs, K., Stieglitz, P., Heytens, L., Fricker, R., van Broeckhoven, C., Deufel, T., Hopkins, P. M., Lunardi, J., Mueller, C. R. A genome wide search for susceptibility loci in three European malignant hyperthermia pedigrees. Hum. Molec. Genet. 6: 953-961, 1997. [PubMed: 9175745] [Full Text: https://doi.org/10.1093/hmg/6.6.953]
Stewart, S. L., Hogan, K., Rosenberg, H., Fletcher, J. E. Identification of the arg1086his mutation in the alpha subunit of the voltage-dependent calcium channel (CACNA1S) in a North American family with malignant hyperthermia. Clin. Genet. 59: 178-184, 2001. [PubMed: 11260227] [Full Text: https://doi.org/10.1034/j.1399-0004.2001.590306.x]