A Family of Hypokalemic Periodic Paralysis with CACNA1S Gene Mutation Showing Incomplete Penetrance in Women

Abstract

Familial hypokalemic periodic paralysis is an autosomal dominant genetic muscle disease characterized by periodic attacks of muscle weakness associated with a decrease in serum potassium. There are two major missense mutation sites in the calcium channel 1 subunit (CACNA1S) gene in these patients. We recently encountered a 13-year-old Japanese boy who had collapsed following exercise and was found to have a low serum potassium level. Clinical and genetic studies including exploration of his family tree proved that he and his maternal relatives had the disease with the missense mutation, Arg528His (CGC CAC). However, his mother and grandmother had no symptoms of the disease, indicating reduced penetrance in female carriers. Sexual difference in the penetrance of this disease and the association between the clinical symptoms and the types of genetic defects are discussed. (Internal Medicine 43: 218-222, 2004)

A Novel Mutation in CACNA1S Gene Associated with Hypokalemic Periodic Paralysis Which has a Gender Difference in the Penetrance

“…Wang et al in 2005 reported a Chinese HypoPP family carrying the Arg528Gly mutation in CAC-NA1S, in which the penetrance rate for male carriers was 100% and for female carriers was 83.3% (Wang et al 2005). Kawamura and colleagues reported a Japanese boy with HypoPP, who was found to carry the Arg528His mutation in CACNA1S, but his mother and grandmother were clinically normal even though they were mutation carriers (Kawamura et al 2004). And a Caucasian family with HypoPP patients was also reported to have incomplete penetrance clinical features (Elbaz et al 1995).…”

Clofibrate-induced apoptosis is mediated by Ca2+-dependent caspase-12 activation

“…Generally, motor nerve signals activate SR network through ryanodine receptor signal, causes calcium release from SR Ca 2+ store, the cytosolic calcium elevation subsequently activates tropomyosin and troponin-1, induces F-actin formation and finally leads to contraction (Ogawa et al, 2002). On the other hand, recent reports (Lin et al, 2005;Nabhani et al, 2005) showed that skeletal muscle also possesses functional dihydropyridine-sensitive (L-type) calcium channel, which is genetically distinguished from L-type Ca 2+ channel on vascular smooth muscle, and mutation of a1 subunit (CACNA1S) in patients causes periodic paralysis (Jurkat-Rot et al, 1994;Kawamura et al, 2004), indicating that pathophysiological Ca 2+ influx also has an important role (B) Caspase-12 activation was inhibited at calcium-free condition. Cells were treated with agents for 30 min and allowed to postincubate with DM for 2 to 6 h. Then they were harvested and assessed for immnoblotting along with the method of Fig.…”

Novel CACNA1S mutation causes autosomal dominant hypokalemic periodic paralysis in a Chinese family

“…Recently, a Japanese boy with HypoPP was found to carry the Arg528His mutation in CACNA1S, but his mother and grandmother are clinically normal even though they are mutation carriers [16]. All these results suggest that there is a gender difference for the mutation penetrance of HypoPP.…”

“…CACNA1S is composed of four homologous domains (DI-DIV), each of them consisting of six transmembrane segments (S1-S6) [9]. Three specific mutations have been identified in the CACNA1S gene in families with HypoPP: Arg528His in DIIS4, and Arg1,239His and Arg123Gly in DIVS4 [3,[10][11][12][13][14][15][16][17][18][19][20]. These mutations are all missense mutations where an arginine residue is replaced by either a histidine or sometimes a glycine residue.…”