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

Abstract

Hypokalemic periodic paralysis (HypoPP) is an autosomal dominant disorder which is characterized by periodic attacks of muscle weakness associated with a decrease in the serum potassium level. The skeletal muscle calcium channel α-subunit gene CACNA1S is a major disease-causing gene for HypoPP, however, only three specific HypoPP-causing mutations, Arg528His, Arg1,239His and Arg1,239Gly, have been identified in CACNA1S to date. In this study, we studied a four-generation Chinese family with HypoPP with 43 living members and 19 affected individuals. Linkage analysis showed that the causative mutation in the family is linked to the CACNA1S gene with a LOD score of 6.7. DNA sequence analysis revealed a heterozygous C to G transition at nucleotide 1,582, resulting in a novel 1,582C→G (Arg528Gly) mutation. The Arg528Gly mutation co-segregated with all affected individuals in the family, and was not present in 200 matched normal controls. The penetrance of the Arg528Gly mutation was complete in male mutation carriers, however, a reduced penetrance of 83% (10/12) was observed in female carriers. No differences were detected for age-at-onset and severity of the disease (frequency of symptomatic attacks per year) between male and female patients. Oral intake of KCl is effective in blocking the symptomatic attacks. This study identifies a novel Arg528Gly mutation in the CACNA1S gene that causes HypoPP in a Chinese family, expands the spectrum of mutations causing HypoPP, and demonstrates a gender difference in the penetrance of the disease.

Voltage sensor charge loss accounts for most cases of hypokalemic periodic paralysis

“…Point mutations in CACNA1S or SCN4A, which encode the skeletal muscle voltage-gated calcium and sodium channels, associate with HypoPP. [1][2][3][4][5][6][7][8][9][10] However, in most studies at least 20% of cases remain genetically undefined. 8,11,12 Sodium and calcium channels have homologous pore-forming ␣ subunits, each containing four domains containing six transmembrane segments.…”

Identification and functional characterization of a novel splicing mutation in RP gene PRPF31

“…A total of 382 fluorescent microsatellite markers from the ABI Mapping Panel MD-10 were genotyped in the adRP family and they are distributed over the entire human autosomes with a resolution of ~10 cM. The genotyping of markers was carried out as described [13].…”

“…A total of 382 fluorescent microsatellite markers from the ABI Mapping Panel MD-10 were genotyped in the adRP family and they are distributed over the entire human autosomes with a resolution of ~10 cM. The genotyping of markers was carried out as described [13].Markers for fine mapping were selected from the Marshfield Medical Genetics database (http://research.marshfieldclinic.org/genetics/) and genotyped as described above.Pairwise logarithm of the odds (LOD) scores were calculated with the Linkage Package 5.2 program assuming an autosomal dominant model, a gene frequency of 0.0001, a penetrance rate of 78% in the family, and an allele frequency of 1/n, where n equals the number of alleles observed. Haplotype was constructed using the Cyrillic program and manual prediction.…”

A novel heterozygous mutation in the Indian hedgehog gene (IHH) is associated with brachydactyly type A1 in a Chinese family

“…Linkage analysis was carried out as described previously (Wang et al 2005). Markers were genotyped using an ABI 3100 Genetic Analyzer and genotypes were analyzed using the GeneMapper 2 Software program (Applied Biosystems, Foster City, CA).…”

“…The PCR products were purified using the QIA Quick Gel Extraction Kit (Qiagen, Valencia, CA), and sequenced using an ABI PRISM 3100 Genetic Analyzer (Applied Biosystems) as described previously (Wang et al 2005).…”