title: 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 alpha-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.
authors.affiliation: Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, Hubei, 430074, China. wangq2@ccf.org
authors.forename: Qiufen
authors.initials: Q
authors.lastname: Wang
authors.forename: Mugen
authors.initials: M
authors.lastname: Liu
authors.forename: Chunsheng
authors.initials: C
authors.lastname: Xu
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Tang
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Liao
authors.forename: Rong
authors.initials: R
authors.lastname: Du
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Wu
authors.forename: Xu
authors.initials: X
authors.lastname: Wang
authors.forename: Ping
authors.initials: P
authors.lastname: Liu
authors.forename: Xianqin
authors.initials: X
authors.lastname: Zhang
authors.forename: Jianfang
authors.initials: J
authors.lastname: Zhu
authors.forename: Xiang
authors.initials: X
authors.lastname: Ren
authors.forename: Tie
authors.initials: T
authors.lastname: Ke
authors.forename: Qing
authors.initials: Q
authors.lastname: Wang
authors.forename: Junguo
authors.initials: J
authors.lastname: Yang
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000595:Amino Acid Sequence; D000818:Animals; D001120:Arginine / Q000235:genetics / Q000378:metabolism; D044466:Asian People / Q000235:genetics*; D001483:Base Sequence; D015220:Calcium Channels / Q000235:genetics*; D020746:Calcium Channels, L-Type; D002675:Child, Preschool; D002681:China; D005260:Female; D006801:Humans; D020514:Hypokalemic Periodic Paralysis / Q000235:genetics* / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D016415:Sequence Alignment
chemical_list: C412223:CACNA1S protein, human; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D001120:Arginine
references.citation: Cell. 2001 Jan 26;104(2):217-31
references.pmid: 11207363
references.citation: J Physiol. 1999 Oct 15;520 Pt 2:321-36
references.pmid: 10523403
references.citation: Clin Genet. 2001 Mar;59(3):178-84
references.pmid: 11260227
references.citation: Nephrol Dial Transplant. 2001 May;16(5):939-44
references.pmid: 11328898
references.citation: Psychiatry Clin Neurosci. 2001 Oct;55(5):539-41
references.pmid: 11555352
references.citation: Muscle Nerve. 2003 Feb;27(2):165-9
references.pmid: 12548523
references.citation: Neurology. 2003 Sep 23;61(6):857-9
references.pmid: 14504341
references.citation: Science. 2003 Nov 28;302(5650):1578-81
references.pmid: 14645853
references.citation: Neurology. 2004 Mar 23;62(6):1012-5
references.pmid: 15037716
references.citation: Intern Med. 2004 Mar;43(3):218-22
references.pmid: 15098604
references.citation: Cell. 1991 Nov 29;67(5):1021-7
references.pmid: 1659948
references.citation: J Neurol Neurosurg Psychiatry. 1992 Apr;55(4):322-4
references.pmid: 1583521
references.citation: Neuron. 1992 May;8(5):891-7
references.pmid: 1316765
references.citation: Cell. 1994 Jun 17;77(6):863-8
references.pmid: 8004673
references.citation: Hum Mol Genet. 1994 Aug;3(8):1415-9
references.pmid: 7987325
references.citation: Am J Hum Genet. 1995 Feb;56(2):374-80
references.pmid: 7847370
references.citation: Cell. 1995 Mar 10;80(5):805-11
references.pmid: 7889574
references.citation: Nat Genet. 1996 Jan;12(1):17-23
references.pmid: 8528244
references.citation: Neuromuscul Disord. 1996 Jan;6(1):27-31
references.pmid: 8845715
references.citation: Genomics. 1996 Feb 1;31(3):392-4
references.pmid: 8838325
references.citation: Am J Med Genet. 1997 Mar 3;69(1):102-6
references.pmid: 9066893
references.citation: Neuromuscul Disord. 1997 Jan;7(1):33-8
references.pmid: 9132138
references.citation: Am J Hum Genet. 1997 Jun;60(6):1316-25
references.pmid: 9199552
references.citation: Nihon Rinsho. 1997 Dec;55(12):3247-52
references.pmid: 9436445
references.citation: J Neurosci. 1998 Dec 15;18(24):10320-34
references.pmid: 9852570