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

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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.

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Abbreviations

CACNA1S :

Skeletal muscle voltage-gated calcium channel α-subunit

HyperPP :

Hyperkalemic periodic paralysis

HypoPP :

Hypokalemic periodic paralysis

KCNE3 :

Voltage-gated potassium channel β subunit gene

PCR :

Polymerase chain reaction

RFLP :

Restriction fragment length polymorphism

SCN4A :

Skeletal muscle voltage-gated sodium channel α-subunit

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Acknowledgements

We are grateful to the family members. This study would be impossible without their enthusiastic participation. This work was supported by two grants from the Chinese Ministry of Science and Technology National High Technology “863” Programs of China No. 2002BA711A07 (one to Q.W. and the other to J.Y.; Professor Yan Shen is the Chief Scientist on the overall project).

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Authors and Affiliations

  1. Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, Hubei, 430074, China

    Qiufen Wang, Mugen Liu, Zhaohui Tang, Wei Li, Xiaoyan Wu, Xu Wang, Ping Liu, Xianqin Zhang, Jianfang Zhu, Xiang Ren, Tie Ke, Qing Wang & Junguo Yang

  2. Institute of Cardiovascular Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China

    Qiufen Wang, Yuhua Liao, Rong Du, Qing Wang & Junguo Yang

  3. College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, 430074, China

    Mugen Liu, Zhaohui Tang, Xu Wang, Ping Liu, Xianqin Zhang, Xiang Ren, Tie Ke & Qing Wang

  4. Neurology, Binzhou Medical College Hospital, Binzhou, Shandong, 256603, China

    Chunsheng Xu

  5. Center for Molecular Genetics, Department of Molecular Cardiology, Lerner Research Institute, The Cleveland Clinic Foundation, and Department of Molecular Medicine and Department of Pathology, Case Western Reserve University, Cleveland, OH, 44195, USA

    Qing Wang

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  1. Qiufen Wang
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  2. Mugen Liu
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  3. Chunsheng Xu
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  4. Zhaohui Tang
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  5. Yuhua Liao
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  7. Wei Li
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  8. Xiaoyan Wu
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  9. Xu Wang
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  10. Ping Liu
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  12. Jianfang Zhu
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  13. Xiang Ren
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  14. Tie Ke
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  15. Qing Wang
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  16. Junguo Yang
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Corresponding authors

Correspondence to Qing Wang or Junguo Yang.

Additional information

Qiufen Wang and Mugen Liu contributed equally to this work

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Wang, Q., Liu, M., Xu, C. et al. Novel CACNA1S mutation causes autosomal dominant hypokalemic periodic paralysis in a Chinese family. J Mol Med 83, 203–208 (2005). https://doi.org/10.1007/s00109-005-0638-4

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  • DOI: https://doi.org/10.1007/s00109-005-0638-4

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