PIP2 binding residues of Kir2.1 are common targets of mutations causing Andersen syndrome

被引:139
作者
Donaldson, MR
Jensen, JL
Tristani-Firouzi, M
Tawil, R
Bendahhou, S
Suarez, WA
Cobo, AM
Poza, JJ
Behr, E
Wagstaff, J
Szepetowski, P
Pereira, S
Mozaffar, T
Escolar, DM
Fu, YH
Ptácek, LJ
机构
[1] Univ Utah, Dept Human Genet & Mol Biol, Salt Lake City, UT USA
[2] Univ Utah, Howard Hughes Med Inst, Salt Lake City, UT USA
[3] Univ Utah, Dept Neurol, Salt Lake City, UT USA
[4] Univ Utah, Dept Pediat Cardiol, Salt Lake City, UT USA
[5] Univ Rochester, Neuromuscular Dis Ctr, Sch Med & Dent, Rochester, NY 14627 USA
[6] Childrens Mercy Hosp, Dept Pediat, Toledo, OH USA
[7] Univ Virginia Hlth Syst, Dept Pediat, Charlottesville, VA USA
[8] Univ Virginia Hlth Syst, Dept Biochem & Mol Genet, Charlottesville, VA USA
[9] George Washington Univ, Childrens Natl Med Ctr, Dept Neurol, Washington, DC USA
[10] George Washington Univ, Childrens Natl Med Ctr, Med Genet Res Ctr, Washington, DC USA
[11] Univ Calif Irvine, Dept Neurol, Irvine, CA 92717 USA
[12] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA
[13] Univ Nice, Inst Pharmacol Mol & Cellulaire, Sophia Antipolis, France
[14] Fac Med Timone, INSERM, U491, Genet Med & Dev, Marseille, France
[15] Hosp Donostia, Unidad Genet, San Sebastian, Spain
[16] Hosp Donostia, Serv Neurol, San Sebastian, Spain
[17] Univ London St Georges Hosp, Sch Med, London SW17 0RE, England
关键词
D O I
10.1212/01.WNL.0000072261.14060.47
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
Background: Mutations in KCNJ2, the gene encoding the inward-rectifying K+ channel Kir2.1, cause the cardiac, skeletal muscle, and developmental phenotypes of Andersen - Tawil syndrome (ATS; also known as Andersen syndrome). Although pathogenic mechanisms have been proposed for select mutations, a common mechanism has not been identified. Methods: Seventeen probands presenting with symptoms characteristic of ATS were evaluated clinically and screened for mutations in KCNJ2. The results of mutation analysis were combined with those from previously studied subjects to assess the frequency with which KCNJ2 mutations cause ATS. Results: Mutations in KCNJ2 were discovered in nine probands. These included six novel mutations ( D71N, T75R, G146D, R189I, G300D, and R312C) as well as previously reported mutations R67W and R218W. Six probands possessed mutations of residues implicated in binding membrane-associated phosphatidylinositol 4,5-bisphosphate (PIP2). In total, mutations in PIP2-related residues accounted for disease in 18 of 29 (62%) reported KCNJ2-based probands with ATS. Also reported is that mutation R67W causes the full clinical triad in two unrelated males. Conclusions: The novel mutations corresponding to residues involved in Kir2.1 channel - PIP2 interactions presented here as well as the overall frequency of mutations occurring in these residues indicate that defects in PIP2 binding constitute a major pathogenic mechanism of ATS. Furthermore, screening KCNJ2 in patients with the complex phenotypes of ATS was found to be invaluable in establishing or confirming a disease diagnosis as mutations in this gene can be identified in the majority of patients.
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页码:1811 / 1816
页数:6
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