Cant煤 Syndrome Is Caused by Mutations in ABCC9

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• 作者：Bregje&#160 ; W.M. van&#160 ; Bon¹ ; ¹⁴ ; Christian Gilissen¹ ; ¹⁴ ; Dorothy&#160 ; K. Grange² ; Raoul&#160 ; C.M. Hennekam³ ; Hü ; lya Kayserili⁴ ; Hartmut Engels⁵ ; Heiko Reutter⁵ ; ⁶ ; John&#160 ; R. Ostergaard⁷ ; Eva Morava⁸ ; Konstantinos Tsiakas⁹ ; Bertrand Isidor¹⁰ ; Martine Le&#160 ; Merrer¹¹ ; Metin Eser⁴ ; Nienke Wieskamp¹ ; Petra de&#160 ; Vries¹ ; Marloes Steehouwer¹ ; Joris&#160 ; A. Veltman¹ ; Stephen&#160 ; P. Robertson¹² ; Han&#160 ; G. Brunner¹ ; Bert&#160 ; B.A. de&#160 ; Vries¹ ; ^{b.devries@gen.umcn.nl} ; Alexander Hoischen¹ ; ¹³
• 刊名：The American Journal of Human Genetics
• 出版年：2012
• 期刊代码：P22_00029297
• 类别：bio
• 出版时间：8 June, 2012
• 卷：90
• 期：6
• 页码：1094-1101
• 文件大小：356 K

摘要

Cant煤 syndrome is a rare disorder characterized by congenital hypertrichosis, neonatal macrosomia, a distinct osteochondrodysplasia, and cardiomegaly. Using an exome-sequencing approach applied to one proband-parent trio and three unrelated single cases, we identified heterozygous mutations in ABCC9 in all probands. With the inclusion of the remaining cohort of ten individuals with Cant煤 syndrome, a total of eleven mutations in ABCC9 were found. The de novo occurrence in all six simplex cases in our cohort substantiates the presence of a dominant disease mechanism. All mutations were missense, and several mutations affect Arg1154. This mutation hot spot lies within the second type 1 transmembrane region of this ATP-binding cassette transporter protein, which may suggest an activating mutation. ABCC9 encodes the sulfonylurea receptor (SUR) that forms ATP-sensitive potassium channels (K_ATP channels) originally shown in cardiac, skeletal, and smooth muscle. Previously, loss-of-function mutations in this gene have been associated with idiopathic dilated cardiomyopathy type 10 (CMD10). These findings identify the genetic basis of Cant煤 syndrome and suggest that this is a new member of the potassium channelopathies.