Abstract：
Cantu syndrome (CS) (OMIM #239850) is an autosomal dominant multiorgan system condition, associated with a characteristic facial phenotype, hypertrichosis, and multiple cardiovascular complications. CS is caused by gain-of-function (GOF) variants in KCNJ8 or ABCC9 that encode pore-forming Kir6.1 and regulatory SUR2 subunits of ATP-sensitive potassium (KATP) channels. A novel heterozygous ABCC9 variant, c.2440G>T; p.Gly814Trp, was identified in three individuals from a four generation Greek family. The membrane potential in cells stably expressing hKir6.1 and hSUR2B with p.Gly814Trp was hyperpolarized compared to cells expressing WT channels, and inside-out patch-clamp assays of KATP channels formed with hSUR2B p.Gly814Trp demonstrated a decreased sensitivity to ATP inhibition, confirming a relatively mild GOF effect of this variant. The specific location of the variant reveals an unrecognized functional role of the first glycine in the signature motif of the nucleotide binding domains in ATP-binding cassette (ABC) protein ion channels.
摘要：
Cantu综合征（CS）（OMIM#239850）是一种常染色体显性遗传的多器官系统疾病，与特征性面部表型相关，多毛症,和多种心血管并发症。CS是由KCNJ8或ABCC9中的功能获得（GOF）变体引起的，这些变体编码ATP敏感性钾（KATP）通道的成孔Kir6.1和调节性SUR2亚基。一个新的杂合ABCC9变体，c.2440G>T;p.Gly814Trp,在一个四代希腊家庭的三个人中被发现。与表达WT通道的细胞相比，用p.Gly814Trp稳定表达hKir6.1和hSUR2B的细胞的膜电位超极化，和由hSUR2Bp.Gly814Trp形成的KATP通道的由内而外的膜片钳测定显示出对ATP抑制的敏感性降低，证实了该变体的相对温和的GOF效应。变体的特定位置揭示了第一甘氨酸在ATP结合盒（ABC）蛋白质离子通道中核苷酸结合结构域的特征基序中的未识别的功能作用。
