A novel GCAP1(N104K) mutation in EF-hand 3 (EF3) linked to autosomal dominant cone dystrophy.
A novel GCAP1(N104K) mutation in EF-hand 3 (EF3) linked to autosomal dominant cone dystrophy.
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DOI：
10.1016/j.visres.2008.07.016
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发表时间：
2008-10
期刊：
影响因子：
1.8
通讯作者：
Baehr, Wolfgang
中科院分区：
文献类型：
--
作者：
Jiang, Li;Wheaton, Dianna;Bereta, Grzegorz;Zhang, Kang;Palczewski, Krzysztof;Birch, David G.;Baehr, Wolfgang
关键词：
GUCA 1A基因编码鸟苷酸环化酶激活蛋白（GCAP 1），其参与脊椎动物视网膜中光转导的调节。我们在一个显性视锥细胞营养不良家族的两个受累成员中发现了一种新的人GUCA 1A基因外显子2的C312 A颠换，将GCAP 1中的Asn-104（N104）替换为Lys（K）。突变N104 K位于第三EF手基序（EF 3），先前显示有助于将无Ca 2+的GCAP 1转化为Ca 2+结合形式的GC抑制剂。在一名患者中，杆ERG在12年期间相当稳定，而30 Hz闪烁ERG和单闪光锥ERG下降。在这两名患者中，双闪光ERG显示，从强烈的测试闪光杆恢复显着延迟。GC刺激的EC 50从野生型GCAP 1中的约250 nM变为GCAP 1（N104 K）突变体中的约800 nM，表明突变体在生理条件下无法呈现无活性形式。GCAP 1中N104被K取代是EF 3环中发现的第一个天然突变。在受影响患者的双闪ERG中观察到的视杆恢复延迟表明了一种新型的显性负效应，其减缓了GC刺激。
The GUCA1A gene encodes a guanylate cyclase-activating protein (GCAP1) that is involved in regulation of phototransduction in the vertebrate retina. We discovered a novel C312A transversion in exon 2 of the human GUCA1A gene, replacing Asn-104 (N104) in GCAP1 with Lys (K), in two affected members of a family with dominant cone dystrophy. The mutation N104K is located in the third EF hand motif (EF3) shown previously to be instrumental in converting Ca2+-free GCAP1 to a GC inhibitor in the Ca2+-bound form. In one patient, rod ERGs were fairly stable over a 12-year-period whereas 30 Hz flicker ERG and single-flash cone ERGs declined. In both patients, double flash ERGs showed that rod recovery from an intense test flash was significantly delayed. The EC50 for GC stimulation shifted from ~250 nM in wild-type GCAP1 to ~800 nM in the GCAP1(N104K) mutant suggesting inability of the mutant to assume an inactive form under physiological conditions. The replacement of N104 by K in GCAP1 is the first naturally occurring mutation identified in the EF3 loop. The rod recovery delays observed in double-flash ERG of affected patients suggest a novel dominant-negative effect that slows GC stimulation.
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影响因子：
4.4
作者：
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