A mutation in guanylate cyclase activator 1A (GUCA1A) in an autosomal dominant cone dystrophy pedigree mapping to a new locus on chromosome 6p21.1
A mutation in guanylate cyclase activator 1A (GUCA1A) in an autosomal dominant cone dystrophy pedigree mapping to a new locus on chromosome 6p21.1
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DOI：
10.1093/hmg/7.2.273
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发表时间：
1998-02-01
影响因子：
3.5
通讯作者：
Bhattacharya, SS
中科院分区：
文献类型：
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作者：
Payne, AM;Downes, SM;Bhattacharya, SS
我们报道了一个常染色体显性遗传性视锥细胞营养不良家系中鸟苷环化酶激活蛋白(GCAP1)基因鸟苷酸环化酶激活子1A(GUCA1A)的一个突变(Y99C)。连锁分析排除了所有已知的视锥细胞和视锥-视杆细胞营养不良基因，除染色体6p21.1区域外，该区域含有与显性视锥-视杆细胞营养不良相关的RDS基因。RDS基因的异源双链分析和直接测序未能显示该基因编码区的序列变化，光感受器外段高表达的钙结合蛋白GCAP1的基因也位于6p21.1，进行了突变筛查，所有受影响的个体都表现出单碱基错义突变(A->；G)该基因外显子2的第99位密码子导致GCAP1蛋白酪氨酸到半胱氨酸的改变，206名无关的正常对照中没有这种改变，我们认为这种改变至少会扰乱GCAP1的EF3手，从而阻止钙结合，从而干扰激活，由此对cGMP产生的影响将可预测地改变开放的cGMP门控阳离子通道的数量，并可以解释视锥感光细胞的最终死亡。
We report a mutation (Y99C) in guanylate cyclase activator 1A(GUCA1A), the gene for guanylate cyclase activating protein (GCAP1), in a family with autosomal dominant cone dystrophy. Linkage analysis excluded all the known cone and cone-rod dystrophy loci, except the chromosome 6p21.1 region, This is known to contain the RDS gene, which is associated with dominant cone-rod dystrophy. Screening of the RDS gene by heteroduplex analysis and direct sequencing failed to demonstrate sequence changes in the coding region of this gene, The gene for GCAP1, a calcium binding protein which is highly expressed in photoreceptor outer segments, is also located in 6p21.1, It was screened for mutations, and all affected individuals showed a single base pair missense mutation (A-->G) at codon 99 in exon 2 of this gene generating a tyrosine-to-cysteine change in the GCAP1 protein, This change was absent from 206 unrelated normal controls, We propose that this change would at least disrupt the EF3 hand of GCAP1 thereby preventing calcium binding and consequently interfere with activation, The resulting effect on cGMP production would predictably modify the number of open cGMP gated cation channels, and could explain the ultimate demise of cone photoreceptor cells.