The GUCY2D gene encodes for the photoreceptor guanylate cyclase GC-E that synthesizes the intracellular messenger of photoreceptor excitation cGMP and is regulated by intracellular Ca²⁺-sensor proteins named guanylate cyclase-activating proteins (GCAPs). Over 140 disease-causing mutations have been described so far in GUCY2D, 88% of which cause autosomal recessive Leber congenital amaurosis (LCA) while heterozygous missense mutations cause autosomal dominant cone-rod degeneration (adCRD). Mutations in GUCY2D are one of the major causes of all LCA cases and are the major cause of adCRD. A single amino acid, arginine at position 838, is likely to be the most sensitive one in GC-E as four single mutations and two complex mutations were reported to affect R838.

The biochemical effect of 45 GC-E variants was studied showing a clear genotype-phenotype correlation: LCA-causing mutations either show reduced ability or complete inability to synthesize cGMP from GTP, while CRD-causing mutations are functional, but shift the Ca²⁺-sensitivity of the GC-E − GCAP complex.

Eight animal models of retinal guanylate cyclase deficiency have been reported including knockout (KO) mouse and chicken models. These two models were used for gene augmentation therapy that yielded promising results.

Here we integrate the available information on the genetics, biochemistry and phenotype that is related to GUCY2D mutations. These data clearly show that mutation type (missense versus null) and localization (dimerization domain versus other protein domains) are correlated with the pattern of inheritance, impact on enzymatic function and retinal phenotype. Such clear correlation is unique to GUCY2D while mutations in many other retinal disease genes show variable phenotypes and lack of available biochemical assays.

所述GUCY2D基因编码用于将所述感光苷酸环化酶GC-E，其合成感光体激发cGMP的细胞内信使，并通过细胞内Ca调节²⁺多个传感器的蛋白质命名为鸟苷酸环化酶活化蛋白（GCAPs）。迄今为止，已经在GUCY2D中描述了140多种致病突变，其中88％引起常染色体隐性隐性Leber先天性黑ur病（LCA），而杂合错义突变则导致常染色体显性圆锥杆变性（adCRD）。GUCY2D中的突变是所有LCA案件的主要原因之一，也是adCRD的主要原因。一个单一的氨基酸，第838位的精氨酸，可能是GC-E中最敏感的一个，因为据报道有四个单一突变和两个复杂突变会影响R838。

研究了45个GC-E变体的生化作用，显示出明显的基因型与表型相关性：导致LCA的突变显示出降低的能力或完全无法从GTP合成cGMP，而导致CRD的突变起作用，但Ca ²⁺转移-GC-E-GCAP复合物的灵敏性。

已经报道了八种视网膜鸟苷酸环化酶缺乏症的动物模型，包括基因敲除（KO）小鼠和鸡模型。这两个模型用于基因扩增治疗，产生了可喜的结果。

在这里，我们整合了与GUCY2D突变相关的遗传学，生物化学和表型方面的可用信息。这些数据清楚地表明，突变类型（缺失与否）和定位（二聚结构域与其他蛋白质结构域）与遗传模式，对酶功能和视网膜表型的影响相关。这种明显的相关性是GUCY2D所独有的，而许多其他视网膜疾病基因的突变则表现出可变的表型和缺乏可用的生化分析方法。