Mutation Analysis Identifies GUCY2D as the Major Gene Responsible for Autosomal Dominant Progressive Cone Degeneration
Mutation Analysis Identifies GUCY2D as the Major Gene Responsible for Autosomal Dominant Progressive Cone Degeneration
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DOI：
10.1167/iovs.08-1901
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发表时间：
2008-11-01
影响因子：
4.4
通讯作者：
Kohl, Susanne
中科院分区：
文献类型：
--
作者：
Kitiratschky, Veronique B. D.;Wilke, Robert;Kohl, Susanne
目的。编码视网膜鸟苷酸环化酶-1蛋白(RetGC-1)的GUCY2D基因杂合性突变可导致常染色体显性遗传性视锥变性和视锥视杆变性(adCD，adCRD)。方法采用直接测序、聚合酶链式反应和限制性内切酶长度多态分析等方法对27个adCD和adCRD无关家系的GUCY2D基因进行突变分析。结果：27例患者中有11例(40%)检测到GUCY2D基因突变，所有突变均聚为密码子838，其中包括两个已知错义突变和一个新的错义突变：p.R838C、p.R838H和p.R838G。单倍型分析显示，在所分析的6个P.R838C突变携带者中，只有2个具有共同的单倍型，而P.R838H突变携带者中没有一个具有相同的单倍型。结论GUCY2D是导致常染色体显性锥体进行性变性的主要基因。所有已识别的突变都定位于密码子838。单倍型分析表明，在大多数情况下，这些突变是独立出现的。因此，密码子838很可能是GUCY2D基因的突变热点。(投资眼科VS科学。2008年；49：5015-5023)doi：10.1167/iovs.08-1901
PURPOSE. Heterozygous mutations in the GUCY2D gene, which encodes the membrane-bound retinal guanylyl cyclase-1 protein (RetGC-1), have been shown to cause autosomal dominant inherited cone degeneration and cone-rod degeneration (adCD, adCRD). The present study was a comprehensive screening of the GUCY2D gene in 27 adCD and adCRD unrelated families of these rare disorders.METHODS. Mutation analysis was performed by direct sequencing as well as PCR and subsequent restriction length polymorphism analysis (PCR/RFLP). Haplotype analysis was performed in selected patients by using microsatellite markers.RESULTS. GUCY2D gene mutations were identified in 11 (40%) of 27 patients, and all mutations clustered to codon 838, including two known and one novel missense mutation: p.R838C, p.R838H, and p.R838G. Haplotype analysis showed that among the studied patients only two of the six analyzed p. R838C mutation carriers shared a common haplotype and that none of the p.R838H mutation carriers did.CONCLUSIONS. GUCY2D is a major gene responsible for progressive autosomal dominant cone degeneration. All identified mutations localize to codon 838. Haplotype analysis indicates that in most cases these mutations arise independently. Thus, codon 838 is likely to be a mutation hotspot in the GUCY2D gene. (Invest Ophthalmol Vis Sci. 2008;49:5015-5023) DOI: 10.1167/iovs.08-1901