Novel complex GUCY2D mutation in Japanese family with cone-rod dystrophy
Novel complex GUCY2D mutation in Japanese family with cone-rod dystrophy
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DOI：
10.1167/iovs.03-0315
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发表时间：
2004-05-01
影响因子：
4.4
通讯作者：
Miyake, Y
中科院分区：
文献类型：
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作者：
Ito, S;Nakamura, M;Miyake, Y
目的.导致常染色体显性视锥-视杆细胞营养不良（CORD）的视网膜鸟苷酸环化酶基因（GUCY 2D）的所有突变均与密码子838中的氨基酸取代相关。在一个日本常染色体显性遗传CORD家系中发现了一个新的GUCY 2D基因I915 T和G917 R杂合复合错义突变。与此突变相关的临床特征进行了描述。从27名锥-杆或锥营养不良患者和11名黄斑营养不良患者中收集血液样品。从外周血白细胞中提取基因组DNA。直接测序GUCY 2D基因的所有18个编码外显子。对携带新突变的PCR产物进行亚克隆，并对每个等位基因进行测序。对该突变家族的成员进行了全面的眼科检查。在一个常染色体显性CORD家族中发现了一种新的杂合复合错义突变T2817 C和G2822 C，分别预测I915 T和G917 R氨基酸取代。这两个核苷酸的改变位于同一等位基因上，并与疾病分离。另外两个已知的错义突变R838 H和R838 C被发现在其他两个CORD家族。与Arg 838突变相关的临床表型与新突变相似。GUCY 2D基因中I915 T和G917 R的杂合复合突变导致常染色体显性CORD，表明不包括密码子838取代的杂合突变可导致这种眼部表型。
Purpose. All mutations in the retinal guanylate cyclase gene (GUCY2D) that causes autosomal dominant cone-rod dystrophy (CORD) are associated with an amino acid substitution in codon 838. A novel heterozygous complex missense mutation of I915T and G917R in the GUCY2D gene was found in a Japanese family with autosomal dominant CORD. The clinical features associated with this mutation were described.Methods. Blood samples were collected from 27 patients with cone-rod or cone dystrophies and from 11 patients with macular dystrophy. Genomic DNA was extracted from peripheral leukocytes. All 18 coding exons of the GUCY2D gene were directly sequenced. The PCR product carrying a novel mutation was subcloned, and each allele was sequenced. A complete ophthalmologic examination was performed in members of the family with the novel mutation.Results. A novel heterozygous complex missense mutation of T2817C and G2822C that would predict I915T and G917R amino acid substitutions, respectively, was found in an autosomal dominant CORD family. The two nucleotide changes were located on the same allele, and segregated with the disease. Two other known missense mutations of R838H and R838C were found in two other CORD families. The clinical phenotype associated with the novel mutation was similar to that with the Arg838 mutations.Conclusions. A heterozygous complex mutation of I915T and G917R in the GUCY2D gene caused autosomal dominant CORD, indicating that a heterozygous mutation that does not include a codon 838 substitution can lead to this ocular phenotype.