Silva Eduardo, Dharmaraj Sharola, Li Ying Ying, Pina Ana Luisa, Carter Robert Colin, Loyer Magali, Traboulsi Elias, Theodossiadis George, Koenekoop Robert, Sundin Olof, Maumenee Irene
Molecular and Developmental Biology Laboratory, Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Ophthalmic Genet. 2004 Sep;25(3):205-17. doi: 10.1080/13816810490513451.
Leber congenital amaurosis (LCA) is a clinically and genetically heterogeneous severe retinal dystrophy presenting in infancy. To explain the phenotypical variability observed in two affected siblings of a consanguineous pedigree diagnosed with LCA and establish a genotype-phenotype correlation, we screened GUCY2D, RPE65, CRX, AIPL1, and RPGRIP1 for mutations. The more severely affected sibling carried a heterozygous missense mutation in the GUCY2D gene (Ile539Val), which did not segregate with the disease phenotype. Subsequently, a homozygous nonsense mutation (Glu102STOP) in the RPE65 gene was identified in both affected siblings, thus identifying the causative gene. This data provides evidence for the presence of genetic modulation in LCA. It appears that the heterozygous GUCY2D mutation further disrupts the already compromised photoreceptor function resulting in more severe retinal dysfunction in the older sibling. We suggest that the unusual phenotypic variability in these two siblings with LCA is caused by the modifying effect of a heterozygous GUCY2D mutation observed against the disease background of a homozygous RPE65 mutation.
莱伯先天性黑蒙（LCA）是一种在婴儿期出现的临床和遗传异质性严重视网膜营养不良。为了解释在一个被诊断为LCA的近亲家系的两名患病同胞中观察到的表型变异性，并建立基因型-表型相关性，我们对GUCY2D、RPE65、CRX、AIPL1和RPGRIP1进行了突变筛查。病情较重的同胞在GUCY2D基因中携带一个杂合错义突变（Ile539Val），该突变与疾病表型不分离。随后，在两名患病同胞中均鉴定出RPE65基因的纯合无义突变（Glu102STOP），从而确定了致病基因。该数据为LCA中存在基因调节提供了证据。似乎杂合的GUCY2D突变进一步破坏了已经受损的光感受器功能，导致年长同胞出现更严重的视网膜功能障碍。我们认为，这两名LCA同胞中不寻常的表型变异性是由在纯合RPE65突变的疾病背景下观察到的杂合GUCY2D突变的修饰作用引起的。
