Zeitz Christina, Gross Alecia K, Leifert Dorothee, Kloeckener-Gruissem Barbara, McAlear Suzanne D, Lemke Johannes, Neidhardt John, Berger Wolfgang
Division of Medical Molecular Genetics and Gene Diagnostics, Institute of Medical Genetics, University of Zurich, Zurich, Switzerland.
Invest Ophthalmol Vis Sci. 2008 Sep;49(9):4105-14. doi: 10.1167/iovs.08-1717. Epub 2008 May 16.
Mutations in RHO, PDE6B, and GNAT1 can lead to autosomal dominant congenital stationary night blindness (adCSNB). The study was conducted to identify the genetic defect in a large Swiss family affected with adCSNB and to investigate the pathogenic mechanism of the mutation.
Two affected cousins of a large Swiss family were examined clinically by standard methods: funduscopy, EOG, ERG, and dark adaptometry. Twelve family members were screened for mutations in RHO. The ability of mutant rhodopsin to activate transducin constitutively was monitored by measuring the catalytic exchange of bound GDP for radiolabeled [(35)S]GTPgammaS in transducin.
A novel mutation was identified in RHO (c.884C>T, p.Ala295Val) in patients with adCSNB. They had full vision under photopic conditions, showed no fundus abnormalities, revealed EOG results in the normal range, but presented night blindness with an altered scotopic ERG. In the presence of 11-cis retinal, the mutant rhodopsin is inactive, similar to wild-type, responding only when exposed to light. However, in the absence of 11-cis-retinal, unlike wild-type opsin, the mutant opsin constitutively activates transducin.
The study adds a fourth rhodopsin mutation associated with CSNB. Although the phenotype of autosomal dominant CSNB may vary slightly in patients showing mutations in RHO, PDE6B, or GNAT1, the disease course seems to be stationary with only scotopic vision being affected. The data indicate that the mutant opsin activates transducin constitutively, which is a consistent and common feature of all four CSNB-associated rhodopsin mutations reported to date.
RHO、PDE6B和GNAT1基因的突变可导致常染色体显性遗传性先天性静止性夜盲（adCSNB）。本研究旨在确定一个患有adCSNB的瑞士大家庭中的基因缺陷，并研究该突变的致病机制。
采用标准方法对一个瑞士大家庭中的两名患病表亲进行临床检查：眼底镜检查、眼电图（EOG）、视网膜电图（ERG）和暗适应测量。对12名家庭成员进行RHO基因突变筛查。通过测量转导素中结合的GDP与放射性标记的[(35)S]GTPγS的催化交换，监测突变型视紫红质组成性激活转导素的能力。
在患有adCSNB的患者中，RHO基因（c.884C>T，p.Ala295Val）发现了一个新的突变。他们在明视觉条件下视力正常，眼底无异常，EOG结果在正常范围内，但表现为夜盲，暗视ERG改变。在存在11-顺式视黄醛的情况下，突变型视紫红质无活性，与野生型相似，仅在光照下有反应。然而，在没有11-顺式视黄醛的情况下，与野生型视蛋白不同，突变型视蛋白组成性激活转导素。
本研究增加了与CSNB相关的第四个视紫红质突变。尽管常染色体显性CSNB患者的表型在RHO、PDE6B或GNAT1基因发生突变时可能略有不同，但病程似乎是静止的，仅暗视觉受影响。数据表明，突变型视蛋白组成性激活转导素，这是迄今为止报道的所有四个与CSNB相关的视紫红质突变的一致且共同的特征。
