Molecular modeling of retinoschisin with functional analysis of pathogenic mutations from human X-linked retinoschisis
Molecular modeling of retinoschisin with functional analysis of pathogenic mutations from human X-linked retinoschisis
复制标题
DOI：
10.1093/hmg/ddq006
复制
发表时间：
2010-04-01
影响因子：
3.5
通讯作者：
Sieving, P. A.
中科院分区：
文献类型：
--
作者：
Sergeev, Y. V.;Caruso, R. C.;Sieving, P. A.
编码视网膜劈裂素 (RS1) 的基因突变会导致 X 连锁视网膜劈裂症 (XLRS)，这是一种影响男性的青少年黄斑和视网膜变性。 RS1 是一种粘附蛋白，被认为可以保护视网膜的结构和功能完整性，但很少有证据表明蛋白质变化与 XLRS 疾病相关的机制。在这里，我们报告了 RS1 蛋白的分子模型，并考虑了人类 XLRS 受试者中发现的突变引起的扰动。然后，我们在 60 名具有 27 个错义突变的 XLRS 患者中评估了分子模型与通过视网膜电图 (ERG) a 波和 b 波确定的视网膜功能之间可能的相关性。 b/a 波比率反映了视网膜中的视觉信号传输。我们根据患者年龄和突变对蛋白质结构的影响对 ERG b/a 比率进行排序。大多数 RS1 突变引起最小的结构扰动并针对蛋白质表面。这些患者的 b/a 比率在年轻和年长受试者中相似。半胱氨酸残基的去除或插入或疏水核心的变化引起的最大结构扰动与b/a比率随年龄的较大差异相关，在较年轻的年龄该比率显着较小，类似于在由于重组RS1敲除基因而没有RS1蛋白表达的小鼠中观察到的ERG随年龄的变化。分子模型表明，预测的视网膜劈裂素结构改变和/或损伤与通过类似于 RS1 敲除小鼠的 ERG 测量的 XLRS 严重程度之间存在关联。
Gene mutations that encode retinoschisin (RS1) cause X-linked retinoschisis (XLRS), a form of juvenile macular and retinal degeneration that affects males. RS1 is an adhesive protein which is proposed to preserve the structural and functional integrity of the retina, but there is very little evidence of the mechanism by which protein changes are related to XLRS disease. Here, we report molecular modeling of the RS1 protein and consider perturbations caused by mutations found in human XLRS subjects. In 60 XLRS patients who share 27 missense mutations, we then evaluated possible correlations of the molecular modeling with retinal function as determined by the electroretinogram (ERG) a- and b-waves. The b/a-wave ratio reflects visual-signal transfer in retina. We sorted the ERG b/a-ratios by patient age and by the mutation impact on protein structure. The majority of RS1 mutations caused minimal structure perturbation and targeted the protein surface. These patients' b/a-ratios were similar across younger and older subjects. Maximum structural perturbations from either the removal or insertion of cysteine residues or changes in the hydrophobic core were associated with greater difference in the b/a-ratio with age, with a significantly smaller ratio at younger ages, analogous to the ERG changes with age observed in mice with no RS1-protein expression due to a recombinant RS1-knockout gene. The molecular modeling suggests an association between the predicted structural alteration and/or damage to retinoschisin and the severity of XLRS as measured by the ERG analogous to the RS1-knockout mouse.