Lin Ruth J, Blumenkranz Mark S, Binkley Jonathan, Wu Kathy, Vollrath Douglas
Department of Genetics, Stanford University School of Medicine, Stanford, California 94305-5120, USA.
Am J Ophthalmol. 2006 Nov;142(5):839-48. doi: 10.1016/j.ajo.2006.06.003. Epub 2006 Sep 20.
To describe the phenotype and genotype of a family with suspected Sorsby fundus dystrophy (SFD).
Case reports and results of deoxyribonucleic acid (DNA) analysis.
Clinical features were determined by complete ophthalmologic examination or by review of medical records. Mutational analysis of the tissue inhibitor of metalloproteinase (TIMP)3 gene was performed by DNA resequencing. Biochemical properties of the mutant TIMP3 protein were studied, and phylogenetic and molecular modeling analyses of TIMP proteins were performed.
Fundi of four affected family members demonstrated active or regressed bilateral choroidal neovascularization, whereas another affected individual displayed severe diffuse pigmentary degeneration associated with nyctalopia characteristic of SFD. Onset of disease occurred in the fifth to seventh decades of life. A heterozygous His158Arg mutation was found in seven affected family members and was absent from an unaffected member and 98 unrelated controls. Bioinformatic analyses indicate that histidine 158 is an evolutionarily conserved residue in most vertebrate TIMP homologs and predict that substitution by arginine disrupts TIMP3 function. The mutant protein appears to be expressed by fibroblasts from an affected family member. Molecular modeling suggests that TIMP3 residue 158 may be part of a protein-protein interaction interface.
A novel mutation in TIMP3 causes a late-onset form of SFD in this family. His158Arg is the first reported TIMP3 SFD coding sequence mutation that does not create an unpaired cysteine. Further study of this unusual mutation may provide insight into the mechanism of SFD pathogenesis.
描述一个疑似患有索斯比眼底营养不良（SFD）的家系的表型和基因型。
病例报告及脱氧核糖核酸（DNA）分析结果。
通过全面的眼科检查或查阅病历确定临床特征。采用DNA重测序对金属蛋白酶组织抑制剂（TIMP）3基因进行突变分析。研究突变型TIMP3蛋白的生化特性，并对TIMP蛋白进行系统发育和分子建模分析。
四名患病家庭成员的眼底显示有活跃或消退的双侧脉络膜新生血管，而另一名患病个体表现出严重的弥漫性色素性变性，并伴有SFD特有的夜盲症。疾病发病于50至70岁。在七名患病家庭成员中发现了杂合的His158Arg突变，一名未患病成员和98名无关对照中未发现该突变。生物信息学分析表明，组氨酸158在大多数脊椎动物TIMP同源物中是一个进化保守的残基，并预测精氨酸取代会破坏TIMP3功能。突变蛋白似乎由一名患病家庭成员的成纤维细胞表达。分子建模表明，TIMP3的158位残基可能是蛋白质-蛋白质相互作用界面的一部分。
TIMP3基因中的一种新突变导致了该家系中一种迟发性形式的SFD。His158Arg是首次报道的TIMP3 SFD编码序列突变，该突变未产生不成对的半胱氨酸。对这种异常突变的进一步研究可能会为SFD发病机制提供深入了解。
