McKay Gareth J, Clarke Stephen, Davis Jason A, Simpson David A C, Silvestri Giuliana
Ophthalmic Research Centre, Institute of Clinical Science, Queen's University of Belfast, Belfast, Northern Ireland, United Kingdom.
Invest Ophthalmol Vis Sci. 2005 Jan;46(1):322-8. doi: 10.1167/iovs.04-0734.
Pigmented paravenous chorioretinal atrophy (PPCRA) is an unusual retinal degeneration characterized by accumulation of pigmentation along retinal veins. The purpose of this study was to describe the phenotype of a family with PPCRA, determine the mode of inheritance, and identify the causal mutation.
Ophthalmic examination was performed on seven family members and serially detailed in the proband over a 3-year period. Blood samples were collected and DNA extracted. All 12 coding exons and the 5' promoter region of the crumbs homologue 1 (CRB1) gene were PCR amplified and DNA sequenced. In silico homology modeling was performed on the mutated protein domain.
Subtle symmetrical chorioretinal atrophy in the inferior quadrant was the earliest clinical sign detectable within this family. Paravenous pigmentation occurred initially in the far periphery, progressing centrally, with atrophy later becoming more widespread, involving the nasal, then the temporal, and finally the upper quadrant. A novel, dominant Val162Met mutation within the fourth EGF-like domain of CRB1 cosegregates with the PPCRA phenotype. It is thought to affect domain structure, because codon 162 is involved in hydrogen bonding between the antiparallel beta-strands of the major beta-sheet, causing sufficient perturbation of the backbone that the domain-stabilizing hydrogen bond does not form or is weakened.
PPCRA was dominantly inherited in this family, but exhibited variable expressivity. Males are more likely to exhibit a severe phenotype, whereas females may remain virtually asymptomatic even in later years. The PPCRA phenotype is associated with a Val162Met mutation in CRB1 which is likely to affect the structure of the CRB1 protein.
色素性静脉旁脉络膜视网膜萎缩（PPCRA）是一种不常见的视网膜变性，其特征为沿视网膜静脉出现色素沉着。本研究的目的是描述一个患有PPCRA的家系的表型，确定遗传方式，并鉴定致病突变。
对7名家庭成员进行了眼科检查，并在3年期间对先证者进行了系列详细检查。采集血样并提取DNA。对crumbs同源物1（CRB1）基因的所有12个编码外显子和5'启动子区域进行PCR扩增并进行DNA测序。对突变蛋白结构域进行了计算机同源建模。
在下象限出现的细微对称性脉络膜视网膜萎缩是该家系中最早可检测到的临床体征。静脉旁色素沉着最初出现在远周边部，向中央发展，随后萎缩范围扩大，累及鼻侧，然后是颞侧，最后是上象限。CRB1第四EGF样结构域内的一个新的显性Val162Met突变与PPCRA表型共分离。据认为它会影响结构域结构，因为密码子162参与了主要β折叠的反平行β链之间的氢键形成，导致主链受到足够的扰动，使得结构域稳定氢键无法形成或减弱。
PPCRA在这个家系中为显性遗传，但表现出可变的表达度。男性更有可能表现出严重的表型，而女性即使在晚年也可能几乎没有症状。PPCRA表型与CRB1中的Val162Met突变相关，该突变可能会影响CRB1蛋白的结构。
