Disease sequence from mutant rhodopsin allele to rod and cone photoreceptor degeneration in man
Disease sequence from mutant rhodopsin allele to rod and cone photoreceptor degeneration in man
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DOI：
10.1073/pnas.95.12.7103
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发表时间：
1998-06-09
影响因子：
11.1
通讯作者：
Jacobson, SG
中科院分区：
文献类型：
--
作者：
Cideciyan, AV;Hood, DC;Jacobson, SG
编码视紫红质（视杆光感受器中的视觉色素）的基因突变会导致从果蝇到人类等物种的视网膜变性。从视杆细胞特异性突变到视杆细胞和视锥细胞退化的致病序列仍不清楚。为了了解人类的疾病过程，我们通过使用视杆细胞和视锥细胞功能以及视网膜组织病理学的非侵入性测试，研究了具有 18 种不同视紫红质基因突变的杂合子。发现了两类疾病表达，并且存在等位基因特异性。 A类突变体会导致生命早期视网膜的视杆细胞功能严重异常；残余视锥细胞功能的形貌与视锥细胞密度平行。 B类突变体在某些视网膜区域或整个视网膜中与成年后的正常视杆细胞相容，并且存在缓慢的刻板疾病序列。疾病表现为视杆光感受器外节的丧失，不是单独的，而是以微小的斑块形式合并成更大的不规则退化区域。锥体外段功能保持正常，直到 > 75% 的杆外段丧失。锥损失的形貌与杆损失的形貌一致。大多数 B 类突变体表现出与视觉周期异常相关的疾病脆弱性从下鼻到上颞的视网膜梯度。 A 类突变等位基因表现得好像具有细胞毒性； B类突变体相对无害，表观遗传因素可能在视网膜变性中发挥主要作用。
Mutations in the gene encoding rhodopsin, the visual pigment in rod photoreceptors, lead to retinal degeneration in species from Drosophila to man. The pathogenic sequence from rod cell-specific mutation to degeneration of rods and cones remains unclear. To understand the disease process in man, we studied heterozygotes with 18 different rhodopsin gene mutations by using noninvasive tests of rod and cone function and retinal histopathology. Two classes of disease expression were found, and there was allele-specificity. Class A mutants lead to severely abnormal rod function across the retina early in life; topography of residual cone function parallels cone cell density. Class B mutants are compatible with normal rods in adult life in some retinal regions or throughout the retina, and there is a slow stereotypical disease sequence. Disease manifests as a loss of rod photoreceptor outer segments, not singly but in microscopic patches that coalesce into larger irregular areas of degeneration. Cone outer segment function remains normal until > 75% of rod outer segments are lost. The topography of cone loss coincides with that of rod loss. Most class B mutants show an inferior-nasal to superior-temporal retinal gradient of disease vulnerability associated with visual cycle abnormalities. Class A mutant alleles behave as if cytotoxic; class B mutants tan be relatively innocuous and epigenetic factors may play a major role in the retinal degeneration.