Glaucoma-causing myocilin mutants require the peroxisomal targeting signal-1 receptor (PTS1R) to elevate intraocular pressure
Glaucoma-causing myocilin mutants require the peroxisomal targeting signal-1 receptor (PTS1R) to elevate intraocular pressure
复制标题
DOI：
10.1093/hmg/ddm001
复制
发表时间：
2007-03-15
影响因子：
3.5
通讯作者：
Clark, Abbot F.
中科院分区：
文献类型：
--
作者：
Shepard, Allan R.;Jacobson, Nasreen;Clark, Abbot F.
青光眼是世界范围内不可逆视力损害和失明的主要原因，并且是一组临床和遗传异质性的视神经病变。myocilin（MYOC）基因的特定突变导致原发性开角型青光眼（POAG），其发病年龄和严重程度各不相同。我们显示了一个突变依赖性，获得的功能之间的关联人类myocilin和过氧化物酶体靶向信号1型受体（PTS1R）。青光眼表型与MYOC特异性突变之间存在相关性，更严重的早发性POAG突变与PTS1R的相关程度更高。人肌球蛋白青光眼突变在小鼠眼睛中的表达导致眼内压升高，这是MYOC青光眼的主要表型。这是第一次证明由突变诱导的隐藏信号位点暴露引起的疾病，该位点导致突变蛋白质错误定位于过氧化物酶体，也是第一个基于疾病基因的人类POAG动物模型。
Glaucoma is a leading cause of worldwide irreversible visual impairment and blindness and is a clinically and genetically heterogenous group of optic neuropathies. Specific mutations in the myocilin (MYOC) gene cause primary open angle glaucoma (POAG) with varying age-of-onset and degree of severity. We show a mutation-dependent, gain-of-function association between human myocilin and the peroxisomal targeting signal type 1 receptor (PTS1R). There was correlation between the glaucoma phenotype and the specific MYOC mutations, with the more severe early-onset POAG mutations having a higher degree of association with PTS1R. Expression of human myocilin glaucomatous mutations in mouse eyes causes elevated intraocular pressure, which is a major phenotype of MYOC glaucoma. This is the first demonstration of a disease resulting from mutation-induced exposure of a cryptic signaling site that causes mislocalization of mutant protein to peroxisomes and the first disease-gene-based animal model of human POAG.