Mutations in genes encoding melanosomal proteins cause pigmentary glaucoma in DBA/2J mice
Mutations in genes encoding melanosomal proteins cause pigmentary glaucoma in DBA/2J mice
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DOI：
10.1038/ng794
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发表时间：
2002-01-01
期刊：
影响因子：
30.8
通讯作者：
John, SWM
中科院分区：
文献类型：
--
作者：
Anderson, MG;Smith, RS;John, SWM
色素性青光眼是人类失明的重要原因。异常释放的虹膜色素和细胞碎片进入眼部引流结构，导致眼内压（IOP）升高和青光眼（1-3）。DBA/2 J（D2）小鼠出现一种色素性青光眼，涉及虹膜色素分散（IPD）和虹膜基质萎缩（伊萨）（4，5）。使用高分辨率的定位技术，测序和功能遗传学测试，我们表明，IPD和伊萨的编码黑素体蛋白的相关基因突变的结果。IPD是由Gpnmb（Gpnmb（R150 X））基因中的提前终止密码子突变引起的，如仅在Gpnmb（R150 X）纯合的D2小鼠中发生IPD所证明的。否则，Gpnmb（R150 X）非纯合的相似D2小鼠不发生IPD。伊萨是由隐性Tyrp 1（B）突变等位基因引起的，并通过转基因导入野生型Tyrp 1来挽救。我们假设IPD和伊萨改变了黑素体，使色素产生的有毒中间体从黑素体中泄漏，导致虹膜疾病和随后的色素性青光眼。这得到了色素产生显著减少的D2眼中IPD和伊萨的挽救的支持。这些数据表明色素的产生和突变的黑素体蛋白基因可能导致人类色素性青光眼。事实上，色素减退严重加重了D2疾病，这表明旨在减少色素产生的治疗策略可能对人类色素性青光眼有益。
Pigmentary glaucoma is a significant cause of human blindness. Abnormally liberated iris pigment and cell debris enter the ocular drainage structures, leading to increased intraocular pressure (IOP) and glaucoma(1-3). DBA/2J (D2) mice develop a form of pigmentary glaucoma involving iris pigment dispersion (IPD) and iris stromal atrophy (ISA)(4,5). Using high-resolution mapping techniques, sequencing and functional genetic tests, we show that IPD and ISA result from mutations in related genes encoding melanosomal proteins. IPD is caused by a premature stop codon mutation in the Gpnmb (Gpnmb(R150X)) gene, as proved by the occurrence of IPD only in D2 mice that are homozygous with respect to Gpnmb(R150X). otherwise, similar D2 mice that are not homozygous for Gpnmb(R150X) do not develop IPD. ISA is caused by the recessive Tyrp1(b) mutant allele and rescued by the transgenic introduction of wildtype Tyrp1. We hypothesize that IPD and ISA alter melanosomes, allowing toxic intermediates of pigment production to leak from melanosomes, causing iris disease and subsequent pigmentary glaucoma. This is supported by the rescue of IPD and ISA in D2 eyes with substantially decreased pigment production. These data indicate that pigment production and mutant melanosomal protein genes may contribute to human pigmentary glaucoma. The fact that hypopigmentation profoundly alleviates the D2 disease indicates that therapeutic strategies designed to decrease pigment production may be beneficial in human pigmentary glaucoma.