Department of Ophthalmology and Visual Sciences, Carver College of Medicine, 3111B Medical Education and Research Facility, University of Iowa, 375 Newton Road, Iowa City, IA52245, USA.
Institute for Vision Research, University of Iowa, Iowa City, IA, USA.
BMC Genomics. 2021 Jun 26;22(1):477. doi: 10.1186/s12864-021-07782-0.
Glaucoma is a leading cause of visual disability and blindness. Release of iris pigment within the eye, pigment dispersion syndrome (PDS), can lead to one type of glaucoma known as pigmentary glaucoma. PDS has a genetic component, however, the genes involved with this condition are largely unknown. We sought to discover genes that cause PDS by testing cohorts of patients and controls for mutations using a tiered analysis of exome data.
Our primary analysis evaluated melanosome-related genes that cause dispersion of iris pigment in mice (TYRP1, GPNMB, LYST, DCT, and MITF). We identified rare mutations, but they were not statistically enriched in PDS patients. Our secondary analyses examined PMEL (previously linked with PDS), MRAP, and 19 other genes. Four MRAP mutations were identified in PDS cases but not in controls (p = 0.016). Immunohistochemical analysis of human donor eyes revealed abundant MRAP protein in the iris, the source of pigment in PDS. However, analysis of MRAP in additional cohorts (415 cases and 1645 controls) did not support an association with PDS. We also did not confirm a link between PMEL and PDS in our cohorts due to lack of reported mutations and similar frequency of the variants in PDS patients as in control subjects.
We did not detect a statistical enrichment of mutations in melanosome-related genes in human PDS patients and we found conflicting data about the likely pathogenicity of MRAP mutations. PDS may have a complex genetic basis that is not easily unraveled with exome analyses.
青光眼是导致视力残疾和失明的主要原因之一。虹膜色素在眼内释放，即色素播散综合征（PDS），可导致一种称为色素性青光眼的青光眼。PDS 具有遗传成分，但是，与这种情况相关的基因在很大程度上尚不清楚。我们通过使用外显子组数据的分层分析，对患者和对照者进行测试，以寻找导致 PDS 的基因。
我们的主要分析评估了导致小鼠虹膜色素分散的黑色素体相关基因（TYRP1、GPNMB、LYST、DCT 和 MITF）。我们发现了罕见的突变，但它们在 PDS 患者中没有统计学上的富集。我们的次要分析检查了 PMEL（先前与 PDS 相关联）、MRAP 和其他 19 个基因。在 PDS 病例中发现了四个 MRAP 突变，但在对照中未发现（p = 0.016）。对人供体眼的免疫组织化学分析显示，MRAP 蛋白在虹膜中大量存在，而虹膜是 PDS 中色素的来源。但是，对其他两个队列（415 例和 1645 例对照）的 MRAP 分析并未支持其与 PDS 相关。由于缺乏报道的突变和 PDS 患者与对照者中变体的相似频率，我们也未能在我们的队列中确认 PMEL 与 PDS 之间的联系。
我们未在 PDS 患者中检测到黑色素体相关基因的突变统计学富集，并且我们发现了有关 MRAP 突变致病性的相互矛盾的数据。PDS 可能具有复杂的遗传基础，用外显子组分析不易阐明。
