Glaucoma-associated WDR36 variants encode functional defects in a yeast model system
Glaucoma-associated WDR36 variants encode functional defects in a yeast model system
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DOI：
10.1093/hmg/ddp027
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发表时间：
2009-04-01
影响因子：
3.5
通讯作者：
Walter, Michael A.
中科院分区：
文献类型：
--
作者：
Footz, Tim K.;Johnson, Jill L.;Walter, Michael A.
原发性开角型青光眼 (POAG) 是全世界失明的主要原因。 POAG 与眼部形态变化和视神经乳头变性以及视野丧失的特征性进展相关。物理绘图工作确定了基因组位点，可在其中寻找致病性 POAG 基因突变。 GLC1G 位点上的 WDR36 最初被鉴定为具有低频率非同义序列变异的基因，该基因是成人发病的 POAG 患者所独有的。此后的研究表明，罕见的 WDR36 序列变异也以类似的低频率存在于正常人群中。缺乏一致的基因型：表型相关性促使我们研究 WDR36 序列变异的功能后果。 WDR36 参与 rRNA 加工，这是核糖体生物合成中的关键步骤，并且与酵母 Utp21p 非常相似，后者是负责 18S rRNA 成熟的小亚基 (SSU) 加工复合体的成员。因此，我们开发了一个酵母模型系统来测试引入 UTP21 的 POAG 相关序列变体的功能和表型后果。单独来看，POAG 变体不会在细胞活力或 rRNA 加工方面产生任何显着缺陷。然而，当与 STI1（与 UTP21 合成相互作用）的破坏相结合时，11 个测试变体中有 5 个增加或降低了细胞活力，这分别对应于前 rRNA 水平的降低或升高。这些结果表明，在正确的遗传背景下，WDR36 序列变异可导致细胞表型改变，支持 WDR36 参与青光眼多基因形式的理论。
Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide. POAG is associated with a characteristic progression of changes to ocular morphology and degeneration at the optic nerve head with the loss of visual fields. Physical mapping efforts identified genomic loci in which to search for causative POAG gene mutations. WDR36, at locus GLC1G, was initially identified as a gene with a low frequency of non-synonymous sequence variations that were exclusive to adult-onset POAG patients. It has since been shown that rare WDR36 sequence variants are also present in the normal population at similarly low frequencies. The lack of a consistent genotype:phenotype correlation prompted us to investigate the functional consequences of WDR36 sequence variations. WDR36 is involved in rRNA processing, a critical step in ribosome biogenesis, and is very similar to yeast Utp21p which is a member of the small subunit (SSU) processome complex responsible for maturation of 18S rRNA. We, therefore, developed a yeast model system to test the functional and phenotypic consequences of POAG-associated sequence variants introduced into UTP21. Alone, the POAG variants did not produce any significant defects in cell viability or rRNA processing. However, when combined with disruption of STI1 (which synthetically interacts with UTP21), 5 of the 11 tested variants had increased or decreased cell viability which corresponded to reduced or elevated levels of pre-rRNA, respectively. These results demonstrate that, in the correct genetic background, WDR36 sequence variants can lead to an altered cellular phenotype, supporting the theory that WDR36 participates in polygenic forms of glaucoma.