Variants in the LIM homeobox transcription factor 1-beta gene (LMX1B) predispose individuals to elevated intraocular pressure (IOP), a key risk factor for glaucoma. However, the effect of LMX1B mutations varies widely between individuals. To better understand mechanisms underlying LMX1B-related phenotypes and individual differences, we backcrossed the Lmx1bV265D (also known as Lmx1bIcst) allele onto the C57BL/6J (B6), 129/Sj (129), C3A/BLiA-Pde6b+/J (C3H), and DBA/2J-Gpnmb+ (D2-G) strain backgrounds. Strain background had a significant effect on the onset and severity of ocular phenotypes in Lmx1bV265D/+ mutant mice. Mice of the B6 background were the most susceptible to developing elevated IOP, severe anterior segment developmental anomalies (including malformed eccentric pupils, iridocorneal strands, and corneal abnormalities) and glaucomatous nerve damage. In contrast, Lmx1bV265D mice of the 129 background were the most resistant to developing anterior segment abnormalities, had less severe IOP elevation than B6 mutants at young ages, and showed no detectable nerve damage. To identify genetic modifiers of susceptibility to Lmx1bV265D-induced glaucoma-associated phenotypes, we performed a mapping cross between mice of the B6 (susceptible) and 129 (resistant) backgrounds. We identified a modifier locus on Chromosome 18, with the 129 allele(s) substantially lessening severity of ocular phenotypes, as confirmed by congenic analysis. By demonstrating a clear effect of genetic background in modulating Lmx1b-induced phenotypes, by providing a panel of strains with different phenotypic severities and by identifying a modifier locus, this study lays a foundation for better understanding the roles of LMX1B in glaucoma with the goal of developing new treatments.

中文翻译：

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遗传背景修改了Lmx1b突变小鼠对青光眼相关表型的脆弱性

LIM同源框转录因子1-beta基因（LMX1B）的变异使个体容易患高眼压（IOP），这是青光眼的关键危险因素。但是，LMX1B突变的影响因人而异。为了更好地了解LMX1B相关表型和个体差异的潜在机制，我们将Lmx1bV265D（也称为Lmx1bIcst）等位基因回交到C57BL / 6J（B6），129 / Sj（129），C3A / BLiA-Pde6b + / J（C3H） ，以及DBA / 2J-Gpnmb +（D2-G）菌株背景。菌株背景对Lmx1bV265D / +突变小鼠的眼表型的发作和严重程度具有重要影响。B6背景的小鼠最容易出现IOP升高，严重的前节发育异常（包括畸形的偏心瞳孔，虹膜角膜束，和角膜异常）和青光眼神经损伤。相比之下，具有129个背景的Lmx1bV265D小鼠对发育中的前节异常最有抵抗力，其IOP升高的严重程度低于B6突变体，且未发现可检测的神经损伤。为了确定对Lmx1bV265D诱导的青光眼相关表型易感性的遗传修饰因子，我们在B6（易感）和129（抗性）背景的小鼠之间进行了作图杂交。我们通过共基因分析证实，在18号染色体上发现了一个修饰位点，其中129个等位基因显着降低了眼表型的严重程度。通过展示遗传背景在调节Lmx1b诱导的表型方面的明显作用，通过提供一组具有不同表型严重性的菌株并鉴定修饰位点，