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Abstract
ABSTRACTVariants in the LIM homeobox transcription factor 1-beta (LMX1B) gene 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 the 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) mouse 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 abnormal IOP distribution, severe anterior segment developmental anomalies (including malformed eccentric pupils, iridocorneal strands and corneal abnormalities) and glaucomatous nerve damage. By 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, providing a panel of strains with different phenotypic severities and 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.
Highlights
Glaucoma is a group of complex disorders that share a characteristic pattern of visual field deficits and retinal ganglion cell degeneration
Recent genome wide association studies (GWAS) studies indicate that LIM homeobox transcription factor 1-beta gene (LMX1B) variants cause elevated intraocular pressure (IOP) and glaucoma in the general human population, without evident anterior segment abnormalities, involvement of other organs/tissues or nail-patella syndrome (NPS) diagnosis (Choquet et al, 2018; Gao et al, 2018; Gharahkhani et al, 2018; Khawaja et al, 2018; MacGregor et al, 2018; Shiga et al, 2018)
Several factors may contribute to differing disease presentations between individuals including the nature of the LMX1B variant, genetic modifiers, and environmental factors
Summary
Glaucoma is a group of complex disorders that share a characteristic pattern of visual field deficits and retinal ganglion cell degeneration. It is a leading cause of blindness worldwide affecting 80 million people (Quigley and Broman, 2006). Important risk factors for glaucoma include elevated intraocular pressure (IOP), genetics, and advanced age. Resistance to AqH drainage from the eye through the SC and TM is important in determining IOP. The mechanisms underlying dysfunctional AqH drainage and subsequent IOP elevation require additional characterization. A majority of glaucoma cases are attributed to primary open angle glaucoma (POAG), where IOP elevation lacks an obvious physical cause (Quigley and Broman, 2006). Research that defines how these genes affect IOP is expected to yield new drug targets and improved treatments for lowering IOP (Choquet et al, 2020)
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