Genetic background modifies vulnerability to glaucoma related phenotypes in
The Authors would like to thank the Histology Services and Computational Services at The Jackson Laboratory, animal care staff at The Jackson laboratory and Columbia University, and Amy Bell for intraocular pressure measurements.
Abstract
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 LMX1Bmutations varies widely between individuals. To better understand mechanisms underlying LMX1B-related phenotypes and individual differences, we backcrossed the Lmx1b V265D (also known as Lmx1b Icst ) 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 Lmx1b V265D/+ mutant mice. Mice of the B6 background were the most susceptible to developing an abnormal IOP distribution, severe anterior segment developmental anomalies (including malformed eccentric pupils, iridocorneal strands, and corneal abnormalities) and glaucomatous nerve damage. In contrast, Lmx1b V265D 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 Lmx1b V265D -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.