Strain dependent differences modulating ocular phenotypes in Lmx1b mutant mice

Abstract

Purpose : Mutations in LMX1B cause anterior segment dysgenesis, elevated IOP and glaucoma, however, there is great phenotypic variability between individuals. Mice with a dominant negative valine to aspartic acid (Lmx1b^V265D) mutation show a similar range of phenotypes. Characterizing genetic modifier genes can provide new mechanistic information. To begin to identify genetic modifiers impacting the effects of Lmx1b mutations in glaucoma, we crossed the Lmx1b^V265D allele onto several inbred mouse strain backgrounds.

Methods : We backcrossed the Lmx1b^V265D allele (also known as Lmx1b^Icst) onto the C57BL/6J (B6), 129S6/SvEvTac (129), C3H/HeJ (C3H), and DBA/2J.Gpnmb(wt) (D2) backgrounds for at least 6 generations. Lmx1b^V265D/+ and wild-type (WT) control littermates were examined using a slit-lamp. We also used, cannulated IOP measurements, histology, and immunofluorescence on whole-mounted eyes to characterize the ocular phenotypes in Lmx1b^V265D/+ mice. To determine loci that modify ocular phenotypes in Lmx1b^V265D mutant mice, we performed a mapping cross between B6 and 129 backgrounds.

Results : We found strain dependent differences in the presentation of ocular phenotypes in Lmx1b^V265D mice. B6.Lmx1b^V265D mice had severe anterior segment clinical features, which included malformed eccentric pupils, irido-corneal strands, corneal haze and corneal scleralization. B6.Lmx1b^V265D mice also showed elevated IOP at early ages and had the most severe glaucomatous nerve damage of any examined strain. 129.Lmx1b^V265D mice displayed mild anterior clinical features compared with the other strains, but did develop elevated IOP. Lmx1b^V265D caused moderate phenotypes on C3H and D2 backgrounds compared to the 129 (resistant) and B6 (susceptible) backgrounds. A mapping cross between B6 and 129 mice with the Lmx1b^V265D allele identified a locus on chromosome 18 that confers differential susceptibility to Lmx1b^V265D induced abnormalities.

Conclusions : Genetic background profoundly influences susceptibility to glaucoma-relevant clinical features in Lmx1b^V265D/+ mice, with an important modifier locus on chromosome 18. Using genetic approaches to map modifier loci in mice with Lmx1b mutations is a valuable approach to uncover genes and pathways that modulate susceptibility to glaucoma.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.