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Genetic studies towards determining disease mechanisms in Lmx1b mutant mice

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Abstract Number: 4251

AuthorBlock: Nicholas Tolman1, Stephen Kneeland1, Saidas Nair2, Katherine MacNicoll1, Sally Cross3, Krish Kizhatil1, Simon John1
1The Jackson Laboratory, Bar Harbor, Maine, United States; 2University of California San Francisco, California, United States; 3University of Edinburgh , , United Kingdom;

DisclosureBlock: Nicholas Tolman, None; Stephen Kneeland, None; Saidas Nair, None; Katherine MacNicoll, None; Sally Cross, None; Krish Kizhatil, None; Simon John, None;

Mutations in LMX1B cause glaucoma. There is a wide range of phenotypic variability between individuals with LMX1B mutations suggesting that genetic modifiers impact individual susceptibility to glaucoma. Mice with dominant Lmx1b mutations (Lmx1bV265D and Lmx1bQ82X) display a similar range of phenotypes to their human counterparts. We characterized ocular phenotypes across multiple inbred mouse strain backgrounds with Lmx1b mutations and identified a modifier locus.

The Lmx1bV265D allele (also known as Lmx1bIcst) was backcrossed onto the C57BL/6J (B6), 129S6/SvEvTac (129), C3H/HeJ (C3H), and DBA/2J.Gpnmb(wt) (D2) backgrounds for at least 6 generations. The Lmx1bQ82X allele was backcrossed onto B6 and D2 backgrounds. Mice were examined using a slit-lamp. IOP measurements, histology, and immunofluorescence on whole-mounted tissue were also performed. To identify genetic modifiers of the Lmx1bV265D mutant phenotype, we performed a mapping cross between B6 and 129 backgrounds.

Differences in the presentation of ocular phenotypes between the different strain backgrounds were evident for both mutant alleles. D2.Lmx1bQ82X mice had age-related IOP elevation and glaucomatous nerve damage. In contrast, B6.Lmx1bQ82X mice did not develop elevated IOP or nerve damage at any examined age. B6.Lmx1bV265D mice had elevated IOP and severe anterior segment developmental anomalies, including malformed eccentric pupils, irido-corneal strands, corneal abnormalities, and abnormal Schlemm’s canal at multiple ages. They also developed glaucomatous nerve damage. In contrast, 129.Lmx1bV265D mice had very mild anterior segment abnormalities, modestly elevated IOP and did not develop glaucomatous nerve damage. On the C3H and D2 backgrounds, Lmx1bV265D mutants had intermediate phenotypes compared to the 129 (resistant) and B6 (susceptible) backgrounds. A mapping cross between B6 and 129 mice with the Lmx1bV265D allele identified a modifier locus on chromosome 18, with the 129 allele substantially lessening phenotypic severity.

Genetic background profoundly influences susceptibility to glaucoma-relevant phenotypes in Lmx1b mutant mice. There is an important modifier locus on chromosome 18 and its future characterization is expected to provide new molecular information about pathways modulating glaucoma-relevant phenotypes.

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