July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
Strain dependent differences modulating ocular phenotypes in Lmx1b mutant mice
Author Affiliations & Notes
  • Nicholas Tolman
    The Jackson Laboratory, Bar Harbor, Maine, United States
    Tufts University, Boston, Massachusetts, United States
  • Katharine H. MacNicoll
    The Jackson Laboratory, Bar Harbor, Maine, United States
  • Krishnakumar Kizhatil
    The Jackson Laboratory, Bar Harbor, Maine, United States
  • Saidas Nair
    University of San Francisco, San Francisco, California, United States
  • Sally H. Cross
    The University of Edinburgh, Edinburgh, United Kingdom
  • Richard S. Smith
    The Jackson Laboratory, Bar Harbor, Maine, United States
  • Simon W John
    The Jackson Laboratory, Bar Harbor, Maine, United States
    Tufts University, Boston, Massachusetts, United States
  • Footnotes
    Commercial Relationships   Nicholas Tolman, None; Katharine MacNicoll, None; Krishnakumar Kizhatil, None; Saidas Nair, None; Sally Cross, None; Richard Smith, None; Simon John, None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 5158. doi:
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      Nicholas Tolman, Katharine H. MacNicoll, Krishnakumar Kizhatil, Saidas Nair, Sally H. Cross, Richard S. Smith, Simon W John; Strain dependent differences modulating ocular phenotypes in Lmx1b mutant mice. Invest. Ophthalmol. Vis. Sci. 2018;59(9):5158.

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      © ARVO (1962-2015); The Authors (2016-present)

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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 (Lmx1bV265D) 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 Lmx1bV265D allele onto several inbred mouse strain backgrounds.

Methods : We backcrossed the Lmx1bV265D allele (also known as Lmx1bIcst) onto the C57BL/6J (B6), 129S6/SvEvTac (129), C3H/HeJ (C3H), and DBA/2J.Gpnmb(wt) (D2) backgrounds for at least 6 generations. Lmx1bV265D/+ 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 Lmx1bV265D/+ mice. To determine loci that modify ocular phenotypes in Lmx1bV265D 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 Lmx1bV265D mice. B6.Lmx1bV265D mice had severe anterior segment clinical features, which included malformed eccentric pupils, irido-corneal strands, corneal haze and corneal scleralization. B6.Lmx1bV265D mice also showed elevated IOP at early ages and had the most severe glaucomatous nerve damage of any examined strain. 129.Lmx1bV265D mice displayed mild anterior clinical features compared with the other strains, but did develop elevated IOP. Lmx1bV265D 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 Lmx1bV265D allele identified a locus on chromosome 18 that confers differential susceptibility to Lmx1bV265D induced abnormalities.

Conclusions : Genetic background profoundly influences susceptibility to glaucoma-relevant clinical features in Lmx1bV265D/+ 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.

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