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Genetic background modifies vulnerability to glaucoma-related phenotypes in Lmx1b mutant mice
Nicholas G Tolman1,2,3, Revathi Balasubramanian1, Danilo G Macalinao3
1Howard Hughes Medical Institute, Department of Ophthalmology, Columbia University Medical Center, and Zuckerman Mind Brain Behavior Institute, New York, NY 10027, USA.
Disease Models & Mechanisms
|January 19, 2021
Summary
Genetic background significantly impacts LMX1B-related glaucoma phenotypes in mice. A modifier locus on chromosome 18 was identified, offering insights into disease variability and potential treatments.
Area of Science:
- Genetics and Ophthalmology
- Molecular Biology and Disease Mechanisms
Background:
- Variants in the LIM homeobox transcription factor 1-beta (LMX1B) gene are linked to elevated intraocular pressure (IOP), a primary glaucoma risk factor.
- The clinical presentation and severity of LMX1B-associated ocular phenotypes exhibit significant inter-individual variability.
Purpose of the Study:
- To investigate the influence of different mouse strain backgrounds on LMX1B-related ocular phenotypes.
- To identify genetic modifiers that contribute to the variable susceptibility to LMX1B-associated glaucoma.
Main Methods:
- Backcrossing of the Lmx1b V265D (Icst) allele onto diverse mouse strain backgrounds (C57BL/6J, 129/Sj, C3H, D2-G).
- Phenotypic analysis of ocular abnormalities, including IOP, anterior segment development, and optic nerve damage across different genetic backgrounds.
- Performing a mapping cross between susceptible (B6) and resistant (129) backgrounds to identify modifier loci.
Main Results:
- Significant strain background-dependent effects on the onset and severity of ocular phenotypes in Lmx1b V265D/+ mice.
- C57BL/6J background mice exhibited the highest susceptibility to severe ocular defects and glaucomatous damage.
- A modifier locus on Chromosome 18 was identified, with 129 alleles significantly reducing phenotype severity.
Conclusions:
- Genetic background plays a crucial role in modulating LMX1B-induced glaucoma-associated phenotypes.
- The study provides a panel of mouse strains with varying disease severities for further research.
- Identification of a novel modifier locus on Chromosome 18 opens avenues for understanding glaucoma pathogenesis and developing targeted therapies.
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