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Genetic background modifies vulnerability to glaucoma-related phenotypes in Lmx1b mutant mice

Variants in the LIM homeobox transcription factor 1-beta (LMX1B) gene predispose individuals to elevated intraocular pressure (IOP), a key risk factor for glaucoma. However, the effect of LMX1B mutations varies widely between individuals. To better understand the mechanisms underlying LMX1B-related...

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Autores principales: Tolman, Nicholas G., Balasubramanian, Revathi, Macalinao, Danilo G., Kearney, Alison L., MacNicoll, Katharine H., Montgomery, Christa L., de Vries, Wilhelmine N., Jackson, Ian J., Cross, Sally H., Kizhatil, Krishnakumar, Nair, K. Saidas, John, Simon W. M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Company of Biologists Ltd 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903917/
https://www.ncbi.nlm.nih.gov/pubmed/33462143
http://dx.doi.org/10.1242/dmm.046953
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author Tolman, Nicholas G.
Balasubramanian, Revathi
Macalinao, Danilo G.
Kearney, Alison L.
MacNicoll, Katharine H.
Montgomery, Christa L.
de Vries, Wilhelmine N.
Jackson, Ian J.
Cross, Sally H.
Kizhatil, Krishnakumar
Nair, K. Saidas
John, Simon W. M.
author_facet Tolman, Nicholas G.
Balasubramanian, Revathi
Macalinao, Danilo G.
Kearney, Alison L.
MacNicoll, Katharine H.
Montgomery, Christa L.
de Vries, Wilhelmine N.
Jackson, Ian J.
Cross, Sally H.
Kizhatil, Krishnakumar
Nair, K. Saidas
John, Simon W. M.
author_sort Tolman, Nicholas G.
collection PubMed
description Variants in the LIM homeobox transcription factor 1-beta (LMX1B) gene predispose individuals to elevated intraocular pressure (IOP), a key risk factor for glaucoma. However, the effect of LMX1B mutations varies widely between individuals. To better understand the 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 abnormal IOP distribution, severe anterior segment developmental anomalies (including malformed eccentric pupils, iridocorneal strands and corneal abnormalities) and glaucomatous nerve damage. By 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.
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spelling pubmed-79039172021-02-24 Genetic background modifies vulnerability to glaucoma-related phenotypes in Lmx1b mutant mice Tolman, Nicholas G. Balasubramanian, Revathi Macalinao, Danilo G. Kearney, Alison L. MacNicoll, Katharine H. Montgomery, Christa L. de Vries, Wilhelmine N. Jackson, Ian J. Cross, Sally H. Kizhatil, Krishnakumar Nair, K. Saidas John, Simon W. M. Dis Model Mech Research Article Variants in the LIM homeobox transcription factor 1-beta (LMX1B) gene predispose individuals to elevated intraocular pressure (IOP), a key risk factor for glaucoma. However, the effect of LMX1B mutations varies widely between individuals. To better understand the 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 abnormal IOP distribution, severe anterior segment developmental anomalies (including malformed eccentric pupils, iridocorneal strands and corneal abnormalities) and glaucomatous nerve damage. By 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. The Company of Biologists Ltd 2021-02-19 /pmc/articles/PMC7903917/ /pubmed/33462143 http://dx.doi.org/10.1242/dmm.046953 Text en © 2021. Published by The Company of Biologists Ltd http://creativecommons.org/licenses/by/4.0This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
spellingShingle Research Article
Tolman, Nicholas G.
Balasubramanian, Revathi
Macalinao, Danilo G.
Kearney, Alison L.
MacNicoll, Katharine H.
Montgomery, Christa L.
de Vries, Wilhelmine N.
Jackson, Ian J.
Cross, Sally H.
Kizhatil, Krishnakumar
Nair, K. Saidas
John, Simon W. M.
Genetic background modifies vulnerability to glaucoma-related phenotypes in Lmx1b mutant mice
title Genetic background modifies vulnerability to glaucoma-related phenotypes in Lmx1b mutant mice
title_full Genetic background modifies vulnerability to glaucoma-related phenotypes in Lmx1b mutant mice
title_fullStr Genetic background modifies vulnerability to glaucoma-related phenotypes in Lmx1b mutant mice
title_full_unstemmed Genetic background modifies vulnerability to glaucoma-related phenotypes in Lmx1b mutant mice
title_short Genetic background modifies vulnerability to glaucoma-related phenotypes in Lmx1b mutant mice
title_sort genetic background modifies vulnerability to glaucoma-related phenotypes in lmx1b mutant mice
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903917/
https://www.ncbi.nlm.nih.gov/pubmed/33462143
http://dx.doi.org/10.1242/dmm.046953
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