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A Dominant-Negative Mutation of Mouse Lmx1b Causes Glaucoma and Is Semi-lethal via LBD1-Mediated Dimerisation
Mutations in the LIM-homeodomain transcription factor LMX1B cause nail-patella syndrome, an autosomal dominant pleiotrophic human disorder in which nail, patella and elbow dysplasia is associated with other skeletal abnormalities and variably nephropathy and glaucoma. It is thought to be a haploinsu...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4014447/ https://www.ncbi.nlm.nih.gov/pubmed/24809698 http://dx.doi.org/10.1371/journal.pgen.1004359 |
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author | Cross, Sally H. Macalinao, Danilo G. McKie, Lisa Rose, Lorraine Kearney, Alison L. Rainger, Joe Thaung, Caroline Keighren, Margaret Jadeja, Shalini West, Katrine Kneeland, Stephen C. Smith, Richard S. Howell, Gareth R. Young, Fiona Robertson, Morag van t' Hof, Rob John, Simon W. M. Jackson, Ian J. |
author_facet | Cross, Sally H. Macalinao, Danilo G. McKie, Lisa Rose, Lorraine Kearney, Alison L. Rainger, Joe Thaung, Caroline Keighren, Margaret Jadeja, Shalini West, Katrine Kneeland, Stephen C. Smith, Richard S. Howell, Gareth R. Young, Fiona Robertson, Morag van t' Hof, Rob John, Simon W. M. Jackson, Ian J. |
author_sort | Cross, Sally H. |
collection | PubMed |
description | Mutations in the LIM-homeodomain transcription factor LMX1B cause nail-patella syndrome, an autosomal dominant pleiotrophic human disorder in which nail, patella and elbow dysplasia is associated with other skeletal abnormalities and variably nephropathy and glaucoma. It is thought to be a haploinsufficient disorder. Studies in the mouse have shown that during development Lmx1b controls limb dorsal-ventral patterning and is also required for kidney and eye development, midbrain-hindbrain boundary establishment and the specification of specific neuronal subtypes. Mice completely deficient for Lmx1b die at birth. In contrast to the situation in humans, heterozygous null mice do not have a mutant phenotype. Here we report a novel mouse mutant Icst, an N-ethyl-N-nitrosourea-induced missense substitution, V265D, in the homeodomain of LMX1B that abolishes DNA binding and thereby the ability to transactivate other genes. Although the homozygous phenotypic consequences of Icst and the null allele of Lmx1b are the same, heterozygous Icst elicits a phenotype whilst the null allele does not. Heterozygous Icst causes glaucomatous eye defects and is semi-lethal, probably due to kidney failure. We show that the null phenotype is rescued more effectively by an Lmx1b transgene than is Icst. Co-immunoprecipitation experiments show that both wild-type and Icst LMX1B are found in complexes with LIM domain binding protein 1 (LDB1), resulting in lower levels of functional LMX1B in Icst heterozygotes than null heterozygotes. We conclude that Icst is a dominant-negative allele of Lmx1b. These findings indicate a reassessment of whether nail-patella syndrome is always haploinsufficient. Furthermore, Icst is a rare example of a model of human glaucoma caused by mutation of the same gene in humans and mice. |
format | Online Article Text |
id | pubmed-4014447 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-40144472014-05-14 A Dominant-Negative Mutation of Mouse Lmx1b Causes Glaucoma and Is Semi-lethal via LBD1-Mediated Dimerisation Cross, Sally H. Macalinao, Danilo G. McKie, Lisa Rose, Lorraine Kearney, Alison L. Rainger, Joe Thaung, Caroline Keighren, Margaret Jadeja, Shalini West, Katrine Kneeland, Stephen C. Smith, Richard S. Howell, Gareth R. Young, Fiona Robertson, Morag van t' Hof, Rob John, Simon W. M. Jackson, Ian J. PLoS Genet Research Article Mutations in the LIM-homeodomain transcription factor LMX1B cause nail-patella syndrome, an autosomal dominant pleiotrophic human disorder in which nail, patella and elbow dysplasia is associated with other skeletal abnormalities and variably nephropathy and glaucoma. It is thought to be a haploinsufficient disorder. Studies in the mouse have shown that during development Lmx1b controls limb dorsal-ventral patterning and is also required for kidney and eye development, midbrain-hindbrain boundary establishment and the specification of specific neuronal subtypes. Mice completely deficient for Lmx1b die at birth. In contrast to the situation in humans, heterozygous null mice do not have a mutant phenotype. Here we report a novel mouse mutant Icst, an N-ethyl-N-nitrosourea-induced missense substitution, V265D, in the homeodomain of LMX1B that abolishes DNA binding and thereby the ability to transactivate other genes. Although the homozygous phenotypic consequences of Icst and the null allele of Lmx1b are the same, heterozygous Icst elicits a phenotype whilst the null allele does not. Heterozygous Icst causes glaucomatous eye defects and is semi-lethal, probably due to kidney failure. We show that the null phenotype is rescued more effectively by an Lmx1b transgene than is Icst. Co-immunoprecipitation experiments show that both wild-type and Icst LMX1B are found in complexes with LIM domain binding protein 1 (LDB1), resulting in lower levels of functional LMX1B in Icst heterozygotes than null heterozygotes. We conclude that Icst is a dominant-negative allele of Lmx1b. These findings indicate a reassessment of whether nail-patella syndrome is always haploinsufficient. Furthermore, Icst is a rare example of a model of human glaucoma caused by mutation of the same gene in humans and mice. Public Library of Science 2014-05-08 /pmc/articles/PMC4014447/ /pubmed/24809698 http://dx.doi.org/10.1371/journal.pgen.1004359 Text en © 2014 Cross et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Cross, Sally H. Macalinao, Danilo G. McKie, Lisa Rose, Lorraine Kearney, Alison L. Rainger, Joe Thaung, Caroline Keighren, Margaret Jadeja, Shalini West, Katrine Kneeland, Stephen C. Smith, Richard S. Howell, Gareth R. Young, Fiona Robertson, Morag van t' Hof, Rob John, Simon W. M. Jackson, Ian J. A Dominant-Negative Mutation of Mouse Lmx1b Causes Glaucoma and Is Semi-lethal via LBD1-Mediated Dimerisation |
title | A Dominant-Negative Mutation of Mouse Lmx1b Causes Glaucoma and Is Semi-lethal via LBD1-Mediated Dimerisation |
title_full | A Dominant-Negative Mutation of Mouse Lmx1b Causes Glaucoma and Is Semi-lethal via LBD1-Mediated Dimerisation |
title_fullStr | A Dominant-Negative Mutation of Mouse Lmx1b Causes Glaucoma and Is Semi-lethal via LBD1-Mediated Dimerisation |
title_full_unstemmed | A Dominant-Negative Mutation of Mouse Lmx1b Causes Glaucoma and Is Semi-lethal via LBD1-Mediated Dimerisation |
title_short | A Dominant-Negative Mutation of Mouse Lmx1b Causes Glaucoma and Is Semi-lethal via LBD1-Mediated Dimerisation |
title_sort | dominant-negative mutation of mouse lmx1b causes glaucoma and is semi-lethal via lbd1-mediated dimerisation |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4014447/ https://www.ncbi.nlm.nih.gov/pubmed/24809698 http://dx.doi.org/10.1371/journal.pgen.1004359 |
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