A Dominant-Negative Mutation of Mouse Lmx1b Causes Glaucoma and Is Semi-lethal via LBD1-Mediated Dimerisation

• Published in: PLoS genetics Vol. 10; no. 5; p. e1004359
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: San Francisco, USA Public Library of Science 01.05.2014
• Subjects: Biology and Life Sciences; Causes of; Defects; Experiments; Gene mutations; Genes; Genetic aspects; Genetic research; Genotype & phenotype; Glaucoma; Kidneys; Medical research; Mutation; Optic nerve; Proteins; Research and Analysis Methods; Studies; Transcription factors
• DOI: 10.1371/journal.pgen.1004359
• ISSN: 1553-7404; 1553-7390

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 Lmxlb 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 Lmxlb 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 Lmxlb 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 Lmxlb 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 Lmxlb. 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.