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PLoS Genet. 2014 May 8;10(5):e1004359. doi: 10.1371/journal.pgen.1004359. eCollection 2014.

A dominant-negative mutation of mouse Lmx1b causes glaucoma and is semi-lethal via LBD1-mediated dimerisation.

Author information

  • 1MRC Human Genetics Unit, MRC IGMM, University of Edinburgh, Edinburgh, United Kingdom.
  • 2The Howard Hughes Medical Institute, The Jackson Laboratory, Bar Harbor, Maine, United States of America.
  • 3Centre for Genomic and Experimental Medicine, IGMM, Edinburgh, United Kingdom.
  • 4UCL Institute of Ophthalmology, London, United Kingdom.
  • 5Electron Microscopy, Pathology, Western General Hospital, Edinburgh, United Kingdom.
  • 6MRC Human Genetics Unit, MRC IGMM, University of Edinburgh, Edinburgh, United Kingdom; The Roslin Institute, University of Edinburgh, Easter Bush, United Kingdom.

Abstract

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.

PMID:
24809698
[PubMed - in process]
PMCID:
PMC4014447
Free PMC Article

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