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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.

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