Nail Patella Syndrome (NPS) is a diverse phenotype inherited in an autosomal dominant manner. The syndrome is characterized by dysplasia of the nails, patellae and elbows, as well as open angle glaucoma and potentially lethal nephropathy. It has been established that NPS is the result of heterozygous loss-of- function mutations in the LIM-homeodomain transcription factor, LMX1B. The NPS mutations identified to date are concentrated within the LIM and homeodomains; none have been found within the carboxy-terminal third of the coding region. Comparison with animal models suggests that the orthopaedic problems associated with NPS result from a failure of dorsalization during limb development. The NPS phenotype can vary markedly within families, as well as between unrelated persons. There is no correlation between the severity of the phenotype and LMX1B mutations. The basis for this variation must originate outside the LIM1B coding sequence. Promoter elements controlling LMX1B expression and molecules that interact with LMX1B will be identified. These sequences will be assessed for variants in NPS families exhibiting a range of phenotypic severity. It will also be determined if the carboxy-terminal domain plays a role in the development of the limbs. Interacting proteins will be identified and transgenic mice lacking this domain will be analyzed. This information may allow an accurate prognosis of NPS severity. Not only will these experiments address the question of phenotypic variation within a single gene disorder, but an understanding of how genes interact in the development of a phenotype will help in deriving the etiology of genetically complex conditions. Furthermore, by identification of elements controlling LMX1B expression and the factors interacting with LMX1B, a better model of limb development will be derived.
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