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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
2R01AR044702-04
Application #
6196499
Study Section
Orthopedics and Musculoskeletal Study Section (ORTH)
Program Officer
Panagis, James S
Project Start
1997-07-01
Project End
2005-06-30
Budget Start
2000-07-07
Budget End
2001-06-30
Support Year
4
Fiscal Year
2000
Total Cost
$346,860
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Migeon, B R; Chowdhury, A K; Dunston, J A et al. (2001) Identification of TSIX, encoding an RNA antisense to human XIST, reveals differences from its murine counterpart: implications for X inactivation. Am J Hum Genet 69:951-60
Hamlington, J D; Jones, C; McIntosh, I (2001) Twenty-two novel LMX1B mutations identified in nail patella syndrome (NPS) patients. Hum Mutat 18:458
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