(Taken from the application): This project has been designed to study the clinical spectrum of Netherton syndrome (NTS), and to elucidate the molecular basis of the disease. NTS is a rare autosomal recessive congenital ichthyosis, associated with hair shaft abnormalities, elevated IgE levels and other immunologic problems. In severe cases, failure to thrive, growth retardation, and immune defects resulting in recurrent infections with fatal consequences may complicate NTS.
We aim to (1) delineate the clinical features of Netherton syndrome (NTS), (2) define the chromosomal location of the disease gene by genetic linkage mapping, and (3) identify the disease gene. (1) Clinical investigations are focused on the multi system manifestations of NTS to better understand the natural history of the disease, the inter- and intra familial variability, and the relationship to overlapping phenotypes, such as ichthyosis linearis circumflexa, congenital ichthyosiform erythroderma and peeling skin syndrome. Our detailed physical, dermatologic, and genetic examinations will allow us to develop diagnostic criteria and to identify a group of patients with similar features for genetic studies. (2) We will ascertain 10-15 NTS families with one or more affected individuals, their unaffected siblings and parents, and collect biological material for DNA analyses of a total of 40-60 samples. Genetic linkage studies to localize the disease gene initially will focus on 3 promising candidate gene loci. We will determine the genotype of all individuals for 4-6 polymorphic marker loci across each candidate region, and evaluate by linkage analysis if there is co-segregation between the disease and the marker loci. If this approach is successful, we aim to identify the disease gene and molecular defects (mutations) that cause NTS in our patients. Alternatively, if there is no detectable linkage, we will pursue a genome screening approach genotyping 400 highly polymorphic DNA markers covering the human genome with an approximate density of 1 marker per 10 cM.. Subsequently, these genotype data will be analyzed statistically by two-point and multipoint linkage analysis to determine linkage of NTS to a particular chromosomal region. (3) Our ultimate goal is to discover the gene whose mutations underlie NTS. We will apply first a candidate gene approach analyzing genes and expressed sequences within this interval for mutations in NTS patients. If unsuccessful, we plan to generate a physical map and contig of this region, which will be screened for large-scale mutations in affected individuals to gain clues to the physical location of the disease gene. Alternatively, we will create a transcript map of all expressed sequences within the critical region using different techniques, including exon trapping and cDNA selection. Potential disease genes will be evaluated for pathogenic mutations in a panel of affected individuals employing direct DNA sequencing, or other methods of mutation detection, which finally will unveil the disease gene. Based on this knowledge, our approach of clinical research paired with molecular research will allow us to draw correlation between genotype and phenotype, refine the disease classification based on molecular defects, facilitate molecular diagnostics (prenatal, pre-implantation, improved genetic counseling), and develop new therapeutic strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Small Research Grants (R03)
Project #
5R03AR047157-02
Application #
6375359
Study Section
Special Emphasis Panel (ZAR1-AAA-B (M1))
Program Officer
Moshell, Alan N
Project Start
2000-08-15
Project End
2003-07-31
Budget Start
2001-08-01
Budget End
2002-07-31
Support Year
2
Fiscal Year
2001
Total Cost
$75,370
Indirect Cost
Name
Thomas Jefferson University
Department
Dermatology
Type
Schools of Medicine
DUNS #
061197161
City
Philadelphia
State
PA
Country
United States
Zip Code
19107