Objective -To establish a cystinuria data base (clinical data and DNA bank) from European populations. -To describe the spectrum of mutations in the rBAT gene causing cystinuria type I. -To study the structure-function relationship of the rBAT transporter. -To search for the gene(s) responsible for cystinuria type II and III. -To clarify the cystinuria phenotypes based on the clinical, biochemical and genetic studies. -To identify the promoter region of the rBAT gene that directs the gene expression of rBAT to epithelial cells of the S3 segment of the nephron.This is a multidisciplinary project, where 6 research groups, including clinicians, biochemists, an electrophysiologist and genetecits, to achieve a better understanding of the molecular basis of cystinuria, a common inherited aminoaciduria with a prevalence ranging between 1:7000 and 1:15.000. The disease is divided into three phenotypes.The new advances in cystinuria research, at the molecular level, have been performed by our groups: i) description of mutations in the rBAT gene (named SLC3Al in GDB) causing cystinuria type I and ii) type II and type III cystinuria are not due to mutations in the rBAT gene. The precise objectives of this proposal are listed below:1) Development of a cystinuria data base, already iniciated by the International Study of the Genetic Renal Diseases (ISGRD) and creation of the corresponding DNA data bank;2) Characterization of new mutations in the rBAT gene;3) To study the relationship between structure and function in rBAT transporter mutants;4) Search for other genes responsible for cystinuria types II and III;5) Identify, characterise, purify, and if possible to clone the putative light subunit of the rBAT protein;6) To identify the promoter region of the rBAT gene that will allow in cell culture models as well as "in vivo" (transgenic mice) to direct the gene expression to the epithelial cells of the S3 segment in the nephron.The cystinuria data bank will support a high enough number of cases to permit the study of the genotype-phenotype relationship, in addition this will provide a suitable amount of rare type II cystinuria families to perform exclusion map studies. To define the spectrum of rBAT mutations it will be necessary to fully characterise the promotor region of the rBAT gene. Clinical classification and linkage studies will determine which families are not linked to the rBAT gene and will generate enough informativity for use in exclusion map studies. This will identify the candidate chromosomal regions for the genes responsible for cystinuria types II and III map. The next step will be to clone these genes. At the protein level if we are able to clone the putative "light" subunit of the rBAT protein we will perform the bichemical and molecular genetics studies to demonstrate the function of rBAT plus the "light" subunit as an active tertiary exchanger for cystine and dibasic amino acids (bO,+-like system) as well as the responsability of the "light subunit" in cystinuria. Simultaneously we will define the relationship between structure and function of the rBAT transporter mutants, by expressing them either in oocytes or in mammalian cells, studying the transport activity, performing structural and cellular biology studies and by reconstituting the wild type and mutant rBAT transporters. Finally at the end of this work a phenotype-genotype correlation will be established. Fields of science natural sciencesbiological sciencesmolecular biologymolecular geneticsmedical and health sciencesclinical medicinenephrologynatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsnatural sciencesbiological sciencesgeneticsmutationnatural scienceschemical sciencesorganic chemistryamines Programme(s) FP4-BIOMED 2 - Specific research, technological development and demonstration programme in the field of biomedicine and health, 1994-1998 Topic(s) 4.6 - RARE DISEASES Call for proposal Data not available Funding Scheme CSC - Cost-sharing contracts Coordinator CANCER RESEARCH INSTITUTE EU contribution No data Address KM 2,7,Gran Via s/n, Km 2,7 08907 HOSPITALET DEL LLOBREGAT Spain See on map Total cost No data Participants (5) Sort alphabetically Sort by EU Contribution Expand all Collapse all IRCCS - OPSEDALE CASA SOLLIEVO DELLA SOFFERENZA Italy EU contribution No data Address Viale Cappuccini 1 71013 SAN GIOVANNI ROTONDO See on map Total cost No data PAEDIATRIC HOSPITAL BAMBINO GESU Italy EU contribution No data Address 4,Piazza Sant' Onofrio 4 00165 Roma See on map Total cost No data THE UNIVERSITY OF TUEBINGEN Germany EU contribution No data Address Gmelinstrasse 5 72076 TUEBINGEN See on map Total cost No data The Hebrew University of Jerusalem - The Authority for Research and Development Israel EU contribution No data Address 91120 Jerusalem See on map Total cost No data UNIVERSITAT DE BARCELONA Spain EU contribution No data Address Avda Diagonal 645 08028 BARCELONA See on map Total cost No data
