title: Digenic Inheritance in Cystinuria Mouse Model.
abstract: Cystinuria is an aminoaciduria caused by mutations in the genes that encode the two subunits of the amino acid transport system b0,+, responsible for the renal reabsorption of cystine and dibasic amino acids. The clinical symptoms of cystinuria relate to nephrolithiasis, due to the precipitation of cystine in urine. Mutations in SLC3A1, which codes for the heavy subunit rBAT, cause cystinuria type A, whereas mutations in SLC7A9, which encodes the light subunit b0,+AT, cause cystinuria type B. By crossing Slc3a1-/- with Slc7a9-/- mice we generated a type AB cystinuria mouse model to test digenic inheritance of cystinuria. The 9 genotypes obtained have been analyzed at early (2- and 5-months) and late stage (8-months) of the disease. Monitoring the lithiasic phenotype by X-ray, urine amino acid content analysis and protein expression studies have shown that double heterozygous mice (Slc7a9+/-Slc3a1+/-) present lower expression of system b0,+ and higher hyperexcretion of cystine than single heterozygotes (Slc7a9+/-Slc3a1+/+ and Slc7a9+/+Slc3a1+/-) and give rise to lithiasis in 4% of the mice, demonstrating that cystinuria has a digenic inheritance in this mouse model. Moreover in this study it has been demonstrated a genotype/phenotype correlation in type AB cystinuria mouse model providing new insights for further molecular and genetic studies of cystinuria patients.
authors.affiliation: Molecular Genetics Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Meritxell
authors.initials: M
authors.lastname: Espino
authors.affiliation: Molecular Genetics Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain; Center for Biomedical Network Research on Rare Diseases (CIBERER), U730, Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Mariona
authors.initials: M
authors.lastname: Font-Llitjós
authors.affiliation: Molecular Genetics Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Clara
authors.initials: C
authors.lastname: Vilches
authors.affiliation: Pathology Department, Canarias University Hospital La Laguna, Tenerife, Spain; Center for Biomedical Network Research on Rare Diseases (CIBERER), U740, La Laguna, Tenerife, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Salido
authors.affiliation: Molecular Genetics Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Prat
authors.affiliation: Molecular Genetics Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain; Center for Biomedical Network Research on Rare Diseases (CIBERER), U730, Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: López de Heredia
authors.affiliation: Institute of Research in Biomedicine (IRB), Barcelona, Spain; Center for Biomedical Network Research on Rare Diseases (CIBERER), U731, Barcelona, Spain; Biochemistry and Molecular Biology Department, Barcelona University (UB)), Barcelona, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Palacín
authors.affiliation: Molecular Genetics Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain; Center for Biomedical Network Research on Rare Diseases (CIBERER), U730, Hospitalet de Llobregat, Barcelona, Spain; Genetic Section, Physiology Science II Department, Barcelona University (UB), Barcelona, Spain.
authors.forename: Virginia
authors.initials: V
authors.lastname: Nunes
mesh_terms: D026923:Amino Acid Transport Systems, Basic / Q000235:genetics* / Q000378:metabolism; D026921:Amino Acid Transport Systems, Neutral / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D003555:Cystinuria / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D040582:Inheritance Patterns; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D020347:Lithiasis / Q000209:etiology / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D010641:Phenotype
chemical_list: D026923:Amino Acid Transport Systems, Basic; D026921:Amino Acid Transport Systems, Neutral; C489858:Slc3a1 protein, mouse; C499488:Slc7a9 protein, mouse