title: Molecular genetics of cystinuria: mutation analysis of SLC3A1 and evidence for another gene in type I (silent) phenotype.
abstract: BACKGROUND
  Cystinuria is a hereditary disorder that affects luminal transport of cystine and dibasic amino acids in kidney and small intestine. Three subtypes have been defined on the basis of urinary excretion of cystine in obligate heterozygotes. Mutations in the SLC3A1 gene have been associated with the Type I phenotype.
  
  
  METHODS
  We investigated 20 cystinuria patients from Quebec (8 Type I/I, 9 Type I/III and 3 Type II/N) for mutations in SLC3A1. DNA was studied by Southern blotting and by the single strand conformation polymorphism (SSCP) protocol to identify mutations. Expression of mutations in Xenopus oocytes was performed to confirm the effect of missense mutations on cystine uptake.
  
  
  RESULTS
  Six novel mutations (2 large deletions, a 2 bp deletion and 3 single bp substitutions) were identified on the Type I allele. Four missense mutations (T216M, S217R, R270L and I618M) were expressed in vitro; the first three changes significantly decreased uptake.
  
  
  CONCLUSIONS
  Combined with our previous work, we have identified 15/16 mutations in SLC3A1 on Type I alleles in the eight Type I/I patients, but only one SLC3A1 mutation on the nine Type I alleles of the Type I/III patients. Therefore, we propose that the Type I phenotype could be caused by mutations in other, as yet unidentified cystinuria genes.
authors.affiliation: Department of Pediatrics, McGill University, Montreal, Canada.
authors.forename: I
authors.initials: I
authors.lastname: Saadi
authors.forename: X Z
authors.initials: XZ
authors.lastname: Chen
authors.forename: M
authors.initials: M
authors.lastname: Hediger
authors.forename: P
authors.initials: P
authors.lastname: Ong
authors.forename: P
authors.initials: P
authors.lastname: Pereira
authors.forename: P
authors.initials: P
authors.lastname: Goodyer
authors.forename: R
authors.initials: R
authors.lastname: Rozen
mesh_terms: D026923:Amino Acid Transport Systems, Basic; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D015139:Blotting, Southern; D002352:Carrier Proteins / Q000235:genetics*; D003555:Cystinuria / Q000235:genetics*; D004252:DNA Mutational Analysis; D017931:DNA Primers; D005192:Family Health; D005260:Female; D015870:Gene Expression; D006579:Heterozygote; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D016297:Mutagenesis, Site-Directed; D009154:Mutation / Q000502:physiology; D009865:Oocytes / Q000502:physiology; D010375:Pedigree; D010641:Phenotype; D015183:Restriction Mapping; D014982:Xenopus laevis
chemical_list: D026923:Amino Acid Transport Systems, Basic; D000596:Amino Acids; D002352:Carrier Proteins; D017931:DNA Primers; D008562:Membrane Glycoproteins; C499489:SLC7A9 protein, human