title: SLC7A9 mutations in all three cystinuria subtypes.
abstract: BACKGROUND
  Cystinuria is an inherited disorder of cystine and dibasic amino acid transport in kidney. Subtypes are defined by the urinary cystine excretion patterns of the obligate heterozygous parents: Type I/N (fully recessive or silent); Type II/N (high excretor); Type III/N (moderate excretor). The first gene implicated in cystinuria (SLC3A1) is associated with the Type I urinary phenotype. A second cystinuria gene (SLC7A9) was recently isolated, and mutations of this gene were associated with dominant (non-Type I) cystinuria alleles. Here we report genotype-phenotype studies of SLC7A9 mutations in a cohort of well-characterized cystinuria probands and their family members.
  
  
  METHODS
  Individual exons of the SLC7A9 gene were screened by single strand conformation polymorphism (SSCP) analysis and sequencing of abnormally migrating fragments.
  
  
  RESULTS
  Seven mutations were identified. A single bp insertion (799insA) was present in four patients: on Type III alleles in two patients and on Type II alleles in two patients. These results suggest that Type II and Type III may be caused by the same mutation and, therefore, other factors must influence urinary cystine excretion. A 4bp deletion in intron 12 (IVS12+4delAGTA) and a missense mutation (1245G-->A, A354T) were identified on Type III alleles. A nonsense codon (1491G-->T, E436X) and a possible splicing mutation (IVS9-17G-->A) were seen in a Type I/III patient, but the mutations could not be assigned to particular alleles. Of additional interest were two missense mutations (316T-->C, I44T and 967C-->T, P261L) linked to Type I alleles.
  
  
  CONCLUSIONS
  Our results provide evidence that some SLC7A9 mutations may be associated with fully recessive (Type I) forms of cystinuria. We also demonstrate SLC7A9 mutations in dominant Types II and III cystinuria. The finding of SLC7A9 mutations in all three subtypes underscores the complex interactions between specific cystinuria genes and other factors influencing cystine excretion. A simpler phenotypic classification scheme (recessive and dominant) for cystinuria is warranted.
authors.affiliation: Department of Human Genetics, McGill University-Montreal Children's Hospital, Montreal, Quebec,Canada.
authors.forename: Daniel
authors.initials: D
authors.lastname: Leclerc
authors.forename: Marylise
authors.initials: M
authors.lastname: Boutros
authors.forename: Daniel
authors.initials: D
authors.lastname: Suh
authors.forename: Qing
authors.initials: Q
authors.lastname: Wu
authors.forename: Manuel
authors.initials: M
authors.lastname: Palacin
authors.forename: James R
authors.initials: JR
authors.lastname: Ellis
authors.forename: Paul
authors.initials: P
authors.lastname: Goodyer
authors.forename: Rima
authors.initials: R
authors.lastname: Rozen
mesh_terms: D000328:Adult; D017398:Alternative Splicing; D026923:Amino Acid Transport Systems, Basic; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D002648:Child; D018389:Codon, Nonsense; D003555:Cystinuria / Q000145:classification / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D017353:Gene Deletion; D005838:Genotype; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism*; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010641:Phenotype
chemical_list: D026923:Amino Acid Transport Systems, Basic; D002352:Carrier Proteins; D018389:Codon, Nonsense; D008562:Membrane Glycoproteins; C499489:SLC7A9 protein, human