title: The genetic diversity of cystinuria in a UK population of patients.
abstract: OBJECTIVE
  To examine the genetic mutations in the first UK cohort of patients with cystinuria with preliminary genotype/phenotype correlation.
  
  
  METHODS
  DNA sequencing and multiplex ligation-dependent probe amplification (MLPA) were used to identify the mutations in 74 patients in a specialist cystinuria clinic in the UK. Patients with type A cystinuria were classified into two groups: Group M patients had at least one missense mutation and Group N patients had two alleles of all other types of mutations including frameshift, splice site, nonsense, deletions and duplications. The levels of urinary dibasic amino acids, age at presentation of disease, number of stone episodes and interventions were compared between patients in the two groups using the Mann-Whitney U-test.
  
  
  RESULTS
  In all, 41 patients had type A cystinuria, including one patient with a variant of unknown significance and 23 patients had type B cystinuria, including six patients with variants of unknown significance. One patient had three sequence variants in SLC7A9; however, two are of unknown significance. Three patients had type AB cystinuria. Three had a single mutation in SLC7A9. No identified mutations were found in three patients in either gene. There were a total of 88 mutations in SLC3A1 and 55 mutations in SLC7A9. There were 23 pathogenic mutations identified in our UK cohort of patients not previously published. In patients with type A cystinuria, the presence of a missense mutation correlated to lower levels of urinary lysine (mean [SE] 611.9 [22.65] vs 752.3 [46.39] millimoles per mole of creatinine [mM/MC]; P=0.02), arginine (194.8 [24.83] vs 397.7 [15.32] mM/MC; P<0.001) and ornithine (109.2 [7.40] vs 146.6 [12.7] mM/MC; P=0.02). There was no difference in the levels of urinary cystine (182.1 [8.89] vs 207.2 [19.23] mM/MC; P=0.23).
  
  
  CONCLUSIONS
  We have characterised the genetic diversity of cystinuria in a UK population including 23 pathogenic mutations not previously published. Patients with at least one missense mutation in SLC3A1 had significantly lower levels of lysine, arginine, and ornithine but not cystine than patients with all other combinations of mutations.
authors.affiliation: The Urology Centre, Guys and St. Thomas' NHS Foundation Trust, London, UK.
authors.forename: Kathie A
authors.initials: KA
authors.lastname: Wong
authors.affiliation: Genetics Department, Guys Hospital, London, UK.
authors.forename: Rachael
authors.initials: R
authors.lastname: Mein
authors.affiliation: School of Biosciences, University of Kent, Canterbury, Kent, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Wass
authors.affiliation: Genetics Department, Guys Hospital, London, UK.
authors.forename: Frances
authors.initials: F
authors.lastname: Flinter
authors.affiliation: The Urology Centre, Guys and St. Thomas' NHS Foundation Trust, London, UK.
authors.forename: Caroline
authors.initials: C
authors.lastname: Pardy
authors.affiliation: The Urology Centre, Guys and St. Thomas' NHS Foundation Trust, London, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Bultitude
authors.affiliation: The Urology Centre, Guys and St. Thomas' NHS Foundation Trust, London, UK.
authors.forename: Kay
authors.initials: K
authors.lastname: Thomas
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D015415:Biomarkers / Q000652:urine*; D003555:Cystinuria / Q000235:genetics*; D005260:Female; D014644:Genetic Variation / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D060885:Multiplex Polymerase Chain Reaction; D020125:Mutation, Missense / Q000235:genetics*; D012307:Risk Factors; D017422:Sequence Analysis, DNA; D006113:United Kingdom; D055815:Young Adult
chemical_list: D015415:Biomarkers
keywords: SLC3A1; SLC7A9; cystinuria; dibasic amino acids; genetics