Genetic Disorders- Development
Kidney International (2002) 62, 1550–1559; doi:10.1046/j.1523-1755.2002.00602.x
SLC7A9 mutations in all three cystinuria subtypes
Daniel Leclerc, Marylise Boutros, Daniel Suh, Qing Wu, Manuel Palacin, James R Ellis, Paul Goodyer and Rima Rozen
Departments of Human Genetics and Pediatrics, McGill University-Montreal Children's Hospital, Montreal, Quebec, Canada; Departments of Biochemistry and Molecular Biology, University of Barcelona, Barcelona, Spain; and Division of Bioengineering and Physical Science, ORS, National Institutes of Health, Bethesda, Maryland, USA
Correspondence: Dr. Rima Rozen, Montreal Children's Hospital Research Institute, 4060 Ste-Catherine Street West, Rm. 200, Montreal, Quebec, Canada H3Z 2Z3 E-mail: rima.rozen@mcgill.ca
Received 30 January 2002; Revised 14 May 2002; Accepted 11 June 2002.
Abstract
SLC7A9 mutations in all three cystinuria subtypes.
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 (1491GT, E436X) and a possible splicing mutation (IVS9-17GA) 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 (316TC, I44T and 967CT, P261L) linked to Type I alleles.
Conclusion
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.
Keywords:
amino acid, transport, inherited disorder, genetics, kidney, stone, mutation, microcrystals
