Marylise Boutros | PubMed Health

PubMed2005

Transient neonatal cystinuria.

BACKGROUND: Cystinuria is an inherited disorder of luminal reabsorptive transport for cystine and dibasic amino acids in the renal proximal tubule. Two cystinuria genes have been identified. Mutations of SLC7A9, which encodes the luminal transport channel itself, tend to be dominant and mutations of SLC3A1 (rBAT), which encodes a transporter subunit, are always recessive. Patients who inherit two recessive mutations or two dominant mutations have equally severe forms of cystinuria. Heterozygotes excrete cystine in the normal (type I), moderate (type III), or high stone-forming (type II) range. METHODS: Infants with cystinuria were identified via the Quebec Newborn Urinary Screening Program. In a subgroup of these infants, cystinuria was severe in the first months of life, but partially resolved by 2 to 4 years postnatally. We assigned each patient a final cystinuria phenotype at 3 to 4 years. In addition, we characterized SLC3A1 gene expression in fetal and postnatal human kidney. RESULTS: Most infants with transient neonatal cystinuria are eventually classified as type III heterozygotes. All infants with mutant cystinuria genes have exaggerated neonatal cystine excretion except those who inherit two SLC3A1 mutations (type I/I cystinuria); these children have persistent severe cystinuria, implying that wildtype SLC3A1 is required for the maturational effect. Expression of SLC3A1 mRNA was found to be tenfold higher in postnatal vs. fetal kidney; SLC3A1 expression is doubled by the proximal tubule transcription factor, PAX8. rBAT is expressed in the proximal convoluted and straight tubules in both fetal and adult kidney. CONCLUSION: Maturation of SLC3A1 gene expression between midgestation and 4.5 years postnatal age may account for transient neonatal cystinuria.

Amino Acid Transport Systems, Basic↗

PubMed2002

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 (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. 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.

Adult↗