Cystinuria type A (about 45% of the cystinuria cases) is an inherited disorder caused by mutations in SLC3A1 encoding the heavy chain of the renal amino acid transporter responsible for the transport of cysteine and the dibasic amino acids ornithine, lysine and arginine (COLA). This leads to an impairment of their reabsorption in the renal proximal tubule and the small intestine (PMID:24246330).
Cystinuria is an autosomal disorder characterized by impaired epithelial cell transport of cystine and dibasic amino acids (lysine, ornithine, and arginine) in the proximal renal tubule and gastrointestinal tract. The impaired renal reabsorption of cystine and its low ... Cystinuria is an autosomal disorder characterized by impaired epithelial cell transport of cystine and dibasic amino acids (lysine, ornithine, and arginine) in the proximal renal tubule and gastrointestinal tract. The impaired renal reabsorption of cystine and its low solubility causes the formation of calculi in the urinary tract, resulting in obstructive uropathy, pyelonephritis, and, rarely, renal failure (summary by Barbosa et al., 2012).
Wollaston (1810) first described a cystine stone. He found that a glistening yellow bladder stone was composed of an unusual substance, which he called cystic oxide since it came from the bladder. Later analysis showed this to be ... Wollaston (1810) first described a cystine stone. He found that a glistening yellow bladder stone was composed of an unusual substance, which he called cystic oxide since it came from the bladder. Later analysis showed this to be a sulfur-containing amino acid and so this stone ultimately gave its name not only to cystinuria but also to the amino acids cystine and cysteine. Marcet (1817) showed that cystine stones occur also in the kidney. He suspected that the condition might be familial since 2 of his patients were brothers. Cystinuria was one of the 4 inborn errors of metabolism discussed by Garrod (1908). Rosenberg et al. (1966) described 3 forms of cystinuria, each due to presumed homozygosity of a particular mutant allele at 1 locus. In cystinuria I, the homozygote excretes relatively large amounts of cystine, lysine, arginine and ornithine in the urine. Heterozygotes (e.g., parents) have no abnormal amino aciduria. Urinary stones form in all 3 types of cystinuria because of the limited solubility of this amino acid. Cystinuria II is incompletely recessive because heterozygotes have a moderate degree of amino aciduria, mainly cystine and lysine, and may occasionally form cystine stones. Observations in kindreds in which both cystinuria I and cystinuria II are segregating demonstrate that the genes for these are allelic (Hershko et al., 1965). In cystinuria III, intestinal transport of all dibasic amino acids is retained by heterozygotes, and homozygotes excrete cystine in slight excess. Rosenberg (1966) and others observed families in which 'doubly heterozygous' persons (I-II, I-III, or II-III) had full-blown cystinuria. The findings were best explained on the basis of allelism of the genes responsible for the 3 types. Brodehl et al. (1967) reported a 2-year-old girl who was discovered to have isolated hypercystinuria with normal urine levels of arginine, lysine, and ornithine during an evaluation for candidiasis. A younger brother had the same pattern of urinary amino acid excretion. Their unrelated parents and an older sister had normal cystine excretion. The female proband was also noted to have isolated hyperparathyroidism, which was suspected to be familial because another sister and brother had died due to hypocalcemic tetany. Scriver et al. (1970) presented evidence indicating that cystinuria patients are at increased risk for impaired cerebral function. Weinberger et al. (1974) demonstrated an unusually high frequency of type II or III cystinuria among Libyan Jews. Kelly (1978) concluded that the excretion rates of obligate carriers among the relatives of cystinurics suffice to determine the type of cystinuria in the proband. Among 17 patients he studied, type I was the most frequent type and often occurred in compound heterozygotes with type III. When obligatory heterozygotes showed normal amounts of cystine and dibasic amino acids in the urine, they were called type I. When up to twice the normal range was excreted in the urine, they were called type III. When carriers excreted large amounts of cystine and lysine (9-15 times the normal range but less than in most stone-formers), they were called type II. On the basis of a study in Brazil, Giugliani et al. (1985) concluded that there is an increased frequency of heterozygotes for types II and III cystinuria among urinary stone-formers and that heterozygosity for these genes is a risk factor for urinary stones.
Calonge et al. (1994) sought mutations in the SLC3A1 gene because of its plausible candidacy as the site of the defect in cystinuria. In affected individuals from 8 different families, they identified 6 missense mutations in the SLC3A1 ... Calonge et al. (1994) sought mutations in the SLC3A1 gene because of its plausible candidacy as the site of the defect in cystinuria. In affected individuals from 8 different families, they identified 6 missense mutations in the SLC3A1 gene (which they referred to as rBAT), which segregated with cystinuria and accounted for 30% of the cystinuria chromosomes studied. Homozygosity for the most common mutation, met467-to-thr (104614.0001), was detected in 3 cystinuric sibs. This M467T mutation nearly abolished the amino acid transport activity induced by rBAT in Xenopus oocytes. Kastner (1994) also found mutations in the SLC3A1 gene; 1 patient was a genetic compound of a deletion in the maternal chromosome and a single base substitution in the paternal chromosome. Gasparini et al. (1995) pointed out that all mutations identified in the SLC3A1 gene to that point belonged to cystinuria type I alleles, accounting for approximately 44% of all type I cystinuric chromosomes. After analysis of 70% of the FLC3A1 coding region, they had detected normal sequences in cystinuria type II and type III cases. The mutant alleles occurred in homozygous type I/I and in heterozygotes of type I/III, indicating genetic heterogeneity of cystinuria. They referred to linkage data also supporting genetic heterogeneity of cystinuria. Their studies were done in Italians and Spaniards, which may explain their conclusion that genetic heterogeneity of cystinuria exists; Pras et al. (1994) failed to find linkage evidence of heterogeneity in Jewish families which may have come from a more homogeneous background. On the basis of biochemical data, Goodyer et al. (1993) had suggested a complementation model with an interaction and expression of mutated alleles of 2 different genes, 1 for cystinuria type I and the other for cystinuria type III. First-degree relatives of type I patients had no abnormal urinary amino acid excretion, while type II and type III heterozygous individuals showed increased amounts of cystine in the dibasic amino acids in their urine. Moreover, oral cystine loading fails to raise serum cystine levels in type I and type II patients but results in nearly normal elevation of plasma cystine levels in type III patients, thus demonstrating a different intestinal defect. Gasparini et al. (1995) suggested that the genes involved in cystinuria types II and III may be genes coding for cystine transporters expressed in the S1 and S2 segments of the proximal tubule and/or a functionally associated subunit of an oligomeric rBAT transporter. In Libyan Jewish, North American, Italian, and Spanish patients with non-type I cystinuria, the International Cystinuria Consortium (1999) identified mutations in the SLC7A9 gene. The Libyan Jewish patients were homozygous for a founder missense mutation (604144.0001) that abolished b(0,+)AT amino acid uptake activity when cotransfected with rBAT in COS cells. In other patients, they identified 4 missense mutations and 2 frameshift mutations. The authors were not able to fully differentiate between type II and type III phenotypes: according to the urinary amino acid profile, most of the patients described seemed to have inherited type III cystinuria from both parents, but there were exceptions. The results suggested that types II and III, and in some cases type I, represent allelic differences in SLC7A9. Other factors, genetic and environmental, were probably involved. In 1 patient, mutations in SLC7A9 (604144.0002) and in SLC3A1 (104614.0001) were found. These preliminary results suggested that cystinuria is a digenic disease in some of the mixed type I/non-type I patients and supported the hypothesis of partial genetic complementation (Goodyer et al., 1993). The International Cystinuria Consortium (1999) offered 2 hypotheses as to why mutations in the SLC3A1 gene are recessive, whereas mutations in the SLC7A9 gene are incompletely recessive. First, if the active b(0,+) transporter is constituted by more than 1 rBAT and b(0,+)AT subunit, 1 mutated allele of the light subunit might produce a dominant defect, whereas 1 mutated allele of the rBAT heavy subunit would produce a trafficking defect. Second, the light subunit might associate with a protein other than rBAT and express cystine transport activity in a different proximal tubular segment. In situ hybridization and immunolocalization studies showed expression of the light subunit in the epithelial cells of the proximal straight tubule, like the heavy subunit, but higher expression in the proximal convoluted tubule. Most of the renal cystine reabsorption occurs in the proximal convoluted tubule via a low-affinity system not identified at the molecular level. If the SLC7A9 gene also encodes this transport system, a partial defect in this major renal reabsorption mechanism would explain the incompletely recessive phenotype of non-type I cystinuria. The International Cystinuria Consortium (2001) reported the genomic structure of SLC7A9 and 28 new mutations in this gene that, together with 7 previously reported, characterized 79% of the mutant alleles in 61 non-type I cystinuria patients. Therefore, SLC7A9 appears to be the main non-type I cystinuria gene. The most frequent SLC7A9 missense mutations found were gly105 to arg (G105R; 604144.0002), val170 to met (V170M; 604144.0001), ala182 to thr (A182T; 604144.0003), and arg333 to trp (R333W; 604144.0008). Among heterozygotes carrying these mutations, A182T heterozygotes showed the lowest urinary excretion values of cystine and dibasic amino acids, correlating with significant residual transport activity in vitro. In contrast, mutations G105R, V170M, and R333W were associated with a complete or nearly complete loss of transport activity, leading to a more severe urinary phenotype in heterozygotes. SLC7A9 mutations located in the putative transmembrane domains of b(0,+)AT and affecting conserved amino acid residues with a small side chain were associated with a severe phenotype, while mutations in nonconserved residues gave rise to a mild phenotype. The authors presented a genotype-phenotype correlation in non-type I cystinuria, and hypothesized that a mild urinary phenotype in heterozygotes may be associated with mutations permitting significant residual transport activity. Dello Strologo et al. (2002) studied the amino acid excretion patterns of 189 heterozygotes with mutations in either SLC3A1 or SLC7A9. All SLC3A1 carriers and 14% of SLC7A9 carriers showed a normal amino acid urinary pattern (type I phenotype). The remainder of the SLC7A9 carriers showed the non-I phenotype: 80.5% were type III and 5.5%, type II. Dello Strologo et al. (2002) concluded that the traditional classification of cystinuria patients was imprecise and proposed a new classification based on genotype: type A, due to mutation in the SLC3A1 gene; type B, due to mutation in the SLC7A9 gene; and type AB, due to a mutation in both the SLC3A1 and SLC7A9 genes. Leclerc et al. (2002) identified 2 missense mutations in the SLC7A9 gene (see 604144.0009 and 604144.0010) linked to type I alleles in a type I homozygote and in a patient with mixed (I/II) cystinuria, respectively. They also found that a single SLC7A9 mutation (799insA; see 601411.0011) was present on 2 type II and 2 type III alleles in 4 patients with mixed cystinuria, suggesting that type II and type III cystinuria may be caused by the same mutation and, therefore, that other factors must influence urinary cystine excretion. Harnevik et al. (2003) analyzed the SLC3A1 and SLC7A9 genes in 16 unclassified Swedish cystinuria patients, 15 of whom were stone-forming. In 1 of the stone-forming patients, Harnevik et al. (2001) had previously identified compound heterozygosity for mutations in the SLC3A1 gene (see 104614.0001 and 104614.0008); this patient was found by Harnevik et al. (2003) to have a mutation in the SLC7A9 gene (604144.0010) as well. In 9 patients, only 1 mutation in SLC3A1 was found; 1 patient had only 1 mutation in SLC7A9; and in 4 patients, no mutations were identified. Harnevik et al. (2003) suggested that other mechanisms of gene inactivation, such as gene silencing, or additional genes may contribute to the pathogenesis of cystinuria. Font-Llitjos et al. (2005) classified 164 unrelated cystinuria patients and their relatives on the basis of urine excretion of cystine and dibasic amino acids by obligate heterozygotes and screened for mutations in the SLC3A1 and SLC7A9 genes. They identified phenotype I heterozygotes with mutations in SLC7A9 (e.g., 604144.0001-604144.0004 and 604144.0012) and phenotype non-I heterozygotes with duplication of exons 5 to 9 of the SLC3A1 gene (104614.0007). Font-Llitjos et al. (2005) also identified 2 individuals of mixed phenotype and digenic inheritance with 3 mutations each: 1 had a mutation in each SLC3A1 allele and a mutation in 1 SLC7A9 allele (104614.0001, 104614.0007, and 604144.0013, respectively), and the other had a mutation in each SLC7A9 allele and a mutation in 1 SLC3A1 allele (604144.0002, 604144.0012, and 104614.0001, respectively). In a brother and sister with isolated hypercystinuria previously reported by Brodehl et al. (1967), Eggermann et al. (2007) identified a likely causative mutation in the SLC7A9 gene (T123M; 604144.0014). Both sibs, who had never formed urinary stones, also carried an I260M variant in the SLC7A9 gene that was not found in more than 100 controls; however, it was also present in their healthy older sister who had normal aminoaciduria values, and Eggermann et al. (2007) concluded that I260M is a rare polymorphism. The female proband had also been noted to have isolated hypoparathyroidism by Brodehl et al. (1967); during follow-up with Eggermann et al. (2007), she was diagnosed with autoimmune polyendocrinopathy type I (APS1; 240300) and found to be compound heterozygous for 2 common mutations in the AIRE1 gene (607358.0001 and 607358.0003), which were not found in her healthy sister or her brother. Barbosa et al. (2012) reported 12 Portuguese probands with cystinuria, who were classified as homozygous (7 patients) or heterozygous non-type I (5 patients) according to the concentration of cystine in the urine. Among the 7 homozygous patients, 6 had onset of lithiasis or urinary tract infection in the first or second decades. The seventh patient was ascertained in infancy due to neonatal hypotonia. The 6 patients with urinary symptoms all had relatives with lithiasis. Among the 5 non-type I patients diagnosed as children, 2 presented with lithiasis and 2 were ascertained during workup for developmental delay and autism spectrum disorder, respectively. Molecular analysis showed that 6 of the 7 homozygous patients had 2 mutations in the SLC3A1 gene (see, e.g., 104614.0001; 104614.0007; 104614.0009). Three of the patients were compound heterozygous for the exon 5-9 duplication (104614.0007) and another pathogenic SLC3A1 mutation. The seventh patient had 1 mutation in the SLC7A9 gene and another variant in the SLC7A9 gene that may have contributed to the disorder. Four of the 5 non-type I patients had a mutation in the SCL7A9 gene; 1 patient was heterozygous for the exon 5-9 duplication in SLC3A1. Overall, the most common pathogenic mutations in both genes were large genomic rearrangements (33.3% of mutant alleles) and M467T in SLC3A1 (104614.0001) (11.1% of mutant alleles).
The overall prevalence of cystinuria is approximately 1 in 7,000 neonates, ranging from 1 in 2,500 neonates in Libyan Jews to 1 in 100,000 among Swedes (review by Barbosa et al., 2012).