Pathophysiology and treatment of cystinuria

Chillarón, Josep; Font-Llitjós, Mariona; Fort, Joana; Zorzano, António; Goldfarb, David S.; Nunes, Virginia; Palacı́n, Manuel

doi:10.1038/nrneph.2010.69

Cited by 190 publications

(204 citation statements)

References 125 publications

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“…The duplication of exons 5-9 and the missense mutation c.1400T.C, p.(Met467Thr) were the most frequent SLC3A1 (14). The SLC7A9 mutation c.671C.T, p.(Ala224Val) described in a German family in 2002 (36) is rare in reported literature (12) but had a high frequency (15%) in our cohort.…”

Section: Discussionmentioning

confidence: 54%

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Clinical and Genetic Analysis of Patients with Cystinuria in the United Kingdom

Rhodes

Yarram-Smith²,

Rice

et al. 2015

Clinical Journal of the American Society of Nephrology

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Background and objectives Cystinuria is a rare inherited renal stone disease. Mutations in the amino acid exchanger System b 0,+ , the two subunits of which are encoded by SLC3A1 and SLC7A9, predominantly underlie this disease. The work analyzed the epidemiology of cystinuria and the influence of mutations in these two genes on disease severity in a United Kingdom cohort.Design, setting, participants, & measurements Prevalent patients were studied from 2012 to 2014 in the northeast and southwest of the United Kingdom. Clinical phenotypes were defined, and genetic analysis of SLC3A1 and SLC7A9 combining Sanger sequencing and multiplex ligation probe-dependent amplification was performed.Results In total, 76 patients (42 men and 34 women) were studied. All subjects had proven cystine stones. Median age of presentation (first stone episode) was 24 years old, but 21% of patients presented after 40 years old. Patients had varied clinical courses, with 37% of patients having $10 stone episodes; 70% had evidence of CKD, and 9% had reached ESRD as a result of cystinuria and its complications. Patients with cystinuria received a variety of different therapies, with no obvious treatment consensus. Notably, 20% of patients had staghorn calculi, with associated impaired renal function in 80% of these patients. Genetic analysis revealed that biallelic mutations were present in either SLC3A1 (n=27) or SLC7A9 (n=20); 22 patients had only one mutated allele detected (SLC3A1 in five patients and SLC7A9 in 17 patients). In total, 37 different mutant variant alleles were identified, including 12 novel mutations; 22% of mutations were caused by large gene rearrangements. No genotypephenotype association was detected in this cohort.Conclusions Patients with cystinuria in the United Kingdom often present atypically with staghorn calculi at $40 years old and commonly develop significant renal impairment. There is no association of clinical course with genotype. Treatments directed toward reducing stone burden need to be rationalized and developed to optimize patient care.

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Section: Discussionmentioning

confidence: 54%

“…Cohorts of patients from Europe, Asia, and North America have been genotyped (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21) along with a recently published group of United Kingdom patients (22).…”

Section: Introductionmentioning

confidence: 99%

Clinical and Genetic Analysis of Patients with Cystinuria in the United Kingdom

Rhodes

Yarram-Smith²,

Rice

et al. 2015

Clinical Journal of the American Society of Nephrology

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“…Mutations on the gene encoding 4F2hc (Slc3a2), which associates with several members of the Slc7 family, are not connected to any physiological anomaly. 46 in glial processes close to inhibitory neurons that use glycine as a neurotransmitter. When overexpressed in polarized epithelial cells, the isoforms Glyt1a and Glyt1b localize to the apical and basolateral membranes, respectively.…”

Section: Partner Proteinsmentioning

confidence: 99%

Collectrin and ACE2 in renal and intestinal amino acid transport

Singer¹,

Camargo²

2011

Channels

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Neutral amino acid transporters of the SLC6 family are expressed at the apical membrane of kidney and/or small intestine, where they (re-)absorb amino acids into the body. In this review we present the results concerning the dependence of their apical expression on their association to partner proteins. We will in particular focus on the situation of B(0)AT1 and B(0)AT3, which associate with members of the renin-angiotensin system (RAS), namely Tmem27 and angiotensin-converting enzyme 2 (ACE2), in a tissue specific manner. The role of this association in relation to the formation of a functional unit related to Na(+) or amino acid transport will be assessed. We will conclude with some remarks concerning the relevance of this association to Hartnup disorder, where some mutations have been shown to differentially interact with the partner proteins

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“…4F2hc interacts with most of the light chains in HATs whereas rBAT has been known to form a heterodimer only with b 0,+ AT/ SLC7A9. Because the rBAT-b 0,+ AT complex is presented on the apical membrane of proximal tubules in the kidney and involved in the reabsorption of cystine and dibasic amino acids, the mutations of either rBAT or b 0,+ AT cause cystinuria, a disorder of renal reabsorption of cystine and dibasic amino acids leading to serious renal lithiasis due to low solubility of cystine (7).…”

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confidence: 99%

Novel cystine transporter in renal proximal tubule identified as a missing partner of cystinuria-related plasma membrane protein rBAT/SLC3A1

Nagamori

Wiriyasermkul

Guarch

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Heterodimeric amino acid transporters play crucial roles in epithelial transport, as well as in cellular nutrition. Among them, the heterodimer of a membrane protein b 0,+ AT/SLC7A9 and its auxiliary subunit rBAT/ SLC3A1 is responsible for cystine reabsorption in renal proximal tubules. The mutations in either subunit cause cystinuria, an inherited amino aciduria with impaired renal reabsorption of cystine and dibasic amino acids. However, an unsolved paradox is that rBAT is highly expressed in the S3 segment, the late proximal tubules, whereas b 0,+ AT expression is highest in the S1 segment, the early proximal tubules, so that the presence of an unknown partner of rBAT in the S3 segment has been proposed. In this study, by means of coimmunoprecipitation followed by mass spectrometry, we have found that a membrane protein AGT1/SLC7A13 is the second partner of rBAT. AGT1 is localized in the apical membrane of the S3 segment, where it forms a heterodimer with rBAT. Depletion of rBAT in mice eliminates the expression of AGT1 in the renal apical membrane. We have reconstituted the purified AGT1-rBAT heterodimer into proteoliposomes and showed that AGT1 transports cystine, aspartate, and glutamate. In the apical membrane of the S3 segment, AGT1 is suggested to locate itself in close proximity to sodium-dependent acidic amino acid transporter EAAC1 for efficient functional coupling. EAAC1 is proposed to take up aspartate and glutamate released into luminal fluid by AGT1 due to its countertransport so that preventing the urinary loss of aspartate and glutamate. Taken all together, AGT1 is the long-postulated second cystine transporter in the S3 segment of proximal tubules and a possible candidate to be involved in isolated cystinuria.amino acid transporter | cystine reabsorption | cystinuria | kidney T he heteromeric amino acid transporter (HAT) family is one of the major amino acid transporter families responsible for cellular uptake and epithelial transport (1-3). HATs form heterodimers composed of a 12 membrane spanning light chain (SLC7) that catalyzes transport functions and a single membrane spanning heavy chain (SLC3) essential for plasma membrane localization and stabilization of the light chains. Two heavy chains, SLC3A1/ rBAT and SLC3A2/4F2hc/CD98hc, covalently bound to light chains via a disulfide bridge have been identified so far (4-6). 4F2hc interacts with most of the light chains in HATs whereas rBAT has been known to form a heterodimer only with b 0,+ AT/ SLC7A9. Because the rBAT-b 0,+ AT complex is presented on the apical membrane of proximal tubules in the kidney and involved in the reabsorption of cystine and dibasic amino acids, the mutations of either rBAT or b 0,+ AT cause cystinuria, a disorder of renal reabsorption of cystine and dibasic amino acids leading to serious renal lithiasis due to low solubility of cystine (7).An unsolved paradox on rBAT and b 0,+ AT has been the discrepancy between the distribution of rBAT and that of b 0,+ AT (5,(8)(9)(10). rBAT is the most abundant in the S3 segmen...

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Pathophysiology and treatment of cystinuria

Cited by 190 publications

References 125 publications

Clinical and Genetic Analysis of Patients with Cystinuria in the United Kingdom

Clinical and Genetic Analysis of Patients with Cystinuria in the United Kingdom

Collectrin and ACE2 in renal and intestinal amino acid transport

Novel cystine transporter in renal proximal tubule identified as a missing partner of cystinuria-related plasma membrane protein rBAT/SLC3A1

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