A novel missense mutation of SLC7A9 frequent in Japanese cystinuria cases affecting the C-terminus of the transporter

Shigeta, Yasuteru; Kanai, Yoshikatsu; Chairoungdua, Arthit; Ahmed, Nesar; Sakamoto, Shinichi; Matsuo, Hirotaka; Kim, D.K.; Fujimura, Masaaki; Anzai, Naohiko; Mizoguchi, Kenichi; Ueda, Takeshi; Akakura, Koichiro; Ichikawa, Tomohiko; Itô, Haruo; Endou, Hitoshi

doi:10.1038/sj.ki.5000241

Cited by 29 publications

(29 citation statements)

References 30 publications

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“…Tanaka et al 4 reported a 45-year-old man with recurrent renal stones who developed ataxia and extrapyramidal signs, suggesting both cerebellar and basal ganglia involvement. Unlike these cases, our case had no urinary stones, probably because of the milder phenotype associated with the heterozygous (not homozygous) mutation in the SLC7A9 gene, and no SLC3A1 gene abnormality 1. In fact, the present case had a lower urinary cystine concentration than the Japanese cases.…”

Section: Discussioncontrasting

confidence: 56%

“…Lee et al 2 reported a 13-year-old Korean boy with cystinuria with a heterozygous G173R mutation in the SLC7A9 gene, who had intellectual disability and sensory ataxia from posterior column impairment, but no renal stones. Shigeta et al 1 reported that 35 out of 41 patients with cystinuria in Japan had a cystinuria-specific heterozygous and/or homozygous mutation of SLC7A9 with no other polymorphic gene abnormality. Also, there were 25 cases with the P482L homozygous mutation in SLC7A9 and six cases had heterozygous P482L mutations, as in this case.…”

Section: Discussionmentioning

confidence: 99%

“…Laboratory findings show elevated urinary concentrations of cystine and dibasic amino acids, including lysine, arginine and ornithine. This results from an abnormality in the heterodimeric cystine transporter, consisting of a single membrane-spanning type II glycoprotein rBAT and 12-membrane-spanning protein b 0,+ AT/BAT1 subunits in the renal proximal tubules and intestinal epithelia 1. A recent proposed classification of cystinuria was based on its genetic aspects:2

type A cystinuria caused by homozygous SLC3A1 (encoding rBAT) mutations;

type B caused by homozygous SLC7A9 (encoding b 0,+ AT/BAT1) mutations;

type AB showing one mutation in each of these genes.

…”

Section: Introductionmentioning

confidence: 99%

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A case of cystinuria presenting with cerebellar ataxia and dementia

2016

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Cystinuria normally manifests as recurrent urinary stones and renal dysfunction, but can present to neurologists with ataxia, posterior column impairment, intellectual deficiency and pyramidal and extrapyramidal signs; the neuroradiological features include cerebellar, brainstem and cerebral atrophy. It is an autosomal recessive disease caused by a transport disorder of cystine and dibasic amino acids in renal proximal tubules. Most cases have an SLC3A1 and/or SLC7A9 gene mutation but some recent Japanese patients have had distinct heterozygous gene mutations. We report a patient with cystinuria with a heterozygous P482L mutation in the SLC7A9 gene, presenting with atrophy in the cerebellum, brainstem and cerebrum and with no urinary stones. Cystine, an amino acid comprising two cysteine molecules, is transported into cells via a cystine transporter. It is essential for producing hydrogen sulfate and the cellular antioxidant glutathione: these exert neuroprotection in astrocytes and cerebellar Purkinje cells. Although cystinuria is a metabolic disorder associated with renal dysfunction, we suspect that a trafficking defect of transporter rBAT-BAT1 in brain might cause neuronal degeneration, leading to cerebellar and cerebral atrophy.

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Section: Discussioncontrasting

confidence: 56%

Section: Discussionmentioning

confidence: 99%

type A cystinuria caused by homozygous SLC3A1 (encoding rBAT) mutations;

type B caused by homozygous SLC7A9 (encoding b 0,+ AT/BAT1) mutations;

type AB showing one mutation in each of these genes.

…”

Section: Introductionmentioning

confidence: 99%

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A case of cystinuria presenting with cerebellar ataxia and dementia

2016

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“…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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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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“…23,24,27 Several explanations have been pro posed to account for these patients with no known muta tion; for example, mutations leading to cystinuria might be in unexplored regions of SLC3A1 and SLC7A9, or mutations in a third, as yet uncharacterized gene might lead to cystinuria. 6 Furthermore, hypomorphic poly morphisms in c ombination with a mutated allele might have a role in cystinuria.…”

Section: Key Pointsmentioning

confidence: 98%

Cystinuria—a urologist's perspective

et al. 2014

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Cystinuria is a genetic disease that leads to frequent formation of stones. In patients with recurrent stone formation, particularly patients <30 years old or those who have siblings with stone disease, urologists should maintain a high index of suspicion of the diagnosis of cystinuria. Patients with cystinuria require frequent follow-up and a multidisciplinary approach to diagnosis, prevention and management. Patients have reported success in preventing stone episodes by maintaining dietary changes using a tailored review from a specialist dietician. For patients who do not respond to conservative lifestyle measures, medical therapy to alkalinize urine and thiol-binding drugs can help. A pre-emptive approach to the surgical management of cystine stones is recommended by treating smaller stones with minimally invasive techniques before they enlarge to a size that makes management difficult. However, a multimodal approach can be required for larger complex stones. Current cystinuria research is focused on methods of monitoring disease activity, novel drug therapies and genotype-phenotype studies. The future of research is collaboration at a national and international level, facilitated by groups such as the Rare Kidney Stone Consortium and the UK Registry of Rare Kidney Diseases.

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A novel missense mutation of SLC7A9 frequent in Japanese cystinuria cases affecting the C-terminus of the transporter

Cited by 29 publications

References 30 publications

A case of cystinuria presenting with cerebellar ataxia and dementia

A case of cystinuria presenting with cerebellar ataxia and dementia

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

Cystinuria—a urologist's perspective

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