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At least 19 recordsLinked to original sources
PubMed2026

Generation of a novel Slc7a9G105R mutant mouse identifies new biomarkers for cystinuria.

INTRODUCTION: Cystinuria is a rare inherited disease characterized by increased urinary cystine levels resulting in the formation of cystine stones in the urinary tract. Mutations in the genes encoding the cystine transporter complex, SLC3A1 and SLC7A9, are the primary drivers of the disease. Current mouse models used to study cystinuria rely on gene deficiency or spontaneous mutations in mice that do not accurately reflect the pathogenic mutations found in humans. METHODS: We generated a novel Slc7a9G105R knock-in mouse model in which glycine at position 105 is replaced by arginine, recapitulating the most common pathogenic mutation in human SLC7A9. Disease onset and progression were assessed using micro-CT imaging, fecal metagenomics, and urine and serum metabolomics and proteomics. RESULTS: Both male and female Slc7a9G105R mice developed a cystinuria phenotype by nine weeks of age, characterized by substantial cystine stone formation and increased urinary cystine, lysine, arginine, and ornithine. Slc7a9G105R mice displayed distinct serum and urinary metabolite profiles, mapped to dibasic amino acid pathways, and serum protein profiles, mapped to disease progression. Fecal metagenomics revealed that Slc7a9G105R mice had a heterogeneous microbiota with altered functional pathways, including increased L-cysteine biosynthesis. Antibiotic-induced depletion of the microbiota did not affect cystine stone burden but reduced urinary tract inflammation. Prophylactic or therapeutic dietary supplementation with alpha-lipoic acid reduced stone burden and inflammation, but it also caused urothelial damage. Untargeted metabolomics analysis following alpha-lipoic acid supplementation identified metabolites that can increase cystine solubility, reduce inflammation, and damage epithelial cells. Correlation analysis revealed novel serum metabolite biomarkers of stone burden, including 2-hydroxybutyric acid and 2-amino-2-thiazoline-4-carboxylic acid, which were also detected in human serum. CONCLUSIONS: Collectively, the Slc7a9G105R mutant mouse model offers a precise, rapid-onset, and translational platform for investigating cystinuria pathogenesis and evaluating potential therapeutic strategies.

SLC7A9↗
PubMed1979

Childhood cystinuria in New South Wales. Results in children who were followed up after being detected by urinary screening in infancy.

Homozygous cystinuria was diagnosed in 45 children and 19 of their siblings in the course of routine urine screening of 6-week-old infants in New South Wales. These children were followed for up to 14 years. During this time there were 5 clinical episodes of renal disease which could be ascribed to cystinuria. There was normal mental development in all the children except one. Of 49 children over 3 years, 4 had height centiles less than the midparent height centile, while 45 had height centiles equal to or above the midparent centiles. Family testing in these 45 cases showed that 60% were type I cystinurics, and 35% were of the mixed or compound type (5% were not classified). Data from the parents and grandparents showed that renal tract calculi had occurred in 14 of them. This study shows that children with homozygous cystinuria, detected by urinary screening in infancy, rarely have renal symptoms. Mental development was normal as was growth in height. There was an increased incidence of noncystine stone formation among the relatives of these children. The incidence of homozygous cystinuria in New South Wales in one in 17 286.

Adolescent↗
PubMed1979

Heterozygous cystinuria and calcium oxalate urolithiasis.

Many variables are known to be associated with the formation of calcium oxalate urolithiasis but none is essential for the initiation or growth of stones. It is likely that the predisposition to stone formation is related to multiple factors. We herein describe still another metabolic state that seems to predispose to calcium oxalate stone disease, namely heterozygosity for cystinuria. Cystine screening tests were done on 24-hour urine specimens obtained from 126 patients in whom recurrent calcium oxalate stones form and 84 controls and quantitative amino acid determinations were done on all positive specimens. Of those studied 17 of 126 stone patients and 1 of 84 controls were heterozygous cystinurics. A test of the differences between the relative frequencies of cystinuria heterozygotes in the 2 groups with Fisher's exact test revealed them to be highly significant (p less than 0.001). Our study indicates that carrier status for 1 of the cystinuria genes predisposes to calcium oxalate stone formation but, like other factors related to urolithiasis, it is not a necessary cause of stone disease.

Adolescent↗
PubMed1979

[The hyperaminoacidurias with special reference to cystinuria].

Increased urinary excretion of free amino acids is a sign which requires determination of the underlying cause. Physiological aspects of tubular transport with emphasis on the role played by transport proteins or carriers are briefly discussed. Subsequently we present a resumptive classification. In prerenal hyperaminoaciduria the urinary excretion of amino acids just reflects the error in amino acid metabolism. Depending on tubular reabsorption of the amino acid involved in the metabolic error three types can be distinguished: the overflow, the competitive and the non-threshold hyperaminoacidurias. Renal hyperaminoaciduria can either be specific for individual or group-related amino acids, or generalized involving all amino acids. With the exception of classical cystinuria the various hyperaminoacidurias have more theoretical than clinical importance. Generalized hyperaminoaciduria is always a symptom of severe tubular disturbance which can be produced by various metabolic diseases, intoxications or deficiency states. Finally we present our experience in the treatment of cystinuria with mercaptopropionyl-glycine.

Amino Acids↗
PubMed1978

Cystinuria genotypes predicted from excretion patterns.

Genotypes of 17 patients with cystinuria were predicted from data based on excretion rates of the families' obligate carriers. The methodology differed from that used by other investigators as it did not employ intestinal biopsy studies or loading dose measurements. The Type I form was more common than either Type II or Type III and frequently occurred in combination to give compound heterozygous genotypes with the Type III form.

Adolescent↗
PubMed1979

A new screening method for cystinuria. A simple and safe screening kit.

The new kit (Urocystin) presented here utilizes the dark brown coloration which a neutral aqueous solution of cystine develops rapidly upon addition of nickel ion and sodium hydrosulfite (Na2S2O4). What is needed is pouring 4 ml of the urine sample into the kit, and the kit is able to judge without fail any urine sample with a cystine concentration of 50 microgram/ml or more as positive. No pretreatment of the sample is necessary. The kit contains no hazardous reagents at all. The kit has thus turned screening of cystinuria into an extremely simple affair.

Cystinuria↗
PubMed1979

Skin and bone lesions (dermato-osteolathyrism), possible side effects of D-penicillamine treatment, in a boy with cystinuria.

A 2 1/4 year-old boy was treated for cystinuria and urolithiasis with high fluid intake, sodium bicarbonate, and D-penicillamine, over a period of 5 3/4 years, unauthorized interruptions and prescribed pauses included. Therapy was partially sucessful but regrowth of calculi coincided with interruptions of D-penicillamine administration and also with the institution of a low-dose D-penicillamine regime. Flat feet, scoliosis, pectus carinatum, hypermobility of joints, molluscoid pseudotumors and atrophic scars were alarming side effects of D-penicillamine. However, the possibility was not excluded that a forme fruste of an Ehlers-Danlos syndrome preexisted in this boy and was effected by D-penicillamine. Only the molluscoid pseudotumors regressed when D-penicillamine was reduced or omitted temporarily. Osteolathyrism caused by D-penicillamine has hitherto not been reported in man.

Atrophy↗
PubMed1977

Low Dose D-penicillamine in cystinuria.

(1) A single dose of D-penicillamine (not more than 750 mg) taken at 2200 h, together with a prescribed fluid intake of two to three litres during the waking hours, without extra drinks at night, is sufficient to keep the concentration of the urinary cystine below the saturating concentration of urine throughout the 24 h period. (2) This regime does not materially reduce the total 24 h excretion of cystine. (3) The effect of D-penicillamine is mainly seen in the urine excreted between 0200 and 0800 h. (4) This regime is provisionally recommended for the prevention of cystine stone recurrence but not for stone dissolution. Larger total amounts of D-penicillamine given in divided doses are still recommended for the latter purpose.

Adolescent↗