Analysis of SLC25A13 gene variants in 16 infants with intrahepatic cholestasis caused by citrin protein deficiency / 中华医学遗传学杂志

OBJECTIVE@#To explore the characteristics of SLC25A13 gene variants in 16 infants with neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD).@*METHODS@#The infants were subjected to high-throughput DNA sequencing for coding exons and flanking regions of the target genes. Suspected variants were verified by Sanger sequencing and bioinformatic analysis.@*RESULTS@#Among the 16 NICCD cases, 15 were found to harbor pathogenic variants. Among these, IVS14-9A>G, c.1640G>A, c.762T>A, c.736delG, c.1098Tdel and c.851G>A were previously unreported.@*CONCLUSION@#Six novel SLC25A13 variants were found by high-throughput sequencing, which has enriched the spectrum of SLC25A13 gene variants and provided a basis for genetic counseling and prenatal diagnosis.

Identification of the Mutations in the Prostaglandin Transporter Gene, SLCO2A1 and Clinical Characterization in Korean Patients with Pachydermoperiostosis

Pachydermoperiostosis (PDP), or primary hypertrophic osteoarthropathy, is a rare genetic disease affecting both skin and bones. Both autosomal dominant with incomplete penetrance and recessive inheritance of PDP have been previously confirmed. Recently, hydroxyprostaglandin dehydrogenase (HPGD) and solute carrier organic anion transporter family member 2A1 (SLCO2A1) were reported as pathogenic genes responsible for PDP. Both genes are involved in prostaglandin E2 (PGE2) degradation. We aimed to identify responsible genes for PDP and the clinical features in Korean patients with PDP. Six affected individuals and their available healthy family members from three unrelated Korean families with PDP were studied. All of the patients displayed complete phenotypes of PDP with finger clubbing, pachydermia, and periostosis. Mutation analysis revealed a novel heterozygous mutation in the SLCO2A1 gene at nucleotide 302 causing a substitution of the amino acid isoleucine to serine at codon 101 (p.IIe101Ser) in affected individuals. We also identified known SLCO2A1 mutations, one homozygous for c.940+1G>A, and another compound heterozygous for c.940+1G>A and c.1807C>T (p.Arg603*) from two PDP families. Genetic analyses of the PDP patients showed no abnormality in the HPGD gene. Our study further supports the role of mutations in the SLCO2A1 gene in the pathogenesis of PDP and could provide additional clues to the genotype-phenotype relations of PDP.

Impacto dos polimorfismos genéticos SLCO1B1 sobre a hiperbilirrubinemia neonatal: revisão sistemática com metanálise / The impact of SLCO1B1 genetic polymorphisms on neonatal hyperbilirubinemia: a systematic review with meta-analysis

OBJETIVO: Determinar se três variantes (388 G>A, 521 T>C, 463 C>A) do membro 1B1 da família de transportadores de ânions orgânicos portadores de solutos (SLCO1B1) se associam à hiperbilirrubinemia neonatal. FONTE DE DADOS: Foi realizada busca na Infraestrutura do Conhecimento Nacional da China e em MEDLINE. A revisão sistemática com metanálise incluiu estudos genéticos que avaliaram a associação entre hiperbilirrubinemia neonatal e as variantes 388 G>A, 521 T>C, 463 C>A de SLCO1B1 entre janeiro de 1980 e dezembro de 2012. Foi realizada seleção e extração de dados por dois analistas, de forma independente. SUMÁRIO DOS ACHADOS: Foram incluídos dez artigos no estudo. Os resultados revelaram que SLCO1B1 388 G>A se associa a um aumento do risco de hiperbilirrubinemia neonatal (OR< 1,39; IC 95%: 1,07 a 1,82) em recém-nascidos chineses, mas não em recém-nascidos caucasianos, tailandeses, latino-americanos ou malaios. A mutação SLCO1B1 521 T>C mostrou baixo risco de hiperbilirrubinemia neonatal em recém-nascido chineses, e não foram encontradas associações importantes no Brasil nem em recém-nascidos caucasianos, asiáticos, tailandeses e malaios. Não houve diferenças significativas da SLCO1B1 463 C>A entre o grupo com hiperbilirrubinemia e o grupo controle. CONCLUSÃO: O estudo mostrou que a mutação 388 G>A do gene SLCO1B1 é fator de risco para desenvolver hiperbilirrubinemia neonatal em recém-nascidos chineses, mas não em populações caucasianas, tailandesas, brasileiras ou malaias; a mutação SLCO1B1 521 T>C fornece proteção de hiperbilirrubinemia neonatal em recém-nascidos chineses, mas não nas populações caucasianas, tailandesas, brasileiras ou malaias.

OBJECTIVE: To determine whether three variants (388 G>A, 521 T>C, and 463 C>A) of the solute carrier organic anion transporter family member 1B1 (SLCO1B1) are associated with neonatal hyperbilirubinemia. DATA SOURCE: The China National Knowledge Infrastructure and MEDLINE databases were searched. The systematic review with meta-analysis included genetic studies which assessed the association between neonatal hyperbilirubinemia and 388 G>A, 521 T>C, and 463 C>A variants of SLCO1B1 between January of 1980 and December of 2012. Data selection and extraction were performed independently by two reviewers. SUMMARY OF THE FINDINGS: Ten articles were included in the study. The results revealed that SLCO1B1 388 G>A is associated with an increased risk of neonatal hyperbilirubinemia (OR, 1.39; 95% CI, 1.07-1.82) in Chinese neonates, but not in white, Thai, Latin American, or Malaysian neonates. The SLCO1B1 521 T>C mutation showed a low risk of neonatal hyperbilirubinemia in Chinese neonates, while no significant associations were found in Brazilian, white, Asian, Thai, and Malaysian neonates. There were no significant differences in SLCO1B1 463 C>A between the hyperbilirubinemia and the control group. CONCLUSION: This study demonstrated that the 388 G>A mutation of the SLCO1B1 gene is a risk factor for developing neonatal hyperbilirubinemia in Chinese neonates, but not in white, Thai, Brazilian, or Malaysian populations; the SLCO1B1 521 T>C mutation provides protection for neonatal hyperbilirubinemia in Chinese neonates, but not in white, Thai, Brazilian, or Malaysian populations.

Effect of pitavastatin in different SLCO1B1 backgrounds on repaglinide pharmacokinetics and pharmacodynamics in healthy Chinese males

The effect of pitavastatin and SLCO1B1 genetic background on the pharmacokinetic and pharmacodynamic properties of repaglinide was investigated. In this randomized, placebo-controlled, crossover study, twelve healthy Chinese males were administered with pitavastatin 4 mg/d or the placebo for 5 d followed by repaglinide 4 mg given orally on d 5. Plasma repaglinide and glucose levels were measured by liquid chromatography-tandem mass spectrometry [LC/MS/MS] and the glucose oxidase method, respectively. Treatment with pitavastatin significantly increased the peak plasma concentration [C[max]] of repaglinide [P=0.003] in SLCO1B1[asterisk]1b homozygotes [P=0.015] and SLCO1B1[asterisk]15 carriers [P=0.031]. Treatment with pitavastatin led to a marginal increase in the area under plasma concentration-time curve from 0 h to infinity [AUC[0][rightwards arrow][infinity]] of repaglinide [P=0.091]. There was no significant difference in pharmacokinetic parameters or hypoglycemic effects of repaglinide among SLCO1B1 genotypes in either the pitavastatin or control group. Pitavastatin increased the C[max] of the plasma concentration of repaglinide in an SLCO1B1 genotype dependent manner, but had no apparent effect on the pharmacodynamics of repaglinide in healthy volunteers. The p values for this statement were not reported

A Case of Exercise-induced Acute Renal Failure with G774A Mutation in SCL22A12 Causing Renal Hypouricemia

Acute renal failure with severe loin pain which develops after anaerobic exercise is rare. One of predisposing factors of exercise-induced acute renal failure is renal hypouricemia. Idiopathic renal hypouricemia is a genetic disorder characterized by hypouricemia with abnormally high renal tubular uric acid excretion. The mutation in SCL22A12 gene which encodes renal uric acid transporter, URAT1, is the known major cause of this disorder. We here described a 25-yr-old man showing idiopathic renal hypouricemia with G774A mutation in SCL22A12 who presented exercise-induced acute renal failure. There have been a few reports of mutational analysis in Korean idiopathic renal hypouricemia without acute renal failure. This is the first report of genetically diagnosed idiopathic renal hypouricemia with exercise-induced acute renal failure in Korea.

Organic anion transporter protein (OATP1B1) encoded by SLCO1B1 gene polymorphism (388A>G) & susceptibility in gallstone disease.

BACKGROUND & OBJECTIVES: Organic anion transport protein 1B1 (OATP1B1) is a major transporter protein for bile salt uptake in the enterohepatic circulation of bile salts. As the role of SLCO1B1 gene (encodes OATP1B1 or liver specific transporter-1) 388 A>G polymorphism in susceptibility towards gallstone disease is unclear the prevalence of this polymorphism in healthy north Indian population was investigated. METHODS: Peripheral venous blood of 270 unrelated northern Indian patients with symptomatic gallstone disease and 270 unrelated healthy control subjects was screened for SLCO1B1 gene 388 A>G polymorphism by PCR-RFLP method and genotyping was done on 12 per cent polyacrylamide gel. The cross-sectional data on accrual of cases and controls were collected and odds ratio with 95 per cent CI calculated as for case-control design. RESULTS: Allele frequencies of 388 G were 45 per cent in gallstone cases and 44 per cent in controls with no statistical significance. Genotype frequencies in gallstone cases and controls for, genotype AA were 30 and 32 per cent; AG: 51 and 47 per cent and GG: 16 and 21 per cent respectively. No significant association of any allele or genotype with gallstone disease was found. INTERPRETATION & CONCLUSION: Although the prevalence of SLCO1B1 gene 388A>G polymorphism in north Indian population in high, yet this polymorphism does not appear to play a significant role in susceptibility to gallstone formation.

Co-localization and interaction of human organic anion transporter 4 with caveolin-1 in primary cultured human placental trophoblasts

The human organic anion transporter 4 (hOAT4) has been identified as the fourth isoform of OAT family. hOAT4 contributes to move several negatively charged organic compounds between cells and their extracellular milieu. The functional characteristics and regulatory mechanisms of hOAT4 remain to be elucidated. It is well known that caveolin plays a role in modulating proteins having some biological functions. To address this issue, we investigated the co-localization and interaction between hOAT4 and caveolin-1. hOAT4 and caveolin-1 (mRNA and protein expression) were observed in cultured human placental trophoblasts isolated from placenta. The confocal microscopy of immuno-cytochemistry using primary cultured human trophoblasts showed hOAT4 and caveolin-1 were co-localized at the plasma membrane of the cell. This finding was confirmed by Western blot analysis using isolated caveolae-enriched membrane fractions and immune-precipitates from the trophoblasts. When synthesized cRNA of hOAT4 along with scrambled- or antisense-oligodeoxynucleotide (ODN) of Xenopus caveolin-1 were co-injected to Xenopus oocytes, the [3H]estrone sulfate uptake was significantly decreased by the co-injection of antisense ODN but not by scrambled ODN. These findings suggest that hOAT4 and caveolin-1 share a cellular expression in the plasma membrane and caveolin-1 up-regulates the organic anionic compound uptake by hOAT4 under the normal physiological condition.