ABSTRACT
OBJECTIVE: To explore the clinical characteristics and genetic basis of two Chinese pedigrees affected with Joubert syndrome. METHODS: Clinical data of the two pedigrees was collected. Genomic DNA was extracted from peripheral blood samples and subjected to high-throughput sequencing. Candidate variants were verified by Sanger sequencing. Prenatal diagnosis was carried out for a high-risk fetus from pedigree 2. RESULTS: The proband of pedigree 1 was a fetus at 23+5 weeks gestation, for which both ultrasound and MRI showed "cerebellar vermis malformation" and "molar tooth sign". No apparent abnormality was noted in the fetus after elected abortion. The fetus was found to harbor c.812+3G>T and c.1828G>C compound heterozygous variants of the INPP5E gene, which have been associated with Joubert syndrome type 1. The proband from pedigree 2 had growth retardation, mental deficiency, peculiar facial features, low muscle tone and postaxial polydactyly of right foot. MRI also revealed "cerebellar dysplasia" and "molar tooth sign". The proband was found to harbor c.485C>G and c.1878+1G>A compound heterozygous variants of the ARMC9 gene, which have been associated with Joubert syndrome type 30. Prenatal diagnosis found that the fetus only carried the c.485C>G variant. A healthy infant was born, and no anomalies was found during the follow-up. CONCLUSION: The compound heterozygous variants of the INPP5E and ARMC9 genes probably underlay the disease in the two pedigrees. Above finding has expanded the spectrum of pathogenic variants underlying Joubert syndrome and provided a basis for genetic counseling and prenatal diagnosis.
Subject(s)
Abnormalities, Multiple , Eye Abnormalities , Kidney Diseases, Cystic , Female , Humans , Pregnancy , Pedigree , Cerebellum/diagnostic imaging , Cerebellum/abnormalities , Abnormalities, Multiple/genetics , Abnormalities, Multiple/diagnosis , Eye Abnormalities/genetics , Eye Abnormalities/diagnosis , Kidney Diseases, Cystic/genetics , Kidney Diseases, Cystic/diagnosis , Phosphoric Monoester Hydrolases/genetics , Retina/diagnostic imaging , Retina/abnormalities , East Asian People , MutationABSTRACT
OBJECTIVE: CYP3A4*1G (G > A) in human CYP3A4 intron 10 is associated with therapeutic effects of CYP3A4-metabolized drugs. The aim of this study was to predict its function in the regulation of CYP3A4 expression. METHODS: Functional analysis of the CYP3A4*1G allele was performed using bioinformatic methods and enhancer or promoter reporter assays in HepG2 cells. RESULTS: Transcription regulatory elements like CAATboxes, TATA-boxes, Sp1, SMARCA3.01, and Box II-like sequence were present in the intron 10 of CYP3A4. SMARCA3.01 and Box II-like sequence were responsible for differential binding of transcription factors on the CYP3A4*1G allele. In CYP3A4*1G, the G allele enhanced expression of the CYP3A4 promoter in a position-dependent and orientation-dependent manner, however, the A allele enhanced expression of the CYP3A4 promoter in a position-independent and orientation-independent manner. In addition, the G allele and the A allele both displayed strong transcriptional activation, but the latter showed higher promoter activity than the former. Also, the A allele showed greater activity than the CYP3A4 promoter. CONCLUSION: These results in vitro suggest that CYP3A4*1G regulates CYP3A4 intron 10 enhancer and promoter activity in an allelic-dependent manner.
Subject(s)
Alleles , Cytochrome P-450 CYP3A/genetics , Cytochrome P-450 CYP3A/metabolism , Enhancer Elements, Genetic , Introns , Promoter Regions, Genetic , Base Sequence , Binding Sites , Computational Biology , Gene Expression Regulation, Enzymologic , Genes, Reporter , Genotype , Hep G2 Cells , Humans , Molecular Sequence Data , Phenotype , Transcription Factors/metabolism , Transcription, Genetic , Transcriptional Activation , TransfectionABSTRACT
BACKGROUND: Gender differences in pharmacokinetics have been reported to have important clinical consequences; however, no information about differences in the pharmacokinetics of the cholesterol-lowering drug simvastatin lactone and its metabolite, simvastatin hydroxy acid, in males and females is available. OBJECTIVE: The aim of this study was to investigate the effect of gender on the pharmacokinetics of simvastatin lactone and simvastatin hydroxy acid in healthy Han Chinese volunteers. METHODS: 16 healthy volunteers (8 males and 8 females) were orally administered a single dose of 40 mg simvastatin lactone after an overnight fast. Plasma was then collected 24 hours after simvastatin lactone administration. Concentrations of simvastatin lactone and simvastatin hydroxy acid were measured by high performance liquid chromatography/mass spectrometry/mass spectrometry (HPLC/MS/MS). RESULTS: There were no significant associations between the pharmacokinetic parameters of simvastatin lactone and gender. For simvastatin hydroxy acid, peak plasma concentrations (Cmax) and dose-normalized by the subject weight Cmax (NCmax) were higher in females than in males. Furthermore, NCmax and dose-normalized by the subject weight AUC (NAUC0-24h, NAUC0-∞) ratios of simvastatin hydroxy acid to simvastatin lactone in females were higher than in males. CONCLUSION: This study indicates that gender affects the plasma concentrations of active simvastatin hydroxy acid, but has no significant effect on parent simvastatin lactone. Raised plasma concentrations of simvastatin hydroxy acid in females may enhance the risk of systemic adverse effects during simvastatin lactone treatment.