X‐linked hypophosphatemia (XLHR) is caused by loss‐of‐function mutations in the phosphate regulating endopeptidase homolog X‐linked (PHEX) gene. Considerable controversy exists regarding genotype–phenotype correlations in XLHR. The present study describes the clinical features and molecular genetic bases of 53 pediatric patients with XLHR. Overall, 47 different mutations were identified, of which 27 were not previously described in the literature or entered in the Human Gene Mutation Database (HGMD). A high prevalence (72.34%) of truncating variants was observed in XLHR patients. The clinical presentation and severity of XLHR did not show an evident correlation between the truncating and non‐truncating mutation types in our cohort. To further delineate the characteristics of PHEX variants underlying this nonsignificant trend, we assessed the effects of 10 PHEX variants on protein expression, cellular trafficking, and endopeptidase activity. Our results showed that the nonsense mutations p.Arg567*, p.Gln714*, and p.Arg747* caused a reduction of protein molecular weight and a trafficking defect. Among seven non‐truncating mutations, the p.Cys77Tyr, p.Cys85Ser, p.Ile281Lys, p.Ile333del, p.Ala514Pro, and p.Gly572Ser mutants were not secreted into the medium and remained trapped inside cells in an immature form, whereas the p.Gly553Glu mutant was terminally glycosylated and secreted into the medium. We further assessed the endopeptidase activity of the p.Gly553Glu mutant using a quenched fluorogenic peptide substrate and revealed that the activity of p.Gly553Glu significantly reduced to 13% compared with the wild type, which indicated disruption of catalytic function. These data not only support the clinical results showing no correlation between disease severity and the type of PHEX mutation but also provide helpful molecular insights into the pathogenesis of XLHR. © 2020 American Society for Bone and Mineral Research.
Acute kidney injury (AKI) has been widely recognized as an important risk factor leading to the occurrence and progression of chronic kidney disease (CKD). Thus, development of the strategies in retarding the transition of AKI to CKD is becoming a hot research field. Recently, accumulating evidence suggested a pathogenic role of mitochondrial dysfunction in both AKI and CKD. Therefore, in the present study, we evaluated the effect of mitochondrial complex 1 inhibition by rotenone on the chronic renal damage induced by acute ischemia-reperfusion. The mice were treated with 45 min unilateral renal ischemia and reperfusion (I/R) to induce an acute renal injury. After three days of I/R injury, rotenone at a dose of 200 ppm in food was administered to the mice. Strikingly, after three weeks treatment with rotenone, we found that the unilateral I/R-induced tubular damage, tubulointerstitial fibrosis were all attenuated by rotenone as determined by the tubular injury score, Masson staining, and the levels of collagen-I, collagen-III, fibronectin, PAI-1, and TGF-β. Meanwhile, the enhanced inflammatory markers of TNF-α, IL-1β, IL-6, and IL-18 and apoptotic markers of Bax and caspase-3 were all significantly blunted by inhibiting mitochondrial complex-1. Moreover, rotenone treatment also partially protected the mitochondria as shown by the restoration of mitochondrial SOD (SOD2), ATPB, and mitochondrial DNA copy number. These findings suggested that inhibition of mitochondrial complex-1 activity by rotenone could retard the progression of AKI to CKD probably via protecting the mitochondrial function to some extent.
Purpose To investigate associations of five typical lifestyle-related behavioral risk factors (insufficient physical activity, prolonged screen viewing, deprived sleeping, consumption of fast food and sugar-sweetened beverage) with health-related quality of life (HRQoL) among school students in China. Methods Students aged 9–17 years (grades 4–12) were randomly selected from primary and high schools in Nanjing, China, to participate in this cross-sectional study in 2018. The outcome variable, HRQoL, was assessed using the Child Health Utility 9D (CHU9D) instrument and scored from 0 (worst) to 1 (best). Physical activity (including screen viewing and sleeping) and dietary intake were measured using a validated Physical Activity Scale and Food Frequency Questionnaire, respectively. Lifestyle-related behaviors were categorized as sufficient/insufficient or no/yes, and their associations with HRQoL were assessed using mixed-effects linear regression models. Results Overall, 4388 participants completed the questionnaire (response rate = 97.6%). Students with insufficient physical activity [mean difference (MD) = − 0.03; 95% confidence interval (CI) = − 0.04, − 0.01], prolonged screen time (MD = − 0.06; 95% CI = − 0.07, − 0.04), insufficient sleeping time (MD = − 0.04; 95% CI = − 0.07, − 0.02), consumption of sugar-sweetened beverage (MD = − 0.02; 95% CI = − 0.03, − 0.01) or fast food intake (MD = − 0.03; 95% CI = − 0.04, − 0.02) reported significantly lower HRQoL scores. When considered additively, each additional lifestyle-related risk factor was associated with an average decrease of 0.03 units (95% CI: − 0.03, − 0.02) CHU9D score. Conclusions For Chinese students, HRQoL was positively associated with physical activity and sleep duration, but negatively with screen time and consumption of sugar-sweetened beverage and fast food. Moreover, lifestyle-related behaviors may have an additive effect on HRQoL.
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