Variants in genes coding for collagen type IV α-chains are frequent causes of persistent, isolated hematuria during childhood.

BACKGROUND: Children with persistent, isolated microscopic hematuria typically undergo a limited diagnostic workup and are monitored for signs of kidney disease in long-term longitudinal follow-up, which can delay diagnosis and allow disease progression in some cases. METHODS: To determine the clinical utility of genetic screening in this population, we performed targeted genetic testing using a custom, 32-gene next-generation sequencing panel for progressive kidney disease on children referred to the Texas Children's Hospital Pediatric Nephrology clinic for persistent, microscopic hematuria (n = 30; cohort 1). Patients with microscopic hematuria identified by urinalysis on at least two separate occasions were eligible for enrollment, but those with other evidence of kidney disease were excluded. Results were analyzed for sequence variants using the American College of Medical Genetics and Genomics (ACMG) guideline for data interpretation and were validated using a secondary analysis of a dataset of children with hematuria and normal kidney function who had undergone genetic testing as part of an industry-sponsored program (cohort 2; n = 67). RESULTS: In cohort 1 33% of subjects (10/30) had pathogenic or likely pathogenic (P/LP) variants in the type IV collagen genes (COL4A3/A4/A5), and 10% (3/30) had variants of uncertain significance in these genes. The high diagnostic rate in type IV collagen genes was confirmed in cohort 2, where 27% (18/67) of subjects had P/LP variants in COL4A3/A4/A5 genes. CONCLUSIONS: Children with persistent, isolated microscopic hematuria have a high likelihood of having pathogenic variants in type IV collagen genes and genetic screening should be considered. A higher resolution version of the Graphical abstract is available as Supplementary information.

Transcriptome signature identifies distinct cervical pathways induced in lipopolysaccharide-mediated preterm birth.

With half a million babies born preterm each year in the USA and about 15 million worldwide, preterm birth (PTB) remains a global health issue. Preterm birth is a primary cause of infant morbidity and mortality and can impact lives long past infancy. The fact that there are numerous, and many currently unidentified, etiologies of PTB has hindered development of tools for risk evaluation and preventative therapies. Infection is estimated to be involved in nearly 40% of PTBs of known etiology; therefore, understanding how infection-mediated inflammation alters the cervical milieu and leads to preterm tissue biomechanical changes are questions of interest. Using RNA-seq, we identified enrichment of components involved in inflammasome activation and unique proteases in the mouse cervix during lipopolysaccharide (LPS)-mediated PTB and not physiologically at term before labor. Despite transcriptional induction of inflammasome components, there was no evidence of functional activation based on assessment of mature IL1B and IL18 proteins. The increased transcription of proteases that target both elastic fibers and collagen and concentration of myeloid-derived cells capable of protease synthesis in the cervical stroma support the structural disruption of elastic fibers as a functional output of protease activity. The recent demonstration that elastic fibers contribute to the biomechanical function of the pregnant cervix suggests their protease-induced disruption in the infection model of LPS-mediated PTB and may contribute to premature loss of mechanical competency and preterm delivery. Collectively, the transcriptomics and ultrastructural data provide new insights into the distinct mechanisms of premature cervical remodeling in response to infection.

DHEA-mediated inhibition of the pentose phosphate pathway alters oocyte lipid metabolism in mice.

Women with polycystic ovary syndrome (PCOS) and hyperandrogenism have altered hormone levels and suffer from ovarian dysfunction leading to subfertility. We have attempted to generate a model of hyperandrogenism by feeding mice chow supplemented with dehydroepiandrosterone (DHEA), an androgen precursor that is often elevated in women with PCOS. Treated mice had polycystic ovaries, low ovulation rates, disrupted estrous cycles, and altered hormone levels. Because DHEA is an inhibitor of glucose-6-phosphate dehydrogenase, the rate-limiting enzyme in the pentose phosphate pathway, we tested the hypothesis that oocytes from DHEA-exposed mice would have metabolic disruptions. Citrate levels, glucose-6-phosphate dehydrogenase activity, and lipid content in denuded oocytes from these mice were significantly lower than controls, suggesting abnormal tricarboxylic acid and pentose phosphate pathway metabolism. The lipid and citrate effects were reversible by supplementation with nicotinic acid, a precursor for reduced nicotinamide adenine dinucleotide phosphate. These findings suggest that elevations in systemic DHEA can have a negative impact on oocyte metabolism and may contribute to poor pregnancy outcomes in women with hyperandrogenism and PCOS.

Improved insulin sensitivity by GLUT12 overexpression in mice.

OBJECTIVE: Evidence suggests that insulin-sensitive glucose transporters (GLUTs) other than GLUT4 may exist. To investigate whether GLUT12 may represent another insulin-sensitive GLUT, transgenic (TG) mice that overexpress GLUT12 were characterized. RESEARCH DESIGN AND METHODS: TG mice that overexpressed GLUT12 under a ß-actin promoter were generated. Glucose metabolism in TG and wild-type control mice was compared using glucose and insulin tolerance tests and hyperinsulinemic-euglycemic clamps. In addition, basal and insulin-stimulated glucose clearance rates into insulin-sensitive peripheral tissues were measured using [(3)H]-2-deoxy-D-glucose. RESULTS: GLUT12 was overexpressed by 40-75% in TG compared with wild-type mice in insulin-sensitive tissues with no change in GLUT4 content. Body weight and fasting blood glucose did not differ between wild-type and TG mice; however, insulin concentrations were reduced in TG mice. Enhanced oral glucose tolerance was noted in TG mice by a reduced blood glucose excursion compared with wild-type mice (P < 0.05). Enhanced insulin sensitivity was noted by a greater decrease in blood glucose in TG mice during insulin tolerance testing. Hyperinsulinemic-euglycemic clamps confirmed enhanced insulin sensitivity in GLUT12-overexpressing mice (P < 0.01). Tissues of TG mice exhibited normal basal glucose clearance rates; however, under insulin-stimulated conditions, glucose clearance was significantly increased (P < 0.01) in tissues of TG mice. CONCLUSIONS: Increased expression of GLUT12 results in improved whole-body insulin sensitivity mediated by an increased glucose clearance rate in insulin-responsive tissues under insulin-stimulated, but not basal, conditions. These findings provide evidence that GLUT12 represents a novel, second insulin-sensitive GLUT.