Small nuclear RNAs (snRNAs) combine with specific proteins to generate small nuclear ribonucleoproteins (snRNPs), the building blocks of the spliceosome. U4 snRNA forms a duplex with U6 and, together with U5, contributes to the tri-snRNP spliceosomal complex. Variants in RNU4-2, which encodes U4, have recently been implicated in neurodevelopmental disorders. Here we show that heterozygous inherited and de novo variants in RNU4-2 and in four RNU6 paralogs (RNU6-1, RNU6-2, RNU6-8 and RNU6-9), which encode U6, recur in individuals with nonsyndromic retinitis pigmentosa (RP), a genetic disorder causing progressive blindness. These variants cluster within the three-way junction of the U4/U6 duplex, a site that interacts with tri-snRNP splicing factors also known to cause RP (PRPF3, PRPF8, PRPF31), and seem to affect snRNP biogenesis. Based on our cohort, deleterious variants in RNU4-2 and RNU6 paralogs may explain up to ~1.4% of otherwise undiagnosed RP cases. This study highlights the contribution of noncoding RNA genes to Mendelian disease and reveals pleiotropy in RNU4-2, where distinct variants underlie neurodevelopmental disorder and retinal degeneration.
Choline was first declared to be an essential nutrient in 1998. Current research on choline intake has been sufficient for the Food and Nutrition Board of the National Academies of Science, Engineering & Medicine to establish a loose guideline, but more investigation into healthy choline intakes is necessary to clarify guidelines. Choline is intimately involved in human metabolism, as an essential precursor for cell membrane components such as phosphatidylcholine and sphingomyelin, lipoprotein and fatty acid trafficking, and the neurotransmitter acetylcholine. It plays an essential role in histone, RNA, and DNA methylation, creatine synthesis, and more. Choline-related pathologies have already been implicated in multiple severe developmental diseases, such as schizophrenia, Down syndrome, and neural tube defects, and age-related diseases such as Alzheimer's. Choline supplementation has been shown to alleviate the symptoms of neurodevelopmental diseases, such as Fetal Alcohol Spectrum Disorder and neonatal hyperbilirubinemia. The choline intake by most adults is estimated to be less than the current recommendations. Choline supplementation, particularly for vulnerable populations such as pregnant women, preterm infants, and cystic fibrosis patients, requires further investigation to establish adequate recommendations and to fully elucidate the consequences of malnutrition. Outcomes of choline deficiency and supplementation, such as neurodevelopment, should be measured. IMPACT: What this article adds to the existing literature An up-to-date summary of the metabolism of choline A review of the role of choline in normal and abnormal neurodevelopment A concise description of sources of choline.
ABSTRACT:Large-scale sequencing efforts have defined up to 27 diagnostic subtypes in B-cell precursor acute lymphoblastic leukemia (B-ALL), leaving few samples unclassified. Extended genomic and transcriptomic profiling in routine diagnostics broadens the sample collection, enabling identification of novel subtypes. We analyzed 4857 patients with B-ALL from 3 cohorts and identified a group of 20 patients (age, 18-66 years; median, 34 years) characterized by a previously undescribed IGH::FENDRR rearrangement exclusive to this subtype (n = 17/20), KRAS p.A146T/V/P mutations (n = 17/20 vs n = 86/4857; P< .001), and distinct DNA methylation/gene expression profiles, including overexpression of the lncRNA FENDRR and the transcription factor FOXF1 (FOXF1/FENDRR) as well as JAK/STAT and RAS/MAPK signaling signatures. A gene expression machine learning classifier accurately identified FOXF1/FENDRR cases in 2 independent cohorts. Patients treated according to German Multicenter Study Group for Adult ALL (GMALL)/Group for Research in Adult ALL (GRAALL) protocols showed very poor chemotherapy response with 8 of 13 exhibiting induction failure or minimal residual disease (MRD) ≥10-3 and 8 of 12 remaining MRD positive after first consolidation/salvage. Intensification including blinatumomab (n = 10) and/or allogeneic stem cell transplantation (n = 12) resulted in ongoing molecular remission in 13 of 16 patients. FOXF1/FENDRR represents a novel B-ALL subtype which might benefit from early immunotherapeutic treatment or targeted interventions.
The choice of vascular access (VA) plays a key role in the success of hemodialysis (HD). Despite their widespread use, central venous catheters (CVCs) are associated with higher rates of dysfunction, thrombosis, and catheter-related bloodstream infections (CRBSI). We investigated current practices in pediatric HD across European pediatric nephrology centers, focusing on VA choices, infection control measures, and CRBSI management. An online questionnaire was e-mailed to 119 members of the European Society for Pediatric Nephrology (ESPN) Dialysis Working Group and European Pediatric Dialysis Working Group (EPDWG). Descriptive statistics were used to summarize practices across centers, comparative analyses between centers in countries with Human Development Index (HDI) > 0.90 and < 0.90. Thirty-one centers across Europe participated in the survey. CVCs were the primary VA in 73.1
Sepiapterin is a naturally occurring pteridine and BH4 precursor that links classic pterin chemistry to tetrahydrobiopterin biology. Tetrahydrobiopterin (BH4; sapropterin) is an essential redox-active cofactor for phenylalanine hydroxylase (PAH), the aromatic amino acid hydroxylases, and nitric oxide synthases, whereas 7,8-dihydrobiopterin (BH2) reflects pterin redox balance and can antagonize BH4-dependent nitric oxide signaling. This review integrates historical and chemical perspectives with current biochemical and clinical understanding of BH4 homeostasis, including de novo synthesis, recycling/oxidation, and the sepiapterin salvage pathway. Sepiapterin is taken up by cells through equilibrative nucleoside transport mechanisms and is intracellularly converted through sepiapterin reductase and dihydrofolate reductase to expand BH4 pools. In healthy volunteers, oral sepiapterin produced marked systemic BH4 exposure with minimal parent-drug exposure (geometric mean Cmax 640 ng/mL for BH4 versus 1.74 ng/mL for sepiapterin after 60 mg/kg) and increased cerebrospinal fluid BH4 after 7 days of 60 mg/kg/day dosing. In phenylketonuria (PKU), the Phase 3 APHENITY trial showed a placebo-adjusted least-squares mean blood phenylalanine reduction of 395.9 μmol/L at Week 6 among sepiapterin-responsive participants, and the Phase 3 AMPLIPHY trial showed greater lowering with sepiapterin 60 mg/kg/day than with sapropterin 20 mg/kg/day (least-squares mean difference 180.4 μmol/L; 95% CI 131.4-229.5; p < 0.0001). Together, these data position sepiapterin as a next-step therapy beyond sapropterin, while underscoring the importance of biomarker studies that quantify BH4, BH2, and the BH4/BH2 ratio in plasma and cerebrospinal fluid.
