The RNA polymerase II complex (pol II) is responsible for transcription of all $21,000 human protein-encoding genes. Here, we describe sixteen individuals harboring de novo heterozygous variants in POLR2A, encoding RPB1, the largest subunit of pol II. An iterative approach combining structural evaluation and mass spectrometry analyses, the use of S. cerevisiae as a model system, and the assessment of cell viability in HeLa cells allowed us to classify eleven variants as probably disease-causing and four variants as possibly diseasecausing. The significance of one variant remains unresolved. By quantification of phenotypic severity, we could distinguish mild and severe phenotypic consequences of the disease-causing variants. Missense variants expected to exert only mild structural effects led to a malfunctioning pol II enzyme, thereby inducing a dominant-negative effect on gene transcription. Intriguingly, individuals carrying these variants presented with a severe phenotype dominated by profound infantile-onset hypotonia and developmental delay. Conversely, individuals carrying variants expected to result in complete loss of function, thus reduced levels of functional pol II from the normal allele, exhibited the mildest phenotypes. We conclude that subtle variants that are central in functionally important domains of POLR2A cause a neurodevelopmental syndrome characterized by profound infantile-onset hypotonia and developmental delay through a dominant-negative effect on pol-II-mediated transcription of DNA.
Summary Objective To determine the likelihood that recommended doses of acetaminophen (APAP) are associated with acute liver failure (ALF) in patients with myopathies Design retrospective analysis Setting level III pediatric intensive care unit Patients two pediatric patients with myopathies and acute liver failure Clinical Investigations We determined acetaminophen protein adduct levels, in combination with a literature review and systematic evaluation of the cases, using the Roussel Uclaf Causality Assessment Method (RUCAM) for drug-induced liver injury (DILI) to assess causality between recommended acetaminophen dosing and acute liver failure in two children with myopathies. Main Results The serum adduct levels were consistent with the values previously reported in children with acute liver injury following APAP overdose. We found four similar cases of ALF in pediatric and adult patients with myopathies following recommended APAP doses in the literature (n=3) and personal communication (n=1).The RUCAM suggested a probable relationship between APAP use at recommended doses and ALF in our myopathy patients. Conclusions Our data suggest that some patients with myopathies receiving recommended doses of APAP may be at increased risk for the development of toxicity resulting in ALF. More studies are needed to corroborate these findings. In the meantime, we would advise physicians to be alert in these patients while taking APAP, especially when critically ill or postoperative.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.