ABSTRACT
Transportin-2 (TNPO2) mediates multiple pathways including non-classical nucleocytoplasmic shuttling of >60 cargoes, such as developmental and neuronal proteins. We identified 15 individuals carrying de novo coding variants in TNPO2 who presented with global developmental delay (GDD), dysmorphic features, ophthalmologic abnormalities, and neurological features. To assess the nature of these variants, functional studies were performed in Drosophila. We found that fly dTnpo (orthologous to TNPO2) is expressed in a subset of neurons. dTnpo is critical for neuronal maintenance and function as downregulating dTnpo in mature neurons using RNAi disrupts neuronal activity and survival. Altering the activity and expression of dTnpo using mutant alleles or RNAi causes developmental defects, including eye and wing deformities and lethality. These effects are dosage dependent as more severe phenotypes are associated with stronger dTnpo loss. Interestingly, similar phenotypes are observed with dTnpo upregulation and ectopic expression of TNPO2, showing that loss and gain of Transportin activity causes developmental defects. Further, proband-associated variants can cause more or less severe developmental abnormalities compared to wild-type TNPO2 when ectopically expressed. The impact of the variants tested seems to correlate with their position within the protein. Specifically, those that fall within the RAN binding domain cause more severe toxicity and those in the acidic loop are less toxic. Variants within the cargo binding domain show tissue-dependent effects. In summary, dTnpo is an essential gene in flies during development and in neurons. Further, proband-associated de novo variants within TNPO2 disrupt the function of the encoded protein. Hence, TNPO2 variants are causative for neurodevelopmental abnormalities.
Subject(s)
Developmental Disabilities/genetics , Drosophila Proteins/genetics , Eye Diseases, Hereditary/genetics , Intellectual Disability/genetics , Karyopherins/genetics , Musculoskeletal Abnormalities/genetics , beta Karyopherins/genetics , ran GTP-Binding Protein/genetics , Alleles , Amino Acid Sequence , Animals , Developmental Disabilities/metabolism , Developmental Disabilities/pathology , Drosophila Proteins/antagonists & inhibitors , Drosophila Proteins/metabolism , Drosophila melanogaster/genetics , Drosophila melanogaster/growth & development , Drosophila melanogaster/metabolism , Eye Diseases, Hereditary/metabolism , Eye Diseases, Hereditary/pathology , Female , Gene Dosage , Gene Expression Regulation, Developmental , Genome, Human , Humans , Infant , Infant, Newborn , Intellectual Disability/metabolism , Intellectual Disability/pathology , Karyopherins/antagonists & inhibitors , Karyopherins/metabolism , Male , Musculoskeletal Abnormalities/metabolism , Musculoskeletal Abnormalities/pathology , Mutation , Neurons/metabolism , Neurons/pathology , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , Sequence Alignment , Sequence Homology, Amino Acid , Whole Genome Sequencing , beta Karyopherins/metabolism , ran GTP-Binding Protein/metabolismABSTRACT
OBJECTIVE: This project aimed to promote evidence-based practices regarding the promotion of sleep and rest using nonpharmacological interventions for infants in the neonatal intensive care unit (NICU) at Children's of Mississippi. INTRODUCTION: Sleep is a basic physiological need that plays a fundamental role in the growth and development of infants. Unfortunately, infants admitted to the NICU after birth may not receive adequate sleep and rest, especially when compared to infants discharged home after delivery. METHODS: The project used the JBI Practical Application of Clinical Evidence System (PACES) and Getting Research in Practice (GRiP) audit tool for promoting change in healthcare practice. A baseline audit of NICU staff and patient caregivers was conducted and measured against five best practice recommendations, followed by implementation of targeted strategies and a follow-up audit. RESULTS: The project team discovered two barriers to sleep promotion and rest in the NICU at Children's of Mississippi: lack of nurse knowledge of evidence-based practices for promotion of sleep and rest for infants in the NICU and a lack of location in the electronic health record to document sleep quality of infants. Strategies were implemented to address these barriers and compliance improved in four of the five audit criteria. CONCLUSIONS: Implementation of an educational PowerPoint that focused on sleep promotion of infants in the NICU was developed and distributed to all of the nurses and resulted in average increased compliance from 43% to 53% for all audit criteria.
Subject(s)
Clinical Competence , Intensive Care Units, Neonatal , Infant, Newborn , Humans , Infant , Child , Mississippi , Sleep , HospitalizationABSTRACT
OBJECTIVE: The objective of this review is to synthesize qualitative evidence regarding the experiences of parents and prospective parents when receiving a diagnosis of Down syndrome for their child in the perinatal period. INTRODUCTION: Increased awareness of parental experiences when receiving a Down syndrome diagnosis for their child may help health care professionals provide the parental support needed to promote the best possible outcomes for these children. INCLUSION CRITERIA: The participants for this review are the parents and prospective parents of a child with Down syndrome. The phenomenon of interest is parents' and prospective parents' experiences when receiving the diagnosis of Down syndrome for their child in the perinatal period. Experiences of prospective parents, parents whose children are living or deceased, and those who terminated a pregnancy because of the diagnosis will be included. METHODS: This review will follow JBI methodology for qualitative reviews. The databases to be searched include Academic Search Premier, AccessPediatrics, Health Source: Nursing/Academic Edition, MEDLINE, CINAHL, Scopus, PsycINFO, and Web of Science. Sources of unpublished studies and gray literature will include ProQuest Dissertations and Theses Sciences and Engineering Collection, MedNar, National Association for Down Syndrome, Down Syndrome International, and WorldWideScience. Studies will be critically appraised by 2 independent reviewers. All studies, regardless of methodological quality, will be included. Data will be extracted by 2 independent reviewers. Findings will be pooled using the meta-aggregation approach. Where textual pooling is not possible, the findings will be presented narratively. The final synthesized findings will be graded according to the ConQual approach. SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO CRD42021250813.