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MedRxiv : the Preprint Server For... May 2024Retinoblastoma (RB) proteins are highly conserved transcriptional regulators that play important roles during development by regulating cell-cycle gene expression. RBL2...
Retinoblastoma (RB) proteins are highly conserved transcriptional regulators that play important roles during development by regulating cell-cycle gene expression. RBL2 dysfunction has been linked to a severe neurodevelopmental disorder. However, to date, clinical features have only been described in six individuals carrying five biallelic predicted loss of function (pLOF) variants. To define the phenotypic effects of mutations in detail, we identified and clinically characterized a cohort of 28 patients from 18 families carrying LOF variants in , including fourteen new variants that substantially broaden the molecular spectrum. The clinical presentation of affected individuals is characterized by a range of neurological and developmental abnormalities. Global developmental delay and intellectual disability were uniformly observed, ranging from moderate to profound and involving lack of acquisition of key motor and speech milestones in most patients. Frequent features included postnatal microcephaly, infantile hypotonia, aggressive behaviour, stereotypic movements and non-specific dysmorphic features. Common neuroimaging features were cerebral atrophy, white matter volume loss, corpus callosum hypoplasia and cerebellar atrophy. In parallel, we used the fruit fly, , to investigate how disruption of the conserved RBL2 orthologueue Rbf impacts nervous system function and development. We found that LOF mutants recapitulate several features of patients harboring variants, including alterations in the head and brain morphology reminiscent of microcephaly, and perturbed locomotor behaviour. Surprisingly, in addition to its known role in controlling tissue growth during development, we find that continued expression is also required in fully differentiated post-mitotic neurons for normal locomotion in , and that adult-stage neuronal re-expression of is sufficient to rescue mutant locomotor defects. Taken together, this study provides a clinical and experimental basis to understand genotype-phenotype correlations in an -linked neurodevelopmental disorder and suggests that restoring expression through gene therapy approaches may ameliorate aspects of LOF patient symptoms.
PubMed: 38746364
DOI: 10.1101/2024.05.03.24306631 -
BioRxiv : the Preprint Server For... Apr 2024Zika virus (ZIKV) infections cause microcephaly in new-borns and Guillain-Barre syndrome in adults raising a significant global public health concern, yet no vaccines or...
Zika virus (ZIKV) infections cause microcephaly in new-borns and Guillain-Barre syndrome in adults raising a significant global public health concern, yet no vaccines or antiviral drugs have been developed to prevent or treat ZIKV infections. The viral protease NS3 and its co-factor NS2B are essential for the cleavage of the Zika polyprotein precursor into individual structural and non-structural proteins and is therefore an attractive drug target. Generation of a robust crystal system of co-expressed NS2B-NS3 protease has enabled us to perform a crystallographic fragment screening campaign with 1076 fragments. 48 binders with diverse chemical scaffolds were identified in the active site of the protease, with another 6 fragment hits observed in a potential allosteric binding site. Our work provides potential starting points for the development of potent NS2B-NS3 protease inhibitors. Furthermore, we have structurally characterized a potential allosteric binding pocket, identifying opportunities for allosteric inhibitor development.
PubMed: 38746305
DOI: 10.1101/2024.04.29.591502 -
BioRxiv : the Preprint Server For... Apr 2024The Zika virus (ZIKV), discovered in Africa in 1947, swiftly spread across continents, causing significant concern due to its recent association with microcephaly in...
The Zika virus (ZIKV), discovered in Africa in 1947, swiftly spread across continents, causing significant concern due to its recent association with microcephaly in newborns and Guillain-Barré syndrome in adults. Despite a decrease in prevalence, the potential for a resurgence remains, necessitating urgent therapeutic interventions. Like other flaviviruses, ZIKV presents promising drug targets within its replication machinery, notably the NS3 helicase (NS3) protein, which plays critical roles in viral replication. However, a lack of structural information impedes the development of specific inhibitors targeting NS3. Here we applied high-throughput crystallographic fragment screening on ZIKV NS3, which yielded structures that reveal 3D binding poses of 46 fragments at multiple sites of the protein, including 11 unique fragments in the RNA-cleft site. These fragment structures provide templates for direct design of hit compounds and should thus assist the development of novel direct-acting antivirals against ZIKV and related flaviviruses, thus opening a promising avenue for combating future outbreaks.
PubMed: 38746241
DOI: 10.1101/2024.04.27.591279 -
EMBO Reports Jun 2024Centrioles organize centrosomes, the cell's primary microtubule-organizing centers (MTOCs). Centrioles double in number each cell cycle, and mis-regulation of this...
Centrioles organize centrosomes, the cell's primary microtubule-organizing centers (MTOCs). Centrioles double in number each cell cycle, and mis-regulation of this process is linked to diseases such as cancer and microcephaly. In C. elegans, centriole assembly is controlled by the Plk4 related-kinase ZYG-1, which recruits the SAS-5-SAS-6 complex. While the kinase activity of ZYG-1 is required for centriole assembly, how it functions has not been established. Here we report that ZYG-1 physically interacts with and phosphorylates SAS-5 on 17 conserved serine and threonine residues in vitro. Mutational scanning reveals that serine 10 and serines 331/338/340 are indispensable for proper centriole assembly. Embryos expressing SAS-5 exhibit centriole assembly failure, while those expressing SAS-5 possess extra centrioles. We show that in the absence of serine 10 phosphorylation, the SAS-5-SAS-6 complex is recruited to centrioles, but is not stably incorporated, possibly due to a failure to coordinately recruit the microtubule-binding protein SAS-4. Our work defines the critical role of phosphorylation during centriole assembly and reveals that ZYG-1 might play a role in preventing the formation of excess centrioles.
Topics: Caenorhabditis elegans; Centrioles; Phosphorylation; Caenorhabditis elegans Proteins; Animals; Cell Cycle Proteins; Protein Binding; Protein Serine-Threonine Kinases; Serine; Amino Acid Sequence; Protein Kinases
PubMed: 38744971
DOI: 10.1038/s44319-024-00157-y -
International Journal of Molecular... Apr 2024has been identified as the causal gene for primary microcephaly type 1, a neurodevelopmental disorder characterized by reduced brain size and delayed growth. As a...
has been identified as the causal gene for primary microcephaly type 1, a neurodevelopmental disorder characterized by reduced brain size and delayed growth. As a multifunction protein, MCPH1 has been reported to repress the expression of TERT and interact with transcriptional regulator E2F1. However, it remains unclear whether MCPH1 regulates brain development through its transcriptional regulation function. This study showed that the knockout of in mice leads to delayed growth as early as the embryo stage E11.5. Transcriptome analysis (RNA-seq) revealed that the deletion of resulted in changes in the expression levels of a limited number of genes. Although the expression of some of E2F1 targets, such as and , was affected, the differentially expressed genes (DEGs) were not significantly enriched as E2F1 target genes. Further investigations showed that primary and immortalized knockout mouse embryonic fibroblasts (MEFs) exhibited cell cycle arrest and cellular senescence phenotype. Interestingly, the upregulation of p19ARF was detected in knockout MEFs, and silencing restored the cell cycle and growth arrest to wild-type levels. Our findings suggested it is unlikely that MCPH1 regulates neurodevelopment through E2F1-mediated transcriptional regulation, and p19ARF-dependent cell cycle arrest and cellular senescence may contribute to the developmental abnormalities observed in primary microcephaly.
Topics: Animals; Mice; Cell Cycle Checkpoints; Cell Cycle Proteins; Cellular Senescence; Cyclin-Dependent Kinase Inhibitor p16; E2F1 Transcription Factor; Fibroblasts; Mice, Knockout; Microcephaly
PubMed: 38731817
DOI: 10.3390/ijms25094597 -
SAGE Open Medicine 2024Arboviruses are RNA viruses and some have the potential to cause neuroinvasive disease and are a growing threat to global health. (Review)
Review
BACKGROUND
Arboviruses are RNA viruses and some have the potential to cause neuroinvasive disease and are a growing threat to global health.
OBJECTIVES
Our objective is to identify and map all aspects of arbovirus neuroinvasive disease, clarify key concepts, and identify gaps within our knowledge with appropriate future directions related to the improvement of global health.
METHODS
: A scoping review of the literature was conducted using PubMed, Scopus, ScienceDirect, and Hinari. : Original data including epidemiology, risk factors, neurological manifestations, neuro-diagnostics, management, and preventive measures related to neuroinvasive arbovirus infections was obtained. Sources of evidence not reporting on original data, non-English, and not in peer-reviewed journals were removed. : An initial pilot sample of 30 abstracts were reviewed by all authors and a Cohen's kappa of = 0.81 (near-perfect agreement) was obtained. Records were manually reviewed by two authors using the Rayyan QCRI software.
RESULTS
A total of 171 records were included. A wide array of neurological manifestations can occur most frequently, including parkinsonism, encephalitis/encephalopathy, meningitis, flaccid myelitis, and Guillain-Barré syndrome. Magnetic resonance imaging of the brain often reveals subcortical lesions, sometimes with diffusion restriction consistent with acute ischemia. Vertical transmission of arbovirus is most often secondary to the Zika virus. Neurological manifestations of congenital Zika syndrome, include microcephaly, failure to thrive, intellectual disability, and seizures. Cerebrospinal fluid analysis often shows lymphocytic pleocytosis, elevated albumin, and protein consistent with blood-brain barrier dysfunction.
CONCLUSIONS
Arbovirus infection with neurological manifestations leads to increased morbidity and mortality. Risk factors for disease include living and traveling in an arbovirus endemic zone, age, pregnancy, and immunosuppressed status. The management of neuroinvasive arbovirus disease is largely supportive and focuses on specific neurological complications. There is a need for therapeutics and currently, management is based on disease prevention and limiting zoonosis.
PubMed: 38711470
DOI: 10.1177/20503121241229847 -
Annals of Medicine and Surgery (2012) May 2024Infantile tremor syndrome (ITS) affects children aged 6-18 months, and is characterized by tremors, pallor, developmental regression, skin pigmentation changes, and...
INTRODUCTION AND IMPORTANCE
Infantile tremor syndrome (ITS) affects children aged 6-18 months, and is characterized by tremors, pallor, developmental regression, skin pigmentation changes, and sparse hypopigmented hair. This case report highlights an ITS presentation in a 16-month-old exclusively breastfed male, emphasizing the significance of complementary feeding.
CASE PRESENTATION
The patient presented with abnormal body movements, loss of developmental milestones, hyperpigmented skin changes, hypopigmented scalp hairs, pallor, and microcephaly. Born to a vegetarian mother with inadequate prenatal care, the child's exclusive breastfeeding till 16 months of age without complementary feeding led to severe developmental delay and moderate malnutrition. Diagnostic workup revealed vitamin B12 deficiency, anaemia, and neurologic abnormalities.
CLINICAL DISCUSSION
ITS is associated with various manifestations, including pallor, hyperpigmentation, and tremors, commonly linked to vitamin B12 deficiency. In this case, developmental delays and malnutrition underscored the importance of early recognition. Despite neurological improvement with vitamin B12 supplementation, ITS's long-term impact on cognitive functions necessitates vigilance and appropriate nutritional interventions.
CONCLUSION
Early recognition of ITS is vital for the prevention of long-term neurodevelopmental sequelae. Injectable vitamin B12 supplementation and nutritional interventions have demonstrated significant developmental gains. Increased awareness among mothers about nutritional intake during pregnancy and lactation is crucial, especially among vegetarians.
PubMed: 38694308
DOI: 10.1097/MS9.0000000000002020 -
Disease Models & Mechanisms Apr 2024Ankyrin repeat and LEM domain-containing 2 (ANKLE2) is a scaffolding protein with established roles in cell division and development, the dysfunction of which is... (Review)
Review
Ankyrin repeat and LEM domain-containing 2 (ANKLE2) is a scaffolding protein with established roles in cell division and development, the dysfunction of which is increasingly implicated in human disease. ANKLE2 regulates nuclear envelope disassembly at the onset of mitosis and its reassembly after chromosome segregation. ANKLE2 dysfunction is associated with abnormal nuclear morphology and cell division. It regulates the nuclear envelope by mediating protein-protein interactions with barrier to autointegration factor (BANF1; also known as BAF) and with the kinase and phosphatase that modulate the phosphorylation state of BAF. In brain development, ANKLE2 is crucial for proper asymmetric division of neural progenitor cells. In humans, pathogenic loss-of-function mutations in ANKLE2 are associated with primary congenital microcephaly, a condition in which the brain is not properly developed at birth. ANKLE2 is also linked to other disease pathologies, including congenital Zika syndrome, cancer and tauopathy. Here, we review the molecular roles of ANKLE2 and the recent literature on human diseases caused by its dysfunction.
Topics: Humans; Nuclear Proteins; Animals; Disease; DNA-Binding Proteins; Mutation
PubMed: 38691001
DOI: 10.1242/dmm.050554 -
BMC Pediatrics Apr 2024To describe the feeding characteristics and growth of children with prenatal exposure to Zika virus (ZIKV) from birth to 48 months.
Feeding characteristics and growth among children with prenatal exposure to Zika virus with and without microcephaly in the microcephaly epidemic research group pediatric cohort.
OBJECTIVE
To describe the feeding characteristics and growth of children with prenatal exposure to Zika virus (ZIKV) from birth to 48 months.
DESIGN
Using data from the prospective Microcephaly Epidemic Research Group Pediatric Cohort (MERG-PC), children without microcephaly born to mothers with evidence of ZIKV infection during pregnancy (ZIKV-exposed children without microcephaly) and children with Zika-related microcephaly were compared using repeated cross-sectional analyses within the following age strata: birth; 1 to 12; 13 to 24; 25 to 36; and 37 to 48 months. The groups were compared in relation to prematurity, birth weight, breastfeeding, alternative feeding routes, dysphagia and anthropometric profiles based on the World Health Organization Anthro z-scores (weight-length/height, weight-age, length/height-age and BMI-age).
RESULTS
The first assessment included 248 children, 77 (31.05%) with microcephaly and 171 (68.95%) without microcephaly. The final assessment was performed on 86 children. Prematurity was 2.35 times higher and low birth weight was 3.49 times higher in children with microcephaly. The frequency of breastfeeding was high (> 80%) in both groups. On discharge from the maternity hospital, the frequency of children requiring alternative feeding route in both groups was less than 5%. After 12 months of age, children with microcephaly required alternative feeding route more often than children without microcephaly. In children with microcephaly, the z-score of all growth indicators was lower than in children without microcephaly.
CONCLUSIONS
Children with Zika-related microcephaly were more frequently premature and low birth weight and remained with nutritional parameters, i.e., weight-for-age, weight-for-length/height and length/height-for-age below those of the children without microcephaly.
Topics: Humans; Microcephaly; Zika Virus Infection; Female; Pregnancy; Prenatal Exposure Delayed Effects; Infant, Newborn; Infant; Male; Pregnancy Complications, Infectious; Child, Preschool; Cross-Sectional Studies; Breast Feeding; Prospective Studies; Child Development; Brazil
PubMed: 38685089
DOI: 10.1186/s12887-024-04728-9 -
European Journal of Medical Genetics Jun 2024Here we report the case of a young boy with developmental delay, thin sparse hair, early closure of the anterior fontanel, bilateral choanal atresia, brachyturicephaly;...
Here we report the case of a young boy with developmental delay, thin sparse hair, early closure of the anterior fontanel, bilateral choanal atresia, brachyturicephaly; and dysmorphic features closely resembling those seen in trichorhinophalangeal syndrome (TRPS). These features include sparse hair, sparse lateral eyebrows, a bulbous pear shaped nose, a long philtrum, thin lips, small/hypoplastic nails, pes planovalgus; bilateral cone-shaped epiphyses at the proximal 5th phalanx, slender long bones, coxa valga, mild scoliosis, and delayed bone age. Given that TRPS had been excluded by a thorough genetic analysis, whole exome sequencing was performed and a heterozygous likely pathogenic variant was identified in the FBXO11 gene (NM_001190274.2: c.1781A > G; p. His594Arg), confirming the diagnosis of the newly individualized IDDFBA syndrome: Intellectual Developmental Disorder, dysmorphic Facies, and Behavioral Abnormalities (OMIM# 618,089). Our findings further delineate the clinical spectrum linked to FBXO11 and highlight the importance of investigating further cases with mutations in this gene to establish a potential genotype-phenotype correlation.
Topics: Humans; Male; Phenotype; F-Box Proteins; Intellectual Disability; Langer-Giedion Syndrome; Nose; Fingers; Child; Choanal Atresia; Mutation; Hair Diseases; Protein-Arginine N-Methyltransferases
PubMed: 38679370
DOI: 10.1016/j.ejmg.2024.104944