Histone H3.3 beyond cancer: Germline mutations in Histone 3 Family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients

Although somatic mutations in Histone 3.3 (H3.3) are well-studied drivers of oncogenesis, the role of germline mutations remains unreported. We analyze 46 patients bearing de novo germline mutations in histone 3 family 3A (H3F3A) or H3F3B with progressive neurologic dysfunction and congenital anomalies without malignancies. Molecular modeling of all 37 variants demonstrated clear disruptions in interactions with DNA, other histones, and histone chaperone proteins. Patient histone posttranslational modifications (PTMs) analysis revealed notably aberrant local PTM patterns distinct from the somatic lysine mutations that cause global PTM dysregulation. RNA sequencing on patient cells demonstrated up-regulated gene expression related to mitosis and cell division, and cellular assays confirmed an increased proliferative capacity. A zebrafish model showed craniofacial anomalies and a defect in Foxd3-derived glia. These data suggest that the mechanism of germline mutations are distinct from cancer-associated somatic histone mutations but may converge on control of cell proliferation

Attitudes and Beliefs of COVID-19 and Vaccine Uptake among Amish Women

The Amish, a Christian religious group living in rural areas with distinct beliefs about remaining separate from the outside world, have communities in 31 states and four Canadian provinces with just over 600 settlements. Their access to health care and technology is often limited. Several studies have noted low vaccination rates for preventable diseases among the Amish, often due to lack of knowledge about efficacy and safety of vaccines. To gain an understanding of beliefs surrounding COVID-19 and attitudes toward vaccine uptake, we surveyed 863 Amish and Mennonite women throughout Ohio who participated in rural mobile health clinics between 2015 and 2019 at two time periods: before and after the 2020 election. We received 372 completed surveys, 252 of which were completed by respondents who identified themselves as Amish. While 100% of the Amish respondents had heard of COVID-19 and 90% reported knowing someone who had contracted the disease, a mere 1.7% (4) indicated a willingness to get vaccinated. In terms of COVID-19 diagnosis, post-election participants were two times more likely to report having a positive test than pre-election respondents (p = .011). Qualitative analyses revealed significant differences in keywords used to describe COVID-19. Post-election respondents were less likely to use words like "evil" and "bad" and associate COVID-19 with the flu. A notable shift in vaccine hesitancy among Amish participants centered on the perceived politicization of the pandemic and safety/efficacy of the vaccines. Public health efforts should center on raising awareness of the severity of COVID-19 and the benefits of vaccine uptake for distinctive subcultures like the Amish

Terror Capitalism and Uyghur Dispossession — with Darren Byler

Sociocultural anthropologist and assistant professor at SFU’s School for International Studies, Darren Byler joins Am Johal to speak about his latest book, Terror Capitalism: Uyghur Dispossession and Masculinity in a Chinese City. Darren describes how China surveilles and dispossesses Uyghur populations through a mass digital surveillance system, connecting it to the war on terror. Darren and Am also discuss the similarities and differences between the colonialism of China with India, Israel, and other Western countries.  Finally, the conversation goes into how Uyghur men protect their wellbeing by developing anti-colonial friendships. The conversation also highlights how many Han Chinese people are building a community of inter-ethnic solidarity to refuse the colonial structures of the state system

Expanding the molecular spectrum and the neurological phenotype related to CAMTA1 variants

The CAMTA1-associated phenotype was initially defined in patients with intragenic deletions and duplications who showed nonprogressive congenital ataxia, with or without intellectual disability. Here, we describe 10 individuals with CAMTA1 variants: nine previously unreported (likely) pathogenic variants comprising one missense, four frameshift and four nonsense variants, and one missense variant of unknown significance. Six patients were diagnosed following whole exome sequencing and four individuals with exome-based targeted panel analysis. Most of them present with developmental delay, manifesting in speech and motor delay. Other frequent findings are hypotonia, cognitive impairment, cerebellar dysfunction, oculomotor abnormalities, and behavioral problems. Feeding problems occur more frequently than previously observed. In addition, we present a systematic review of 19 previously published individuals with causal variants, including copy number, truncating, and missense variants. We note a tendency of more severe cognitive impairment and recurrent dysmorphic features in individuals with a copy number variant. Pathogenic variants are predominantly observed in and near the N- and C- terminal functional domains. Clinical heterogeneity is observed, but 3 '-terminal variants seem to associate with less pronounced cerebellar dysfunction

Histone H3.3 beyond cancer : Germline mutations in Histone 3 Family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients

Germ line mutations in H3F3A and H3F3B cause a previously unidentified neurodevelopmental syndrome. Although somatic mutations in Histone 3.3 (H3.3) are well-studied drivers of oncogenesis, the role of germline mutations remains unreported. We analyze 46 patients bearing de novo germline mutations in histone 3 family 3A (H3F3A) or H3F3B with progressive neurologic dysfunction and congenital anomalies without malignancies. Molecular modeling of all 37 variants demonstrated clear disruptions in interactions with DNA, other histones, and histone chaperone proteins. Patient histone posttranslational modifications (PTMs) analysis revealed notably aberrant local PTM patterns distinct from the somatic lysine mutations that cause global PTM dysregulation. RNA sequencing on patient cells demonstrated up-regulated gene expression related to mitosis and cell division, and cellular assays confirmed an increased proliferative capacity. A zebrafish model showed craniofacial anomalies and a defect in Foxd3-derived glia. These data suggest that the mechanism of germline mutations are distinct from cancer-associated somatic histone mutations but may converge on control of cell proliferatio

Spliceosome malfunction causes neurodevelopmental disorders with overlapping features

: Pre-mRNA splicing is a highly coordinated process. While its dysregulation has been linked to neurological deficits, our understanding of the underlying molecular and cellular mechanisms remains limited. We implicated pathogenic variants in U2AF2 and PRPF19, encoding spliceosome subunits in neurodevelopmental disorders (NDDs), by identifying 46 unrelated individuals with 23 de novo U2AF2 missense variants (including seven recurrent variants in 30 individuals) and six individuals with de novo PRPF19 variants. Eight U2AF2 variants dysregulated splicing of a model substrate. Neuritogenesis was reduced in human neurons differentiated from human pluripotent stem cells carrying two U2AF2 hyper-recurrent variants. Neural loss of function of the Drosophila orthologs, U2af50 and Prp19, led to lethality, abnormal mushroom body (MB) patterning, and social deficits, differentially rescued by wild-type and mutant U2AF2 or PRPF19. Transcriptome profiling revealed splicing substrates or effectors (including Rbfox1, a third splicing factor), which rescued MB defects in U2af50 deficient flies. Upon re-analysis of negative clinical exomes followed by data sharing, we further identified six NDD patients carrying RBFOX1 missense variants which, by in vitro testing, showed loss of function. Our study implicates three splicing factors as NDD causative genes and establishes a genetic network with hierarchy underlying human brain development and function