VPS13 protein family members VPS13A through VPS13C have been associated with various recessive movement disorders. We describe the first disease association of rare recessive VPS13D variants ...including frameshift, missense, and partial duplication mutations with a novel complex, hyperkinetic neurological disorder. The clinical features include developmental delay, a childhood onset movement disorder (chorea, dystonia, or tremor), and progressive spastic ataxia or paraparesis. Characteristic brain magnetic resonance imaging shows basal ganglia or diffuse white matter T2 hyperintensities as seen in Leigh syndrome and choreoacanthocytosis. Muscle biopsy in 1 case showed mitochondrial aggregates and lipidosis, suggesting mitochondrial dysfunction. These findings underline the importance of the VPS13 complex in neurological diseases and a possible role in mitochondrial function. Ann Neurol 2018;83:1089–1095
Several genes predisposing to autism spectrum disorders (ASDs) with or without epilepsy have been identified, many of which are implicated in synaptic function. Here we report a Q555X mutation in ...synapsin 1 (SYN1), an X-linked gene encoding for a neuron-specific phosphoprotein implicated in the regulation of neurotransmitter release and synaptogenesis. This nonsense mutation was found in all affected individuals from a large French-Canadian family segregating epilepsy and ASDs. Additional mutations in SYN1 (A51G, A550T and T567A) were found in 1.0 and 3.5% of French-Canadian individuals with autism and epilepsy, respectively. The majority of these SYN1 mutations were clustered in the proline-rich D-domain which is substrate of multiple protein kinases. When expressed in synapsin I (SynI) knockout (KO) neurons, all the D-domain mutants failed in rescuing the impairment in the size and trafficking of synaptic vesicle pools, whereas the wild-type human SynI fully reverted the KO phenotype. Moreover, the nonsense Q555X mutation had a dramatic impact on phosphorylation by MAPK/Erk and neurite outgrowth, whereas the missense A550T and T567A mutants displayed impaired targeting to nerve terminals. These results demonstrate that SYN1 is a novel predisposing gene to ASDs, in addition to epilepsy, and strengthen the hypothesis that a disturbance of synaptic homeostasis underlies the pathogenesis of both diseases.
Growing genetic evidence is converging in favor of common pathogenic mechanisms for autism spectrum disorders (ASD), intellectual disability (ID or mental retardation) and schizophrenia (SCZ), three ...neurodevelopmental disorders affecting cognition and behavior. Copy number variations and deleterious mutations in synaptic organizing proteins including
NRXN1
have been associated with these neurodevelopmental disorders, but no such associations have been reported for
NRXN2
or
NRXN3
. From resequencing the three neurexin genes in individuals affected by ASD (
n
= 142), SCZ (
n
= 143) or non-syndromic ID (
n
= 94), we identified a truncating mutation in
NRXN2
in a patient with ASD inherited from a father with severe language delay and family history of SCZ. We also identified a de novo truncating mutation in
NRXN1
in a patient with SCZ, and other potential pathogenic ASD mutations. These truncating mutations result in proteins that fail to promote synaptic differentiation in neuron coculture and fail to bind either of the established postsynaptic binding partners LRRTM2 or NLGN2 in cell binding assays. Our findings link
NRXN2
disruption to the pathogenesis of ASD for the first time and further strengthen the involvement of
NRXN1
in SCZ, supporting the notion of a common genetic mechanism in these disorders.
Childhood-onset schizophrenia (COS), defined by the onset of illness before age 13 years, is a rare severe neurodevelopmental disorder of unknown etiology. Recently, sequencing studies have ...identified rare, potentially causative de novo variants in sporadic cases of adult-onset schizophrenia and autism. In this study, we performed exome sequencing of 17 COS trios in order to test whether de novo variants could contribute to this disease. We identified 20 de novo variants in 17 COS probands, which is consistent with the de novo mutation rate reported in the adult form of the disease. Interestingly, the missense de novo variants in COS have a high likelihood for pathogenicity and were enriched for genes that are less tolerant to variants. Among the genes found disrupted in our study, SEZ6, RYR2, GPR153, GTF2IRD1, TTBK1 and ITGA6 have been previously linked to neuronal function or to psychiatric disorders, and thus may be considered as COS candidate genes.
Background Little is known about the genetics of nonsyndromic intellectual disability (NSID). Recently, we reported de novo truncating mutations in the SYNGAP1 gene of 3 of 94 NSID cases, suggesting ...that its disruption represents a common cause of autosomal dominant NSID. Methods To further explore the involvement of SYNGAP1 in NSID, we sequenced its exons and intronic boundaries in 60 additional sporadic cases of NSID, including 30 patients with autism spectrum disorders (ASD) and 9 with epilepsy, and in 380 control individuals. Results We identified de novo out-of-frame deletions in two patients with NSID and mild generalized epilepsy (c.2677delC/p.Q893RfsX184 and c.321_324delGAAG/p. K108VfsX25) and a de novo splicing mutation (c.2294 + 1G>A), which results in the creation of a premature stop codon, in a patient with NSID and autism. No splicing or truncating mutations were found in control subjects. Conclusions We provide evidence that truncating mutations in SYNGAP1 are common in NSID and can be also associated with autism.
Novel de novo SHANK3 mutation in autistic patients Gauthier, Julie; Spiegelman, Dan; Piton, Amélie ...
American journal of medical genetics. Part B, Neuropsychiatric genetics,
5 April 2009, Letnik:
150B, Številka:
3
Journal Article
An increasing number of genes predisposing to autism spectrum disorders (ASDs) has been identified, many of which are implicated in synaptic function. This 'synaptic autism pathway' notably includes ...disruption of SYN1 that is associated with epilepsy, autism and abnormal behavior in both human and mice models. Synapsins constitute a multigene family of neuron-specific phosphoproteins (SYN1-3) present in the majority of synapses where they are implicated in the regulation of neurotransmitter release and synaptogenesis. Synapsins I and II, the major Syn isoforms in the adult brain, display partially overlapping functions and defects in both isoforms are associated with epilepsy and autistic-like behavior in mice. In this study, we show that nonsense (A94fs199X) and missense (Y236S and G464R) mutations in SYN2 are associated with ASD in humans. The phenotype is apparent in males. Female carriers of SYN2 mutations are unaffected, suggesting that SYN2 is another example of autosomal sex-limited expression in ASD. When expressed in SYN2 knockout neurons, wild-type human Syn II fully rescues the SYN2 knockout phenotype, whereas the nonsense mutant is not expressed and the missense mutants are virtually unable to modify the SYN2 knockout phenotype. These results identify for the first time SYN2 as a novel predisposing gene for ASD and strengthen the hypothesis that a disturbance of synaptic homeostasis underlies ASD.
Introduction This study analyzes the existing academic literature to identify the effects of artificial intelligence (AI) on human resource (HR) activities, highlighting both opportunities and ...associated challenges, and on the roles of employees, line managers, and HR professionals, collectively referred to as the HR triad. Methods We employed the scoping review method to capture and synthesize relevant academic literature in the AI–human resource management (HRM) field, examining 27 years of research (43 peer-reviewed articles are included). Results Based on the results, we propose an integrative framework that outlines the five primary effects of AI on HR activities: task automation, optimized HR data use, augmentation of human capabilities, work context redesign, and transformation of the social and relational aspects of work. We also detail the opportunities and challenges associated with each of these effects and the changes in the roles of the HR triad. Discussion This research contributes to the ongoing debate on AI-augmented HRM by discussing the theoretical contributions and managerial implications of our findings, along with avenues for future research. By considering the most recent studies on the topic, this scoping review sheds light on the effects of AI on the roles of the HR triad, enabling these key stakeholders to better prepare for this technological change. The findings can inform future academic research, organizations using or considering the application of AI in HRM, and policymakers. This is particularly timely, given the growing adoption of AI in HRM activities.
Background
In a context where organizations struggle to attract and retain highly qualified workers, organizations need to prioritize the psychological health of employees as a retention factor. To ...do so, they need to provide a healthy work environment. As an integral part of the employee experience, managers are an important factor in employee retention. In past studies, researchers have focused on the importance of leadership in boosting employees’ health without, however, considering factors encouraging such behavior in managers. Recently, some scholars have become interested in managers’ health as a resource allowing them to adopt good leadership behavior. Indeed, these studies reveal interesting links between managers’ emotional state and their behavior as leaders. Other studies, underscore the importance of considering the organizational context to better understand managers’ psychological health that may influence their leadership behaviors. This study proposes to examine the complex process by which organizational culture influences managers’ psychological health, which acts as a resource favoring the adoption of good leadership behaviors that are known to be constructive and have positive effects on employee.
Methods
Path analyses with the CALIS procedure SAS software, version 9.4 were conducted on a sample of 522 managers in three healthcare facilities in the province of Quebec, Canada.
Results
The results revealed that group culture is associated with the two indicators of managers’ psychological health at work. The results also demonstrated that managers’ psychological distress at work is positively related to transactional and
laissez-faire
leadership styles whereas psychological well-being at work is positively related to transformational and transactional leadership. Concerning indirect associations, there is a significant and positive indirect association between group culture and transformational leadership and there is also a significant and negative association between group culture and
laissez-faire
leadership. Finally, there is also an indirect association between hierarchical culture and transactional leadership.
Conclusion
Our study provides a more in-depth understanding of the relationship between organizational culture and leadership styles. More specifically, our findings highlight the benefits of implementing a group organizational culture to enhance psychological well-being, reduce psychological distress symptoms and promote good leadership behaviors.
The integrated mutual gains model suggests five provisional sets of human resource management (HRM) practices that should benefit both employees and organizations and, as such, be explicitly designed ...to have a positive impact on wellbeing, which, in turn, can affect performance.
An extensive review of the literature on scales that used a high-performance work system to assess HRM practices, as well as an extraction of items related to the theoretical dimensions of the integrated mutual gains model, were performed. Based on these preliminary steps, an initial scale with the 66 items found most relevant in the literature was developed and assessed regarding its factorial structure, internal consistency, and reliability over a two-week period.
Exploratory factorial analysis following test -retest resulted in a 42-item scale for measuring 11 HRM practices. Confirmatory factor analyses resulted in a 36-item instrument for measuring 10 HRM practices and showed adequate validity and reliability.
Even though the five provisional sets of practices were not validated, the practices that emerged from them were assembled into alternative sets of practices. These sets of practices reflect HRM activities that are considered conducive to employees' wellbeing and, consequently, their job performance. Consequently, the "High Wellbeing and Performance Work System Scale" was created. Nonetheless, future research is necessary to evaluate the predictive capacity of this new scale.
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