Navigating the Same Storm but Not in the Same Boat: Mental Health Vulnerability and Coping in Women University Students During the First COVID-19 Lockdown in the UK.

Having a mental health diagnosis in both general and student populations has been found to be a risk factor for negative coping and increased psychological distress during the COVID-19 pandemic. Drawing on a subset of data from a large contemporaneous research study, this report explores the experiences of 36 women students with and without reported pre-existing mental health diagnoses during the first UK lockdown, in spring 2020. Specifically, the data explored self-reported coping with the restrictions, with the abrupt move to online learning, and the loss of support; as well as students' perceived strengths and difficulties in balancing their student role with family roles such as being a partner and/or a parent. Students with a pre-existing mental health diagnosis reported higher levels of loneliness compared to a matched sample of non-students, and more avoidant coping and negative emotional coping than students without a diagnosis. Qualitative data illustrate how parenting intersects with well-being and stress as both a protective and risk factor for women university students. This research report adds to the evidence base on the impact of the COVID-19 pandemic on the student population, and how pre-existing mental health diagnoses intersect with coping behaviours and vulnerability in women students. Exploration of potential vulnerabilities can provide opportunities for targeted support, and identifying effective coping has the potential to inform effective interventions.

A novel NGF mutation clarifies the molecular mechanism and extends the phenotypic spectrum of the HSAN5 neuropathy.

BACKGROUND: Nerve growth factor ß (NGFß) and tyrosine kinase receptor type A (TRKA) are a well studied neurotrophin/receptor duo involved in neuronal survival and differentiation. The only previously reported hereditary sensory neuropathy caused by an NGF mutation, c.661C>T (HSAN5), and the pathology caused by biallelic mutations in the TRKA gene (NTRK1) (HSAN4), share only some clinical features. A consanguineous Arab family, where five of the six children were completely unable to perceive pain, were mentally retarded, did not sweat, could not discriminate temperature, and had a chronic immunodeficiency, is reported here. The condition is linked to a new homozygous mutation in the NGF gene, c.[680C>A]+[681_682delGG]. METHODS: Genetic linkage and standard sequencing techniques were used to identify the causative gene. Using wild-type or mutant over-expression constructs transfected into PC12 and COS-7 cells, the cellular and molecular consequences of the mutations were investigated. RESULTS: The mutant gene produced a precursor protein V232fs that was unable to differentiate PC12 cells. V232fs was not secreted from cells as mature NGFß. CONCLUSIONS: Both the clinical and cellular data suggest that the c.[680C>A]+[681_682delGG] NGF mutation is a functional null. The HSAN5 phenotype is extended to encompass HSAN4-like characteristics. It is concluded that the HSAN4 and HSAN5 phenotypes are parts of a phenotypic spectrum caused by changes in the NGF/TRKA signalling pathway.

WDR62 is associated with the spindle pole and is mutated in human microcephaly.

Autosomal recessive primary microcephaly (MCPH) is a disorder of neurodevelopment resulting in a small brain. We identified WDR62 as the second most common cause of MCPH after finding homozygous missense and frame-shifting mutations in seven MCPH families. In human cell lines, we found that WDR62 is a spindle pole protein, as are ASPM and STIL, the MCPH7 and MCHP7 proteins. Mutant WDR62 proteins failed to localize to the mitotic spindle pole. In human and mouse embryonic brain, we found that WDR62 expression was restricted to neural precursors undergoing mitosis. These data lend support to the hypothesis that the exquisite control of the cleavage furrow orientation in mammalian neural precursor cell mitosis, controlled in great part by the centrosomes and spindle poles, is critical both in causing MCPH when perturbed and, when modulated, generating the evolutionarily enlarged human brain.

Critical consequences of finding three pathogenic mutations in an individual with recessive disease.

The authors report the unexpected finding of three different nonsense mutations in two unrelated individuals with a diagnosis of autosomal recessive primary microcephaly. In each case one phenotypically normal parent was found to carry two of the nonsense mutations, presumably in cis. This finding of 'triple pathogenic mutations' is of unknown incidence but has significant implication for genetic counselling. A failure to detect all three mutations could result in both false positive and false negative diagnoses in other family members. Both of these potential problems can be avoided by always genotyping the parents.

Primary microcephaly: do all roads lead to Rome?

The relatively large brain and expanded cerebral cortex of humans is unusual in the animal kingdom and is thought to have promoted our adaptability and success as a species. One approach for investigating neurogenesis is the study of autosomal recessive primary microcephaly (MCPH), in which prenatal brain growth is significantly reduced without an effect on brain structure. To date, eight MCPH loci and five genes have been identified. Unexpectedly, all MCPH proteins are ubiquitous and localise to centrosomes for at least part of the cell cycle. Here, we focus on recent functional studies of MCPH proteins that reveal the centrosome as a final integration point for many regulatory pathways affecting prenatal neurogenesis in mammals.

An SCN9A channelopathy causes congenital inability to experience pain.

The complete inability to sense pain in an otherwise healthy individual is a very rare phenotype. In three consanguineous families from northern Pakistan, we mapped the condition as an autosomal-recessive trait to chromosome 2q24.3. This region contains the gene SCN9A, encoding the alpha-subunit of the voltage-gated sodium channel, Na(v)1.7, which is strongly expressed in nociceptive neurons. Sequence analysis of SCN9A in affected individuals revealed three distinct homozygous nonsense mutations (S459X, I767X and W897X). We show that these mutations cause loss of function of Na(v)1.7 by co-expression of wild-type or mutant human Na(v)1.7 with sodium channel beta(1) and beta(2) subunits in HEK293 cells. In cells expressing mutant Na(v)1.7, the currents were no greater than background. Our data suggest that SCN9A is an essential and non-redundant requirement for nociception in humans. These findings should stimulate the search for novel analgesics that selectively target this sodium channel subunit.

A novel pathway determining multidrug sensitivity in Schizosaccharomyces pombe.

In this study, we show that a mutation isolated during a screen for determinants of chemosensitivity in S. pombe results in loss of function of a previously uncharacterized protein kinase now named Hal4. Hal4 shares sequence homology to Hal4 and Hal5 in S. cerevisiae, and previous evidence indicates that these kinases positively regulate the major potassium transporter Trk1,2 and thereby maintain the plasma membrane potential. Disruption of this ion homeostasis pathway results in a hyperpolarized membrane and a concomitant increased sensitivity to cations. We demonstrate that a mutation in hal4+ results in hyperpolarization of the plasma membrane. In addition to the original selection agent, the hal4-1 mutant is sensitive to a variety of chemotherapeutic agents and stress-inducing compounds. Furthermore, this wider chemosensitive phenotype is also displayed by corresponding mutants in S. cerevisiae, and in a trk1deltatrk2delta double deletion mutant in S. pombe. We propose that this pathway and its role in regulating the plasma membrane potential may act as a pleiotropic determinant of sensitivity to chemotherapeutic agents.