The Impact of Major Depressive Disorder on the Academic Achievement of Australian Adolescents

This item is only available electronically.Academic achievement attained by adolescents is important for future career success as well as personal and social growth. Major Depressive Disorder (MDD) has the potential to adversely affect both academic outcomes and personal development. This thesis investigated the association between MDD and academic achievement in Australian adolescents. The thesis analysed de-identified data describing 13 to 15 year old’s, who participated in the second Australian Child and Adolescent Survey of Mental Health and Wellbeing (n=1077), undertaken in 2013 to 2015. Academic achievement was assessed using linked National Assessment Program Literacy and Numeracy (NAPLAN) scores of the students, and MDD was assessed using parent reports from the Diagnostic Interview Schedule for Children version IV (DISC-IV). It was hypothesised that adolescents with MDD would have lower levels of academic achievement, and a higher percentage of days absent from school. Bivariate and multivariate logistic regression were conducted to assess the strength of the association between MDD and NAPLAN scores, and to identify if the association was modified by school absence. Although limited by a small number of participants with MDD, there was some evidence to support these hypotheses. The results suggested that adolescents aged 13 to 15 years with MDD may be more susceptible to lower academic outcomes, and higher school absence, as compared to their peers. The results contribute to the awareness and understanding of the association between MDD and academic achievement at a national scale.Thesis (B.PsychSc(Hons)) -- University of Adelaide, School of Psychology, 202

Genes for cognitive function: Developments on the X

Developments in human genome research enabled the first steps toward a molecular understanding of cognitive function. That there are numerous genes on the X chromosome affecting intelligence at the lower end of the cognitive range is no longer in doubt. Naturally occurring mutations have so far led to the identification of seven genes accounting for a small proportion of familial nonspecific X-linked mental retardation. These new data indicate that normal expression of many more X-linked and autosomal genes contribute to cognitive function. The emerging knowledge implicating genes in intracellular signaling pathways provides the insight to identify as candidates other X-linked and autosomal genes regulating the normal development of cognitive function. Recent advances in unravelling the underlying molecular complexity have been spectacular but represent only the beginning, and new technologies will need to be introduced to complete the picture

Developmental disorders: deciphering exomes on a grand scale

Jozef Gecz, Mark Corbet

A Upf3b-mutant mouse model with behavioral and neurogenesis defects.

Nonsense-mediated RNA decay (NMD) is a highly conserved and selective RNA degradation pathway that acts on RNAs terminating their reading frames in specific contexts. NMD is regulated in a tissue-specific and developmentally controlled manner, raising the possibility that it influences developmental events. Indeed, loss or depletion of NMD factors have been shown to disrupt developmental events in organisms spanning the phylogenetic scale. In humans, mutations in the NMD factor gene, UPF3B, cause intellectual disability (ID) and are strongly associated with autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD) and schizophrenia (SCZ). Here, we report the generation and characterization of mice harboring a null Upf3b allele. These Upf3b-null mice exhibit deficits in fear-conditioned learning, but not spatial learning. Upf3b-null mice also have a profound defect in prepulse inhibition (PPI), a measure of sensorimotor gating commonly deficient in individuals with SCZ and other brain disorders. Consistent with both their PPI and learning defects, cortical pyramidal neurons from Upf3b-null mice display deficient dendritic spine maturation in vivo. In addition, neural stem cells from Upf3b-null mice have impaired ability to undergo differentiation and require prolonged culture to give rise to functional neurons with electrical activity. RNA sequencing (RNAseq) analysis of the frontal cortex identified UPF3B-regulated RNAs, including direct NMD target transcripts encoding proteins with known functions in neural differentiation, maturation and disease. We suggest Upf3b-null mice serve as a novel model system to decipher cellular and molecular defects underlying ID and neurodevelopmental disorders

Cerebral palsy: causes, pathways, and the role of genetic variants

Letter to the Editor. From the Australian Collaborative Cerebral Palsy Research Group at the Robinson Research Institute, the University of Adelaide, Adelaide, AustraliaCerebral palsy (CP) is heterogeneous with different clinical types, comorbidities, brain imaging patterns, causes, and now also heterogeneous underlying genetic variants. Few are solely due to severe hypoxia or ischemia at birth. This common myth has held back research in causation. The cost of litigation has devastating effects on maternity services with unnecessarily high cesarean delivery rates and subsequent maternal morbidity and mortality. CP rates have remained the same for 50 years despite a 6-fold increase in cesarean birth. Epidemiological studies have shown that the origins of most CP are prior to labor. Increased risk is associated with preterm delivery, congenital malformations, intrauterine infection, fetal growth restriction, multiple pregnancy, and placental abnormalities. Hypoxia at birth may be primary or secondary to preexisting pathology and international criteria help to separate the few cases of CP due to acute intrapartum hypoxia. Until recently, 1-2% of CP (mostly familial) had been linked to causative mutations. Recent genetic studies of sporadic CP cases using new-generation exome sequencing show that 14% of cases have likely causative single-gene mutations and up to 31% have clinically relevant copy number variations. The genetic variants are heterogeneous and require function investigations to prove causation. Whole genome sequencing, fine scale copy number variant investigations, and gene expression studies may extend the percentage of cases with a genetic pathway. Clinical risk factors could act as triggers for CP where there is genetic susceptibility. These new findings should refocus research about the causes of these complex and varied neurodevelopmental disorders.Alastair H. MacLennan, Suzanna C. Thompson, Jozef Gec

Phenotype-genotype complexities: opening DOORS

Samuel F Berkovic, Jozef Gec

FRAXE-associated mental retardation protein (FMR2) is an RNA-binding protein with high affinity for G-quartet RNA forming structure

FRAXE is a form of mild to moderate mental retardation due to the silencing of the FMR2 gene. The cellular function of FMR2 protein is presently unknown. By analogy with its homologue AF4, FMR2 was supposed to have a role in transcriptional regulation, but robust evidences supporting this hypothesis are lacking. We observed that FMR2 co-localizes with the splicing factor SC35 in nuclear speckles, the nuclear regions where splicing factors are concentrated, assembled and modified. Similarly to what was reported for splicing factors, blocking splicing or transcription leads to the accumulation of FMR2 in enlarged, rounded speckles. FMR2 is also localized in the nucleolus when splicing is blocked. We show here that FMR2 is able to specifically bind the G-quartet-forming RNA structure with high affinity. Remarkably, in vivo, in the presence of FMR2, the ESE action of the G-quartet situated in mRNA of an alternatively spliced exon of a minigene or of the putative target FMR1 appears reduced. Interestingly, FMR1 is silenced in the fragile X syndrome, another form of mental retardation. All together, our findings strongly suggest that FMR2 is an RNA-binding protein, which might be involved in alternative splicing regulation through an interaction with G-quartet RNA structure

Protocadherin 19 clustering epilepsy and neurosteroids: opportunities for intervention

Steroids yield great influence on neurological development through nuclear hormone receptor (NHR)-mediated gene regulation. We recently reported that cell adhesion molecule protocadherin 19 (encoded by the PCDH19 gene) is involved in the coregulation of steroid receptor activity on gene expression. PCDH19 variants cause early-onset developmental epileptic encephalopathy clustering epilepsy (CE), with altered steroidogenesis and NHR-related gene expression being identified in these individuals. The implication of hormonal pathways in CE pathogenesis has led to the investigation of various steroid-based antiepileptic drugs in the treatment of this disorder, with mixed results so far. Therefore, there are many unmet challenges in assessing the antiseizure targets and efficiency of steroid-based therapeutics for CE. We review and assess the evidence for and against the implication of neurosteroids in the pathogenesis of CE and in view of their possible clinical benefitRebekah de Nys, Raman Kumar and Jozef Gec

Protocadherin 19 (PCDH19) interacts with paraspeckle protein NONO to co-regulate gene expression with estrogen receptor alpha (ERalpha)

De novo and inherited mutations of X-chromosome cell adhesion molecule protocadherin 19 (PCDH19) cause frequent, highly variable epilepsy, autism, cognitive decline and behavioural problems syndrome. Intriguingly, hemizygous null males are not affected while heterozygous females are, contradicting established X-chromosome inheritance. The disease mechanism is not known. Cellular mosaicism is the likely driver. We have identified p54nrb/NONO, a multifunctional nuclear paraspeckle protein with known roles in nuclear hormone receptor gene regulation, as a PCDH19 protein interacting partner. Using breast cancer cells we show that PCDH19-NONO complex is a positive co-regulator of ERα-mediated gene expression. Expression of mutant PCDH19 affects at least a subset of known ERα-regulated genes. These data are consistent with our findings that genes regulated by nuclear hormone receptors and those involved in the metabolism of neurosteroids in particular are dysregulated in PCDH19-epilepsy girls and affected mosaic males. Overall we define and characterize a novel mechanism of gene regulation driven by PCDH19, which is mediated by paraspeckle constituent NONO and is ERα-dependent. This PCDH19-NONO-ERα axis is of relevance not only to PCDH19-epilepsy and its comorbidities but likely also to ERα and generally nuclear hormone receptor-associated cancers.Duyen H. Pham, Chuan C. Tan, Claire C. Homan, Kristy L. Kolc, Mark A. Corbett, Dale McAninch, Archa H. Fox, Paul Q. Thomas, Raman Kumar Jozef Gec