Golabi-Ito-Hall syndrome results from a missense mutation in the WW domain of the PQBP1 gene

Background: Golabi, Ito, and Hall reported a family with X linked mental retardation (XLMR), microcephaly, postnatal growth deficiency, and other anomalies, including atrial septal defect, in 1984.Methods: This family was restudied as part of our ongoing study of XLMR, but significant linkage to X chromosome markers could not be found. Extreme short stature and microcephaly as well as other new clinical findings were observed. Mutations in the polyglutamine tract binding protein 1 gene (PQBP1) have recently been reported in four XLMR disorders (Renpenning, Hamel cerebro-palato-cardiac, Sutherland-Haan, and Porteous syndromes) as well as in several other families. The clinical similarity of our family to these patients with mutations in PQBP1, particularly the presence of microcephaly, short stature, and atrial septal defect, prompted examination of this gene.Results: A missense mutation in PQBP1 was identified which changed the conserved tyrosine residue in the WW domain at position 65 to a cysteine (p.Y65C).Conclusions: This is the first missense mutation identified in PQBP1 and the first mutation in the WW domain of the gene. The WW domain has been shown to play an important role in the regulation of transcription by interacting with the PPxY motif found in transcription factors. The p.Y65C mutation may affect the proper functioning of the PQBP1 protein as a transcriptional co-activator

ZC4H2, an XLID gene, is required for the generation of a specific subset of CNS interneurons

Miles-Carpenter syndrome (MCS) was described in 1991 as an XLID syndrome with fingertip arches and contractures and mapped to proximal Xq. Patients had microcephaly, short stature, mild spasticity, thoracic scoliosis, hyperextendable MCP joints, rocker-bottom feet, hyperextended elbows and knees. A mutation, p.L66H, in ZC4H2, was identified in a XLID resequencing project. Additional screening of linked families and next generation sequencing of XLID families identified three ZC4H2 mutations: p.R18K, p.R213W and p.V75in15aa. The families shared some relevant clinical features. In silico modeling of the mutant proteins indicated all alterations would destabilize the protein. Knockout mutations in zc4h2 were created in zebrafish and homozygous mutant larvae exhibited abnormal swimming, increased twitching, defective eye movement and pectoral fin contractures. Because several of the behavioral defects were consistent with hyperactivity, we examined the underlying neuronal defects and found that sensory neurons and motoneurons appeared normal. However, we observed a striking reduction in GABAergic interneurons. Analysis of cell-type-specificmarkers showed a specific loss of V2 interneurons in the brain and spinal cord, likely arising from mis-specification of neural progenitors. Injected human wt ZC4H2 rescued the mutant phenotype. Mutant zebrafish injectedwith human p.L66H or p.R213W mRNA failed to be rescued, while the p.R18K mRNA was able to rescue the interneuron defect. Our findings clearly support ZC4H2 as a novel XLID gene with a required function in interneuron development. Loss of function of ZC4H2 thus likely results in altered connectivity ofmany brain and spinal circuits

A Phenotype of Early Infancy Predicts Reactivity of the Amygdala in Male Adults

One of the central questions that has occupied those disciplines concerned with human development is the nature of continuities and discontinuities from birth to maturity. The amygdala plays a central role in the processing of novelty and emotion in the brain. While there is considerable variability among individuals in the reactivity of the amygdala to novel and emotional stimuli, the origin of these individual differences is not well understood. Four month old infants called high reactive (HR) demonstrate a distinctive pattern of vigorous motor activity and crying to specific unfamiliar visual, auditory, and olfactory stimuli in the laboratory. Low-reactive infants show the complementary pattern. Here we demonstrate that the HR infant phenotype predicts greater amygdalar reactivity to novel faces almost two decades later in adults. A prediction of individual differences in brain function at maturity can be made on the basis of a single behavioural assessment made in the laboratory at four months of age. This is the earliest known human behavioural phenotype that predicts individual differences in patterns of neural activity at maturity. These temperamental differences rooted in infancy may be relevant to understanding individual differences in vulnerability and resilience to clinical psychiatric disorder. Males who were HR infants showed particularly high-levels of reactivity to novel faces in the amygdala that distinguished them as adults from all other sex/temperament subgroups, suggesting that their amygdala is particularly prone to engagement by unfamiliar faces. These findings underline the importance of taking gender into account when studying the developmental neurobiology of human temperament and anxiety disorders. The genetic study of behavioral and biologic intermediate phenotypes (or “endophenotypes”) indexing anxiety-proneness offers an important alternative to examining phenotypes based on clinically-defined disorder. Because the HR phenotype is characterized by specific patterns of reactivity to elemental visual, olfactory, and auditory stimuli, well before complex social behaviors such as shyness or fearful interaction with strangers can be observed, it may be closer to underlying neurobiological mechanisms than behavioral profiles observed later in life. This possibility, together with the fact that environmental factors have less time to impact the four-month phenotype, suggests that this temperamental profile may be a fruitful target for high-risk genetic studies.Psycholog

DNA methylation epi-signature is associated with two molecularly and phenotypically distinct clinical subtypes of Phelan-McDermid syndrome

Background: Phelan-McDermid syndrome is characterized by a range of neurodevelopmental phenotypes with incomplete penetrance and variable expressivity. It is caused by a variable size and breakpoint microdeletions in the distal long arm of chromosome 22, referred to as 22q13.3 deletion syndrome, including the SHANK3 gene. Genetic defects in a growing number of neurodevelopmental genes have been shown to cause genome-wide disruptions in epigenomic profiles referred to as epi-signatures in affected individuals. Results: In this study we assessed genome-wide DNA methylation profiles in a cohort of 22 individuals with Phelan-McDermid syndrome, including 11 individuals with large (2 to 5.8 Mb) 22q13.3 deletions, 10 with small deletions (\u3c 1 Mb) or intragenic variants in SHANK3 and one mosaic case. We describe a novel genome-wide DNA methylation epi-signature in a subset of individuals with Phelan-McDermid syndrome. Conclusion: We identified the critical region including the BRD1 gene as responsible for the Phelan-McDermid syndrome epi-signature. Metabolomic profiles of individuals with the DNA methylation epi-signature showed significantly different metabolomic profiles indicating evidence of two molecularly and phenotypically distinct clinical subtypes of Phelan-McDermid syndrome

Positive change with Ménière’s disease

This is the author's accepted manuscript. The final published article is available from the link below. Copyright © 2009 The British Psychological Society.Objective - The aims of this study were twofold: to determine in what way people with a non-fatal chronic illness experience positive change after the onset of their illness, and to determine whether comparing with other people with Ménière's disease influenced perceiving this change. Design - Using a longitudinal method, questionnaires were administered at baseline and at ten-month follow-up. Method - At both time points 301 people with Ménière's disease completed the Posttraumatic Growth Inventory and at baseline they also completed questionnaires measuring, demographic variables, disease severity, psychological variables (self-esteem, perceived control, and optimism), and social comparison variables. Results - People with Ménière's disease in this study perceived positive change. Greater positive change was perceived on the domain of ‘appreciation of life,’ followed by ‘relating to others,’ ‘personal strength,’ ‘new possibilities,’ and ‘spiritual change’. In addition, more change was perceived at follow-up than at baseline. Social comparison was associated with perceiving change at both time points. Conclusions - People with Ménière's disease do perceive positive change. Perceiving change is an on-going process for people with Ménière's disease, as they perceived more change over time. Social comparison was related to the perception of change, in particular, to the perception of growth in personal strength.Economic and Social Research Council, UK and the Ménière's Society, U

Compassion motivations: Distinguishing submissive compassion from genuine compassion and its association with shame, submissive behavior, depression, anxiety and stress

Abstract Recent research has suggested that being compassionate and helpful to others is linked to well-being. However, people can pursue compassionate motives for different reasons, one of which may be to be liked or valued. Evolutionary theory suggests this form of helping may be related to submissive appeasing behavior and therefore could be negatively associated with well-being. To explore this possibility we developed a new scale called the submissive compassion scale and compared it to other established submissive and shame-based scales, along with measures of depression, anxiety and stress in a group of 192 students. As predicted, a submissive form of compassion (being caring in order to be liked) was associated with submissive behavior, shame-based caring, ego-goals and depression, anxiety, and stress. In contrast, compassionate goals and compassion for others were not. As research on compassion develops, new ways of understanding the complex and mixed motivations that can lie behind compassion are required. The desire to be helpful, kind, and compassionate, when it arises from fears of rejection and desires for acceptance, needs to be explored.N/

On some normability conditions

Various normability conditions of locally convex spaces (including Vogt interpolation classes DN and as well as quasi- and asymptotic normability) are investigated. In particular, it is shown that on the class of Schwartz spaces the property of asymptotic normability coincides with the property GS , which is a natural generalization of Gelfand-Shilov countable normability (cf. [9, 25], where the metrizable case was treated). It is observed also that there are certain natural duality relationships among some of normability conditions

Family-Expressed Emotion, Childhood-Onset Depression, and Childhood-Onset Schizophrenia Spectrum Disorders: Is Expressed Emotion a Nonspecific Correlate of Child Psychopathology or a Specific Risk Factor for Depression?

Expressed emotion (EE) was examined, using the brief Five Minute Speech Sample measure, in families of (1) children with depressive disorders, (2) children with schizophrenia spectrum disorders, and (3) normal controls screened for the absence of psychiatric disorder. Consistent with the hypothesis of some specificity in the association between EE and the form of child disorder, rates of EE were significantly higher among families of depressed children compared to families of normal controls and families of children with schizophrenia spectrum disorders. Within the depressed group, the presence of a comorbid disruptive behavior disorder was associated with high levels of critical EE, underscoring the need to attend to comorbid patterns and subtypes of EE in future research