Assigning single clinical features to their disease-locus in large deletions: the example of chromosome 1q23-25 deletion syndrome

Aim: Assigning a disease-locus within the shortest regions of overlap (SRO) shared by deleted/duplicated subjects presenting this disease is a robust mapping approach, although the presence of different malformation traits and their attendance only in a part of the affected subjects can hinder the interpretation. To overcome the problem of incomplete penetrance, we developed an algorithm that we applied to the deletion region 1q23.3-q25, which contains three SROs, each contributing to the abnormal phenotype without clearly distinguishing between the different malformations. We describe six new subjects, including a healthy father and his daughter, with 1q23.3-q25 deletion of different sizes. The aim of this study was to correlate specific abnormal traits to the haploinsufficiency of specific gene/putative regulatory elements. Methods: Merging cases with those in the literature, we considered four traits, namely intellectual disability (ID), microcephaly, short-hands/feet, and brachydactyly, and conceived a mathematical model to predict with what probability the haploinsufficiency of a specific portion of the deletion region is associated with one of the four malformations. Results: The haploinsufficiency of PBX1 is strongly associated with ID. DNM3 and LHX4 are confirmed as responsible for growth retardation, whereas ATPIB1 was identified as a new candidate gene for microcephaly, short-hands/feet, and brachydactyly. Conclusion: Although our model is hampered by long-term position effects of regulatory elements, synergistic cooperation of several genes, and incomplete clinical assessment, it can be useful for contiguous gene syndromes showing a complex pattern of clinical characteristics. Obviously, functional approaches are needed to warrant its reliability

Sleep deprivation disrupts prepulse inhibition of the startle reflex: reversal by antipsychotic drugs

This is the publisher's version, also available electronically from http://journals.cambridge.org/action/displayAbstract?fromPage=online&aid=2327016&fileId=S1461145708008900Sleep deprivation (SD) is known to induce perceptual impairments, ranging from perceptual distortion to hallucinatory states. Although this phenomenon has been extensively described in the literature, its neurobiological underpinnings remain elusive. In rodents, SD induces a series of behavioural patterns that might be reflective of psychosis and mania, such as hyperlocomotion and sensitization to psychotogenic drugs. Notably, such changes are accompanied by transitory alterations of dopaminergic signalling. Based on the hypothesis that both psychotic and manic disorders reflect gating impairments, the present study was aimed at the assessment of the impact of SD on the behavioural model of prepulse inhibition (PPI) of the startle reflex, a reliable paradigm for the study of informational filtering. Rats subjected to SD (24 h, 48 h, 72 h) exhibited a time-dependent increase in startle reflex and a dramatic deficit in PPI. Both alterations were reversed 24 h after termination of the SD period. Interestingly, PPI disruption was efficiently prevented by haloperidol (0.1 mg/kg i.p.) clozapine (5 mg/kg i.p.) and risperidone (1 mg/kg i.p.). Conversely, neither the anxiolytic diazepam (5 mg/kg i.p.) nor the antidepressant citalopram (5 mg/kg i.p) affected the PPI disruption mediated by SD, although diazepam reversed the enhancement in startle reflex magnitude induced by this manipulation. Our data suggest that SD induces gating deficits that might be relevant to the hallucinatory phenomena observed in humans, and provide a novel reliable animal model where such relationship can be studied

The Shine-Through Masking Paradigm Is a Potential Endophenotype of Schizophrenia

BACKGROUND: To understand the genetics of schizophrenia, a hunt for so-called intermediate phenotypes or endophenotypes is ongoing. Visual masking has been proposed to be such an endophenotype. However, no systematic study has been conducted yet to prove this claim. Here, we present the first study showing that masking meets the most important criteria for an endophenotype. METHODOLOGY/PRINCIPAL FINDINGS: We tested 62 schizophrenic patients, 39 non-affected first-degree relatives, and 38 healthy controls in the shine-through masking paradigm and, in addition, in the Continuous Performance Test (CPT) and the Wisconsin Card Sorting Test (WCST). Most importantly, masking performance of relatives was significantly in between the one of patients and controls in the shine-through paradigm. Moreover, deficits were stable throughout one year. Using receiver operating characteristics (ROC) methods, we show that the shine-through paradigm distinguishes with high sensitivity and specificity between schizophrenic patients, first-order relatives and healthy controls. CONCLUSIONS/SIGNIFICANCE: The shine-through paradigm is a potential endophenotype

Speed of Information Processing and Individual Differences in Intelligence

Navy Personnel Research and Development Centerhttp://archive.org/details/speedofinformati78sac

Posttranslational modifications of the subunits of human chorionic gonadotropin that modulate dimer assembly.

Both malignant and nonmalignant trophoblast cells synthesize and secrete the biologically active hCG $\\alpha$$\\beta$ dimer as well as uncombined (free) $\\alpha$ and $\\beta$ subunits, which have no known biological function. This suggests that dimer formation is not limited by the availability of subunits, but rather by posttranslational modifications of the subunits that influence their ability to combine. I have purified the hCG subunits from JAR choriocarcinoma cells to identify modifications that distinguish the free from the combined subunits, and determined whether these modifications limit $\\alpha$$\\beta$ dimerization by using in vitro combination assays. The secreted free $\\alpha$ subunit is preferentially phosphorylated by intact JAR cells. In in vitro assays, with homogenates of JAR cells as the enzyme source, the $\\alpha$ subunit is phosphorylated on threonine 39, the same site that contains the O-linked carbohydrate in hCG. When the free $\\alpha$ subunit is incubated with the purified urinary CG-$\\beta$ subunit in vitro, the free $\\alpha$ form that is least able to combine has an O-linked carbohydrate on threonine 39. The major limiting factor for combination, however, is the presence of larger N-linked carbohydrate chains on free $\\alpha$. These modifications of the free $\\alpha$ subunit probably occur in the Golgi, whereas the combination reaction is completed while the subunits reside in the ER. Thus, although these modifications of the free $\\alpha$ subunit may limit further combination of hCG subunits before secretion, they are probably not rate-limiting for combination. The rate limiting event for subunit combination in JAR cells is the rate of formation of disulfide bonds in the $\\beta$ subunit, accompanied by a conformational change that leads to a combination-competent $\\beta$ form. Although only half of the $\\beta$ molecules synthesized in JAR cells combine to form dimer, both the free $\\beta$ and the dimer $\\beta$ subunits purified from JAR cells combine to the same extent with the purified urinary hCG $\\alpha$ subunit in vitro, suggesting that free $\\beta$ can combine with $\\alpha$ if given sufficient time. The data suggest that subtle conformational differences make free $\\beta$ less favorable for combination with $\\alpha$ in the short time that dimer assembly must occur in the cell.Ph.D.PharmacologyUniversity of Michiganhttp://deepblue.lib.umich.edu/bitstream/2027.42/162286/1/9001599.pd