Haploinsufficiency of EHMT1 improves pattern separation and increases hippocampal cell proliferation

Contains fulltext : 169681.pdf (publisher's version ) (Open Access)Heterozygous mutations or deletions of the human Euchromatin Histone Methyltransferase 1 (EHMT1) gene are the main causes of Kleefstra syndrome, a neurodevelopmental disorder that is characterized by impaired memory, autistic features and mostly severe intellectual disability. Previously, Ehmt1+/- heterozygous knockout mice were found to exhibit cranial abnormalities and decreased sociability, phenotypes similar to those observed in Kleefstra syndrome patients. In addition, Ehmt1+/- knockout mice were impaired at fear extinction and novel- and spatial object recognition. In this study, Ehmt1+/- and wild-type mice were tested on several cognitive tests in a touchscreen-equipped operant chamber to further investigate the nature of learning and memory changes. Performance of Ehmt1+/- mice in the Visual Discrimination &Reversal learning, object-location Paired-Associates learning- and Extinction learning tasks was found to be unimpaired. Remarkably, Ehmt1+/- mice showed enhanced performance on the Location Discrimination test of pattern separation. In line with improved Location Discrimination ability, an increase in BrdU-labelled cells in the subgranular zone of the dentate gyrus was observed. In conclusion, reduced levels of EHMT1 protein in Ehmt1+/- mice does not result in general learning deficits in a touchscreen-based battery, but leads to increased adult cell proliferation in the hippocampus and enhanced pattern separation ability

An anthropomorphic breathing phantom of the thorax for testing new motion mitigation techniques for pencil beam scanning proton therapy

Motion-induced range changes and incorrectly placed dose spots strongly affect the quality of pencil-beam-scanned (PBS) proton therapy, especially in thoracic tumour sites, where density changes are large. Thus motion-mitigation techniques are necessary, which must be validated in a realistic patient-like geometry. We report on the development and characterisation of a dynamic, anthropomorphic, thorax phantom that can realistically mimic thoracic motions and anatomical features for verifications of proton and photon 4D treatments. The presented phantom is of an average thorax size, and consists of inflatable, deformable lungs surrounded by a skeleton and skin. A mobile 'tumour' is embedded in the lungs in which dosimetry devices (such as radiochromic films) can be inserted. Motion of the tumour and deformation of the thorax is controlled via a custom made pump system driving air into and out of the lungs. Comprehensive commissioning tests have been performed to evaluate the mechanical performance of the phantom, its visibility on CT and MR imaging and its feasibility for dosimetric validation of 4D proton treatments. The phantom performed well on both regular and irregular pre-programmed breathing curves, reaching peak-to-peak amplitudes in the tumour of  90% in the central planes of the target. The results of this study demonstrate that this anthropomorphic thorax phantom is suitable for imaging and dosimetric studies in a thoracic geometry closely-matched to lung cancer patients under realistic motion conditions

Screening of 20 patients with X-linked mental retardation using chromosome X-specific array-MAPH

Copyright © 2007 Elsevier Masson SAS All rights reserved.The rapid advancement of high-resolution DNA copy number assessment methods revealed the significant contribution of submicroscopic genetic imbalances to abnormal phenotypes, including mental retardation. In order to detect submicroscopic genetic imbalances, we have screened 20 families with X-linked mental retardation (XLMR) using a chromosome X-specific array-MAPH platform with median resolution of 238 kb. Among the 20 families, 18 were experimental, as they were not previously screened with any microarray method, and two were blind controls with known aberrations, as they were previously screened by array-CGH. This study presents the first clinical application of chromosome X-specific array-MAPH methodology. The screening of 20 affected males from 20 unrelated XLMR families resulted in the detection of an unknown deletion, spanning a region of 7-23 kb. Family studies and population screening demonstrated that the detected deletion is an unknown rare copy number variant. One of the control samples, carrying approximately 6-Mb duplication was correctly identified, moreover it was found to be interrupted by a previously unknown 19 kb region of normal copy number. The second control 50 kb deletion was not identified, as this particular region was not covered by array-MAPH probes. This study demonstrates that the chromosome X-specific array-MAPH platform is a valuable tool for screening patients with XLMR, or other X-linked disorders, and emerges the need for introducing new high-resolution screening methods for the detection of genetic imbalances. (C) 2007 Elsevier Masson SAS. All fights reserved.Ludmila Kousoulidou, Sven Parkel, Olga Zilina, Priit Palta, Helen Puusepp, Maido Remm, Gillian Turner, Jackie Boyle, Hans van Bokhoven, Arjan de Brouwer, Hilde Van Esch, Guy Froyen, Hans-Hilger Ropers, Jamel Chelly, Claude Moraine, Jozef Gecz, Ants Kurg and Philippos C. Patsalishttp://www.elsevier.com/wps/find/journaldescription.cws_home/705239/description#descriptio

RNA Sequencing and Pathway Analysis Identify Important Pathways Involved in Hypertrichosis and Intellectual Disability in Patients with Wiedemann–Steiner Syndrome

International audienceA growing number of histone modifiers are involved in human neurodevelopmental disorders, suggesting that proper regulation of chromatin state is essential for the development of the central nervous system. Among them, heterozygous de novo variants in KMT2A, a gene coding for histone methyltransferase, have been associated with Wiedemann-Steiner syndrome (WSS), a rare developmental disorder mainly characterized by intellectual disability (ID) and hypertrichosis. As KMT2A is known to regulate the expression of multiple target genes through methylation of lysine 4 of histone 3 (H3K4me), we sought to investigate the transcriptomic consequences of KMT2A variants involved in WSS. Using fibroblasts from four WSS patients harboring loss-of-function KMT2A variants, we performed RNA sequencing and identified a number of genes for which transcription was altered in KMT2A-mutated cells compared to the control ones. Strikingly, analysis of the pathways and biological functions significantly deregulated between patients with WSS and healthy individuals revealed a number of processes predicted to be altered that are relevant for hypertrichosis and intellectual disability, the cardinal signs of this disease

Further delineation of the 15q13 microdeletion and duplication syndromes: a clinical spectrum varying from non-pathogenic to a severe outcome

Background: recurrent 15q13.3 microdeletions were recently identified with identical proximal (BP4) and distal (BP5) breakpoints and associated with mild to moderate mental retardation and epilepsy.Methods: to assess further the clinical implications of this novel 15q13.3 microdeletion syndrome, 18 new probands with a deletion were molecularly and clinically characterised. In addition, we evaluated the characteristics of a family with a more proximal deletion between BP3 and BP4. Finally, four patients with a duplication in the BP3–BP4–BP5 region were included in this study to ascertain the clinical significance of duplications in this region.Results: the 15q13.3 microdeletion in our series was associated with a highly variable intra- and inter-familial phenotype. At least 11 of the 18 deletions identified were inherited. Moreover, 7 of 10 siblings from four different families also had this deletion: one had a mild developmental delay, four had only learning problems during childhood, but functioned well in daily life as adults, whereas the other two had no learning problems at all. In contrast to previous findings, seizures were not a common feature in our series (only 2 of 17 living probands). Three patients with deletions had cardiac defects and deletion of the KLF13 gene, located in the critical region, may contribute to these abnormalities. The limited data from the single family with the more proximal BP3–BP4 deletion suggest this deletion may have little clinical significance. Patients with duplications of the BP3–BP4–BP5 region did not share a recognisable phenotype, but psychiatric disease was noted in 2 of 4 patients.Conclusions: overall, our findings broaden the phenotypic spectrum associated with 15q13.3 deletions and suggest that, in some individuals, deletion of 15q13.3 is not sufficient to cause disease. The existence of microdeletion syndromes, associated with an unpredictable and variable phenotypic outcome, will pose the clinician with diagnostic difficulties and challenge the commonly used paradigm in the diagnostic setting that aberrations inherited from a phenotypically normal parent are usually without clinical consequence