@article{9429, abstract = {De novo loss of function mutations in the ubiquitin ligase-encoding gene Cullin3 lead to autism spectrum disorder (ASD). In mouse, constitutive haploinsufficiency leads to motor coordination deficits as well as ASD-relevant social and cognitive impairments. However, induction of Cul3 haploinsufficiency later in life does not lead to ASD-relevant behaviors, pointing to an important role of Cul3 during a critical developmental window. Here we show that Cul3 is essential to regulate neuronal migration and, therefore, constitutive Cul3 heterozygous mutant mice display cortical lamination abnormalities. At the molecular level, we found that Cul3 controls neuronal migration by tightly regulating the amount of Plastin3 (Pls3), a previously unrecognized player of neural migration. Furthermore, we found that Pls3 cell-autonomously regulates cell migration by regulating actin cytoskeleton organization, and its levels are inversely proportional to neural migration speed. Finally, we provide evidence that cellular phenotypes associated with autism-linked gene haploinsufficiency can be rescued by transcriptional activation of the intact allele in vitro, offering a proof of concept for a potential therapeutic approach for ASDs.}, author = {Morandell, Jasmin and Schwarz, Lena A and Basilico, Bernadette and Tasciyan, Saren and Dimchev, Georgi A and Nicolas, Armel and Sommer, Christoph M and Kreuzinger, Caroline and Dotter, Christoph and Knaus, Lisa and Dobler, Zoe and Cacci, Emanuele and Schur, Florian KM and Danzl, Johann G and Novarino, Gaia}, issn = {2041-1723}, journal = {Nature Communications}, keywords = {General Biochemistry, Genetics and Molecular Biology}, number = {1}, publisher = {Springer Nature}, title = {{Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development}}, doi = {10.1038/s41467-021-23123-x}, volume = {12}, year = {2021}, } @article{7149, abstract = {In recent years, many genes have been associated with chromatinopathies classified as “Cornelia de Lange Syndrome‐like.” It is known that the phenotype of these patients becomes less recognizable, overlapping to features characteristic of other syndromes caused by genetic variants affecting different regulators of chromatin structure and function. Therefore, Cornelia de Lange syndrome diagnosis might be arduous due to the seldom discordance between unexpected molecular diagnosis and clinical evaluation. Here, we review the molecular features of Cornelia de Lange syndrome, supporting the hypothesis that “CdLS‐like syndromes” are part of a larger “rare disease family” sharing multiple clinical features and common disrupted molecular pathways.}, author = {Avagliano, Laura and Parenti, Ilaria and Grazioli, Paolo and Di Fede, Elisabetta and Parodi, Chiara and Mariani, Milena and Kaiser, Frank J. and Selicorni, Angelo and Gervasini, Cristina and Massa, Valentina}, issn = {1399-0004}, journal = {Clinical Genetics}, number = {1}, pages = {3--11}, publisher = {Wiley}, title = {{Chromatinopathies: A focus on Cornelia de Lange syndrome}}, doi = {10.1111/cge.13674}, volume = {97}, year = {2020}, } @article{7488, abstract = {Characteristic or classic phenotype of Cornelia de Lange syndrome (CdLS) is associated with a recognisable facial pattern. However, the heterogeneity in causal genes and the presence of overlapping syndromes have made it increasingly difficult to diagnose only by clinical features. DeepGestalt technology, and its app Face2Gene, is having a growing impact on the diagnosis and management of genetic diseases by analysing the features of affected individuals. Here, we performed a phenotypic study on a cohort of 49 individuals harbouring causative variants in known CdLS genes in order to evaluate Face2Gene utility and sensitivity in the clinical diagnosis of CdLS. Based on the profile images of patients, a diagnosis of CdLS was within the top five predicted syndromes for 97.9% of our cases and even listed as first prediction for 83.7%. The age of patients did not seem to affect the prediction accuracy, whereas our results indicate a correlation between the clinical score and affected genes. Furthermore, each gene presents a different pattern recognition that may be used to develop new neural networks with the goal of separating different genetic subtypes in CdLS. Overall, we conclude that computer-assisted image analysis based on deep learning could support the clinical diagnosis of CdLS.}, author = {Latorre-Pellicer, Ana and Ascaso, Ángela and Trujillano, Laura and Gil-Salvador, Marta and Arnedo, Maria and Lucia-Campos, Cristina and Antoñanzas-Pérez, Rebeca and Marcos-Alcalde, Iñigo and Parenti, Ilaria and Bueno-Lozano, Gloria and Musio, Antonio and Puisac, Beatriz and Kaiser, Frank J. and Ramos, Feliciano J. and Gómez-Puertas, Paulino and Pié, Juan}, issn = {14220067}, journal = {International Journal of Molecular Sciences}, number = {3}, publisher = {MDPI}, title = {{Evaluating Face2Gene as a tool to identify Cornelia de Lange syndrome by facial phenotypes}}, doi = {10.3390/ijms21031042}, volume = {21}, year = {2020}, } @article{7586, abstract = {CLC chloride/proton exchangers may support acidification of endolysosomes and raise their luminal Cl− concentration. Disruption of endosomal ClC‐3 causes severe neurodegeneration. To assess the importance of ClC‐3 Cl−/H+ exchange, we now generate Clcn3unc/unc mice in which ClC‐3 is converted into a Cl− channel. Unlike Clcn3−/− mice, Clcn3unc/unc mice appear normal owing to compensation by ClC‐4 with which ClC‐3 forms heteromers. ClC‐4 protein levels are strongly reduced in Clcn3−/−, but not in Clcn3unc/unc mice because ClC‐3unc binds and stabilizes ClC‐4 like wild‐type ClC‐3. Although mice lacking ClC‐4 appear healthy, its absence in Clcn3unc/unc/Clcn4−/− mice entails even stronger neurodegeneration than observed in Clcn3−/− mice. A fraction of ClC‐3 is found on synaptic vesicles, but miniature postsynaptic currents and synaptic vesicle acidification are not affected in Clcn3unc/unc or Clcn3−/− mice before neurodegeneration sets in. Both, Cl−/H+‐exchange activity and the stabilizing effect on ClC‐4, are central to the biological function of ClC‐3.}, author = {Weinert, Stefanie and Gimber, Niclas and Deuschel, Dorothea and Stuhlmann, Till and Puchkov, Dmytro and Farsi, Zohreh and Ludwig, Carmen F. and Novarino, Gaia and López-Cayuqueo, Karen I. and Planells-Cases, Rosa and Jentsch, Thomas J.}, issn = {14602075}, journal = {EMBO Journal}, publisher = {EMBO Press}, title = {{Uncoupling endosomal CLC chloride/proton exchange causes severe neurodegeneration}}, doi = {10.15252/embj.2019103358}, volume = {39}, year = {2020}, } @article{7877, abstract = {The NIPBL/MAU2 heterodimer loads cohesin onto chromatin. Mutations inNIPBLaccount for most cases ofthe rare developmental disorder Cornelia de Lange syndrome (CdLS). Here we report aMAU2 variant causing CdLS, a deletion of seven amino acids that impairs the interaction between MAU2 and the NIPBL N terminus.Investigating this interaction, we discovered that MAU2 and the NIPBL N terminus are largely dispensable fornormal cohesin and NIPBL function in cells with a NIPBL early truncating mutation. Despite a predicted fataloutcome of an out-of-frame single nucleotide duplication inNIPBL, engineered in two different cell lines,alternative translation initiation yields a form of NIPBL missing N-terminal residues. This form cannot interactwith MAU2, but binds DNA and mediates cohesin loading. Altogether, our work reveals that cohesin loading can occur independently of functional NIPBL/MAU2 complexes and highlights a novel mechanism protectiveagainst out-of-frame mutations that is potentially relevant for other genetic conditions.}, author = {Parenti, Ilaria and Diab, Farah and Gil, Sara Ruiz and Mulugeta, Eskeatnaf and Casa, Valentina and Berutti, Riccardo and Brouwer, Rutger W.W. and Dupé, Valerie and Eckhold, Juliane and Graf, Elisabeth and Puisac, Beatriz and Ramos, Feliciano and Schwarzmayr, Thomas and Gines, Macarena Moronta and Van Staveren, Thomas and Van Ijcken, Wilfred F.J. and Strom, Tim M. and Pié, Juan and Watrin, Erwan and Kaiser, Frank J. and Wendt, Kerstin S.}, issn = {22111247}, journal = {Cell Reports}, number = {7}, publisher = {Elsevier}, title = {{MAU2 and NIPBL variants impair the heterodimerization of the cohesin loader subunits and cause Cornelia de Lange syndrome}}, doi = {10.1016/j.celrep.2020.107647}, volume = {31}, year = {2020}, }