Deciphering molecular mechanisms of CHAMP1 deficiency-associated developmental delay
Final Report Abstract
Neurodevelopmental disorders (NDDs) represent a large and diverse group of disorders including intellectual disability (ID), autism spectrum disorders (ASD), attention deficit hyperactivity disorders and epilepsy. The introduction of high-throughput sequencing technologies such as next generation sequencing (NGS) approaches has substantially improved our understanding of the genetic cause of different forms of NDDs. Indeed, more than 1000 genes have been identified so far, albeit each of them in only a small number of cases. The underlying genes encode proteins involved in different cellular processes which can be either “neuron specific” such as synaptic proteins for instance but also more ubiquitous such as proteins involved in global regulation of gene expression at the translational, transcriptional or post-transcriptional level. In this project, we aimed to identify novel molecular mechanisms and pathways governed by CHAMP1, pathogenic variants in which cause a neurodevelopmental disorder characterized by intellectual disability (ID) with severe speech impairment, and motor developmental delay. Our analyses of various genomeedited cell lines suggest CHAMP1 to be one of the essential human genes that controls a myriad of basic functions that the cells require in order to survive. Further, we show that CHAMP1 haploinsufficiency in patient-derived primary fibroblasts causes chromosome misalignment, supernumerary centrosomes, accumulation of CREST-positive micronuclei and variegated aneuploidy mosaicism. Combination of ChIP-seq (chromatin immunoprecipitation (ChIP) with massively parallel DNA sequencing) and RNA-sequencing revealed that CHAMP1 transcriptionally regulates a myriad of genes involved in cell cycle progression and mitosis. Moreover, we have shown that CHAMP1 exerts transcriptional activity in a cell type and cell cycle dependant manner. Furthermore, we have shown that CHAMP1 regulates CHEK1 and CDK1 in the G2 phase, indicating its role as the regulator of the G2/M checkpoint and providing a molecular explanation for the observed variegated aneuploidy mosaicism. We have also extended our analyses to another C2H2-ZnF containing, DNA-binding transcription factor, BCL11B. Based on the clinical and molecular findings we suggest that BCL11B alterations result in a phenotypic spectrum that can be classified in four subtypes. Moreover, the clinical, molecular and modelling data strongly suggest that the phenotypic diversity of BCL11B-related disorders is strongly dependent on the impact of diverse BCL11B alterations on its DNA binding affinity and specificity, which may result in unprecedented and unpredictable clinical outcomes. Last but not least, we identified several novel disease genes and expanded the phenotype associated with pathogenic variants in AGO2, ANK3, DHX30 and TOR1AIP1. Thereby, providing further evidence that development and function of the nervous system is particularly vulnerable to alterations in gene expression patterns and their regulation.
Publications
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Germline AGO2 mutations impair RNA interference and human neurological development. Nature Communications, 11(1).
Lessel, Davor; Zeitler, Daniela M.; Reijnders, Margot R. F.; Kazantsev, Andriy; Hassani, Nia Fatemeh; Bartholomäus, Alexander; Martens, Victoria; Bruckmann, Astrid; Graus, Veronika; McConkie-Rosell, Allyn; McDonald, Marie; Lozic, Bernarda; Tan, Ee-Shien; Gerkes, Erica; Johannsen, Jessika; Denecke, Jonas; Telegrafi, Aida; Zonneveld-Huijssoon, Evelien; Lemmink, Henny H. ... & Kreienkamp, Hans-Jürgen
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Two novel cases further expand the phenotype of TOR1AIP1-associated nuclear envelopathies. Human Genetics, 139(4), 483-498.
Lessel, Ivana; Chen, Mei-Jan; Lüttgen, Sabine; Arndt, Florian; Fuchs, Sigrid; Meien, Stefanie; Thiele, Holger; Jones, Julie R.; Shaw, Brandon R.; Crossman, David K.; Nürnberg, Peter; Korf, Bruce R.; Kubisch, Christian & Lessel, Davor
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ANK3 related neurodevelopmental disorders: expanding the spectrum of heterozygous loss-of-function variants. neurogenetics, 22(4), 263-269.
Kloth, Katja; Lozic, Bernarda; Tagoe, Julia; Hoffer, Mariëtte J. V.; Van der Ven, Amelie; Thiele, Holger; Altmüller, Janine; Kubisch, Christian; Au, Ping Yee Billie; Denecke, Jonas; Bijlsma, Emilia K. & Lessel, Davor
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Genotype–phenotype correlations and novel molecular insights into the DHX30-associated neurodevelopmental disorders. Genome Medicine, 13(1).
Mannucci, Ilaria; Dang, Nghi D. P.; Huber, Hannes; Murry, Jaclyn B.; Abramson, Jeff; Althoff, Thorsten; Banka, Siddharth; Baynam, Gareth; Bearden, David; Beleza-Meireles, Ana; Benke, Paul J.; Berland, Siren; Bierhals, Tatjana; Bilan, Frederic; Bindoff, Laurence A.; Braathen, Geir Julius; Busk, Øyvind L.; Chenbhanich, Jirat; Denecke, Jonas ... & Lessel, Davor
