Publications by authors named "Fabrice Riet"

8 Publications

  • Page 1 of 1

Translation of GGC repeat expansions into a toxic polyglycine protein in NIID defines a novel class of human genetic disorders: The polyG diseases.

Neuron 2021 06 21;109(11):1825-1835.e5. Epub 2021 Apr 21.

Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U 1258, CNRS UMR 7104, University of Strasbourg, 67404 Illkirch, France. Electronic address:

Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disease characterized by the presence of intranuclear inclusions of unknown origin. NIID is caused by an expansion of GGC repeats in the 5' UTR of the NOTCH2NLC (N2C) gene. We found that these repeats are embedded in a small upstream open reading frame (uORF) (uN2C), resulting in their translation into a polyglycine-containing protein, uN2CpolyG. This protein accumulates in intranuclear inclusions in cell and mouse models and in tissue samples of individuals with NIID. Furthermore, expression of uN2CpolyG in mice leads to locomotor alterations, neuronal cell loss, and premature death of the animals. These results suggest that translation of expanded GGC repeats into a novel and pathogenic polyglycine-containing protein underlies the presence of intranuclear inclusions and neurodegeneration in NIID.
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http://dx.doi.org/10.1016/j.neuron.2021.03.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8186563PMC
June 2021

A new mouse model of ARX dup24 recapitulates the patients' behavioral and fine motor alterations.

Hum Mol Genet 2018 06;27(12):2138-2153

Institut de Génétique et de Biologie Moléculaire et Cellulaire, Université de Strasbourg, 67404 Illkirch, France.

The aristaless-related homeobox (ARX) transcription factor is involved in the development of GABAergic and cholinergic neurons in the forebrain. ARX mutations have been associated with a wide spectrum of neurodevelopmental disorders in humans, among which the most frequent, a 24 bp duplication in the polyalanine tract 2 (c.428_451dup24), gives rise to intellectual disability, fine motor defects with or without epilepsy. To understand the functional consequences of this mutation, we generated a partially humanized mouse model carrying the c.428_451dup24 duplication (Arxdup24/0) that we characterized at the behavior, neurological and molecular level. Arxdup24/0 males presented with hyperactivity, enhanced stereotypies and altered contextual fear memory. In addition, Arxdup24/0 males had fine motor defects with alteration of reaching and grasping abilities. Transcriptome analysis of Arxdup24/0 forebrains at E15.5 showed a down-regulation of genes specific to interneurons and an up-regulation of genes normally not expressed in this cell type, suggesting abnormal interneuron development. Accordingly, interneuron migration was altered in the cortex and striatum between E15.5 and P0 with consequences in adults, illustrated by the defect in the inhibitory/excitatory balance in Arxdup24/0 basolateral amygdala. Altogether, we showed that the c.428_451dup24 mutation disrupts Arx function with a direct consequence on interneuron development, leading to hyperactivity and defects in precise motor movement control and associative memory. Interestingly, we highlighted striking similarities between the mouse phenotype and a cohort of 33 male patients with ARX c.428_451dup24, suggesting that this new mutant mouse line is a good model for understanding the pathophysiology and evaluation of treatment.
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http://dx.doi.org/10.1093/hmg/ddy122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5985730PMC
June 2018

Increased H3K9 methylation and impaired expression of Protocadherins are associated with the cognitive dysfunctions of the Kleefstra syndrome.

Nucleic Acids Res 2018 06;46(10):4950-4965

Radboud University, Department of Molecular Biology, Faculty of Science, 6500 HB Nijmegen, the Netherlands.

Kleefstra syndrome, a disease with intellectual disability, autism spectrum disorders and other developmental defects is caused in humans by haploinsufficiency of EHMT1. Although EHMT1 and its paralog EHMT2 were shown to be histone methyltransferases responsible for deposition of the di-methylated H3K9 (H3K9me2), the exact nature of epigenetic dysfunctions in Kleefstra syndrome remains unknown. Here, we found that the epigenome of Ehmt1+/- adult mouse brain displays a marked increase of H3K9me2/3 which correlates with impaired expression of protocadherins, master regulators of neuronal diversity. Increased H3K9me3 was present already at birth, indicating that aberrant methylation patterns are established during embryogenesis. Interestingly, we found that Ehmt2+/- mice do not present neither the marked increase of H3K9me2/3 nor the cognitive deficits found in Ehmt1+/- mice, indicating an evolutionary diversification of functions. Our finding of increased H3K9me3 in Ehmt1+/- mice is the first one supporting the notion that EHMT1 can quench the deposition of tri-methylation by other Histone methyltransferases, ultimately leading to impaired neurocognitive functioning. Our insights into the epigenetic pathophysiology of Kleefstra syndrome may offer guidance for future developments of therapeutic strategies for this disease.
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http://dx.doi.org/10.1093/nar/gky196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6007260PMC
June 2018

Fasudil treatment in adult reverses behavioural changes and brain ventricular enlargement in Oligophrenin-1 mouse model of intellectual disability.

Hum Mol Genet 2016 06 4;25(11):2314-2323. Epub 2016 May 4.

Institut Cochin, INSERM U1016, CNRS UMR8104, Paris Descartes University, Paris, 75014, France

Loss of function mutations in human Oligophrenin1 (OPHN1) gene are responsible for syndromic intellectual disability (ID) associated with cerebellar hypoplasia and cerebral ventricles enlargement. Functional studies in rodent models suggest that OPHN1 linked ID is a consequence of abnormal synaptic transmission and shares common pathophysiological mechanisms with other cognitive disorders. Variants of this gene have been also identified in autism spectrum disorder and schizophrenia. The advanced understanding of the mechanisms underlying OPHN1-related ID, allowed us to develop a therapeutic approach targeting the Ras homolog gene family, member A (RHOA) signalling pathway and repurpose Fasudil- a well-tolerated Rho Kinase (ROCK) and Protein Kinase A (PKA) inhibitor- as a treatment of ID. We have previously shown ex-vivo its beneficial effect on synaptic transmission and plasticity in a mouse model of the OPHN1 loss of function. Here, we report that chronic treatment in adult mouse with Fasudil, is able to counteract vertical and horizontal hyperactivities, restores recognition memory and limits the brain ventricular dilatation observed in Ophn1 However, deficits in working and spatial memories are partially or not rescued by the treatment. These results highlight the potential of Fasudil treatment in synaptopathies and also the need for multiple therapeutic approaches especially in adult where brain plasticity is reduced.
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http://dx.doi.org/10.1093/hmg/ddw102DOI Listing
June 2016

Analysis of mammalian gene function through broad-based phenotypic screens across a consortium of mouse clinics.

Nat Genet 2015 Sep 27;47(9):969-978. Epub 2015 Jul 27.

Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, Munich, Germany.

The function of the majority of genes in the mouse and human genomes remains unknown. The mouse embryonic stem cell knockout resource provides a basis for the characterization of relationships between genes and phenotypes. The EUMODIC consortium developed and validated robust methodologies for the broad-based phenotyping of knockouts through a pipeline comprising 20 disease-oriented platforms. We developed new statistical methods for pipeline design and data analysis aimed at detecting reproducible phenotypes with high power. We acquired phenotype data from 449 mutant alleles, representing 320 unique genes, of which half had no previous functional annotation. We captured data from over 27,000 mice, finding that 83% of the mutant lines are phenodeviant, with 65% demonstrating pleiotropy. Surprisingly, we found significant differences in phenotype annotation according to zygosity. New phenotypes were uncovered for many genes with previously unknown function, providing a powerful basis for hypothesis generation and further investigation in diverse systems.
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http://dx.doi.org/10.1038/ng.3360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4564951PMC
September 2015

An Early Postnatal Oxytocin Treatment Prevents Social and Learning Deficits in Adult Mice Deficient for Magel2, a Gene Involved in Prader-Willi Syndrome and Autism.

Biol Psychiatry 2015 Jul 20;78(2):85-94. Epub 2014 Nov 20.

Institut de Neurobiologie de la Méditerranée; Aix-Marseille Université, Marseille. Electronic address:

Background: Mutations of MAGEL2 have been reported in patients presenting with autism, and loss of MAGEL2 is also associated with Prader-Willi syndrome, a neurodevelopmental genetic disorder. This study aimed to determine the behavioral phenotype of Magel2-deficient adult mice, to characterize the central oxytocin (OT) system of these mutant mice, and to test the curative effect of a peripheral OT treatment just after birth.

Methods: We assessed the social and cognitive behavior of Magel2-deficient mice, analyzed the OT system of mutant mice treated or not by a postnatal administration of OT, and determined the effect of this treatment on the brain.

Results: Magel2 inactivation induces a deficit in social recognition and social interaction and a reduced learning ability in adult male mice. In these mice, we reveal anatomical and functional modifications of the OT system and show that these defects change from birth to adulthood. Daily administration of OT in the first postnatal week was sufficient to prevent deficits in social behavior and learning abilities in adult mutant male mice. We show that this OT treatment partly restores a normal OT system. Thus, we report that an alteration of the OT system around birth has long-term consequences on behavior and on cognition. Importantly, an acute OT treatment of Magel2-deficient pups has a curative effect.

Conclusions: Our study reveals that OT plays a crucial role in setting social behaviors during a period just after birth. An early OT treatment in this critical period could be a novel therapeutic approach for the treatment of neurodevelopmental disorders such as Prader-Willi syndrome and autism.
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http://dx.doi.org/10.1016/j.biopsych.2014.11.010DOI Listing
July 2015

The homeodomain factor Gbx1 is required for locomotion and cell specification in the dorsal spinal cord.

PeerJ 2013 29;1:e142. Epub 2013 Aug 29.

Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Université de Strasbourg, Illkirch Cedex, France.

Dorsal horn neurons in the spinal cord integrate and relay sensory information to higher brain centers. These neurons are organized in specific laminae and different transcription factors are involved in their specification. The murine homeodomain Gbx1 protein is expressed in the mantle zone of the spinal cord at E12.5-13.5, correlating with the appearance of a discernable dorsal horn around E14 and eventually defining a narrow layer in the dorsal horn around perinatal stages. At postnatal stages, Gbx1 identifies a specific subpopulation of GABAergic neurons in the dorsal spinal cord. We have generated a loss of function mutation for Gbx1 and analyzed its consequences during spinal cord development. Gbx1 (-/-) mice are viable and can reproduce as homozygous null mutants. However, the adult mutant mice display an altered gait during forward movement that specifically affects the hindlimbs. This abnormal gait was evaluated by a series of behavioral tests, indicating that locomotion is impaired, but not muscle strength or motor coordination. Molecular analysis showed that the development of the dorsal horn is not profoundly affected in Gbx1 (-/-) mutant mice. However, analysis of terminal neuronal differentiation revealed that the proportion of GABAergic inhibitory interneurons in the superficial dorsal horn is diminished. Our study unveiled a role for Gbx1 in specifying a subset of GABAergic neurons in the dorsal horn of the spinal cord involved in the control of posterior limb movement.
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http://dx.doi.org/10.7717/peerj.142DOI Listing
September 2013

Reliability, robustness, and reproducibility in mouse behavioral phenotyping: a cross-laboratory study.

Physiol Genomics 2008 Aug 27;34(3):243-55. Epub 2008 May 27.

Gesellschaft für Strahlenforschungdagger-National Research Center for Environment and Health, Institute of Developmental Genetics, Neuherberg, Germany.

Establishing standard operating procedures (SOPs) as tools for the analysis of behavioral phenotypes is fundamental to mouse functional genomics. It is essential that the tests designed provide reliable measures of the process under investigation but most importantly that these are reproducible across both time and laboratories. For this reason, we devised and tested a set of SOPs to investigate mouse behavior. Five research centers were involved across France, Germany, Italy, and the UK in this study, as part of the EUMORPHIA program. All the procedures underwent a cross-validation experimental study to investigate the robustness of the designed protocols. Four inbred reference strains (C57BL/6J, C3HeB/FeJ, BALB/cByJ, 129S2/SvPas), reflecting their use as common background strains in mutagenesis programs, were analyzed to validate these tests. We demonstrate that the operating procedures employed, which includes open field, SHIRPA, grip-strength, rotarod, Y-maze, prepulse inhibition of acoustic startle response, and tail flick tests, generated reproducible results between laboratories for a number of the test output parameters. However, we also identified several uncontrolled variables that constitute confounding factors in behavioral phenotyping. The EUMORPHIA SOPs described here are an important start-point for the ongoing development of increasingly robust phenotyping platforms and their application in large-scale, multicentre mouse phenotyping programs.
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http://dx.doi.org/10.1152/physiolgenomics.90207.2008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2519962PMC
August 2008
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