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RING 14 NON-PROFIT ASSOCIATION
HELP AND RESEARCH FOR CHILDREN WITH RARE GENETIC DISEASES

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GENERATION OF THE RING14 MOUSE MODEL TO BETTER UNDERSTAND THE PATHOPHYSIOLOGY OF THE HUMAN SYNDROME

PRINCIPAL INVESTIGATOR: HERAULT, Yann,  Director Institut Clinique de la Souris,
Group Leader Physiopathology of Aneuploidy, Gene dosage effect and Down syndrome (AneuPat21)  Translational Medicine and Neurogenetics program, Institut de Génétique Biologie Moléculaire et Cellulaire  IGBMC, INSERM U964, CNRS, Université de Strasbourg UMR7104,
http://www.ics-mci.fr/   http://www.igbmc.fr/
DURATION: 2 YEARS FROM AUGUST 2012 TO AUGUST 2014
FINANCED BY: RING14 ITALY & RING14 USA
SUBMITTED TO PEER REVIEW PROCESS WITH INTERNATIONAL BOARD

RING14 represents a rare disease associated with a specific aberration of chromosome 14, the formation of a ring as a consequence of the fusion of the two ends of the chromosomes, with sometimes partial loss of genetic materials at both extremities. RING14 can appear in all the cells, or in a subpopulation (mosaicism) leading to monosomy 14 in other cells. RING14 induces a syndrome characterized by motor and intellectual disabilities, multiple morphological alterations and epilepsy.
 
To better understand the RING14 disease, we propose to generate a mouse model, so that fundamental questions regarding the contribution of chromosome 14 gene orthologs, or of the Ring structure to the disease, can be addressed.
The mouse model for the RING14 syndrome will be used in the future:
-to better understand the transmission of the ring chromosome in mutant cells and the viability of the cells.
-to generate a comprehensive and standardized phenotypic analysis of the models
-to compare the phenotypic assessment in the mouse and in human patients
-to identify the gene(s) responsible of the cognitive / locomotor / epileptic phenotypes and understand their function.
-to further characterize the brain phenotypes to narrow down the pathways altered for a better understanding of processes that could affect different brain regions
-to propose and eventually test therapeutic approaches in the mouse models.
 
Mouse is now the first animal models used for fundamental, biomedical and pharmaceutical integrated research. They share with human a large set of similarities in genes (>95%), in physiology and anatomy. Furthermore laboratory mouse lines are genetically identical and can be breed at relative low cost. Mouse genetic s is extremely powerful with a variety of technique for the manipulation of the mouse genome and the generation of new disease models.
 
Mouse models are used to better understand the physiopathology and to dissect the genotype-phenotype relationships of complex human diseases. To this end, mouse models are used to tackle the complexity of human aneuploidy disorders, such as the Down syndrome (DS) or the monosomy 21 (Brault et al., 2006; Dierssen et al., 2009; Hérault et al., in press). Their impact are supported by recently published data (Besson et al., 2007; Duchon et al., 2011; Pereira et al., 2009; Yu et al., 2010) that clearly show the contribution of mouse models to understanding the consequences of dosage imbalance to human phenotypes and the development of therapeutic approaches for DS people (Braudeau et al., 2011; Gardiner et al., 2010).
 
The mouse model will be a valuable tool to advance the characterization of the developmental and neuronal defects observed in RING14 patients, for example by allowing access to brain tissue. As soon as the mouse line is available, the Ring14 model will be made available to the scientific community through the European Mouse Mutant Archive (www.emmanet.org).Then we anticipate to perform a comprehensive clinical diagnosis and a more behavioral and cognitive assessment of the models that will be linked to molecular analysis at the Mouse Clinical Institute (ICS) or in the group of Y.Herault at the IGBMC. Such analysis will allow to characterize the features observed in the mouse and to start a comparison with human features found in RING14 patients. These studies will be made in collaboration with other centres, expert in the field, and have the potential to foster the development of new therapeutic approaches.

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