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Dissecting The 17q21.31 Deletion And Duplication Syndromes In The Mouse: Role Of Kansl1 And Other Genes In The Region.

Reference : PhD Yann HERAULT

Offer publication : April 5, 2016

Intellectual disabilities (IDs) are common disorders with IQ<70 and limitations in two or more adaptive behaviors such as communication, self-care, social skills, community use, self-direction, health and safety. The estimated prevalence is 2-3 % of the worldwide population. IDs have a strong socio-economic impact not only for the family or their relatives, but also for society. IDs are associated with a strong genetic heterogeneity. Over 700 ID genes have been identified in nonsyndromic and syndromic intellectual disability loci on the X-chromosome or on autosomes and additional copy number variants (>400kb).
The Koolen-de Vries syndrome (KdVS) is associated with the 17q21.31 deletion and leads to several clinical features including hypotonia, intellectual disability, friendly behavior, and craniofacial changes. Molecular analysis revealed the presence of a recurrent genomic fragment of 500k-650kb which
contains 5 protein-coding genes: CRHR1, SPPL2C, MAPT, STH, and KANSL1. Atypical deletions and loss-of-function mutations of KANSL1 have been found in several patients with phenotypes similar to carriers of the 17q21.31 deletion. We generated model mice carrying the deletion (Del/+) and the reciprocal duplication (Dup/+) for the 17q21.31 syntenic region, which is conserved on the mouse chromosome 11. Characterization studies
revealed several robust phenotypes in the mouse models similar to human condition. We accumulated evidences showing that Kansl1 is playing a major role in mouse models recapitulating most of the phenotypes observed. KANSL1encodes the KAT8 Regulatory NSL Complex Subunit 1 which is part of a histone acetyltransferase-containing complex regulating gene expression.

In order to go further in the understanding of the pathophysiological mechanisms of the 17q21.31 KdVS we propose to:
1) Investigate the role of Kansl1 in glutamatergic (Camk2+) and gabaergic (dlx5+) neurons using conditional approach in order to evaluate the developmental and physiological consequences of Kansl1 loss of function. We will use the battery of tests that unravelled the deletion phenotypes
2) Combine Kansl1 loss of function with the duplication syndrome to determine its impact in this genetic condition.
3) Consider the rescue of Kansl1 dosage as a therapeutic route. We will express Kansl1 in the adult deletion model using AAV based strategy in the adult brain and will estimate the recovery of cognitive function in the deletion model.
4) Decipher the role of other individual genes from the region in the KdVS, with specific focus on Mapt and Crhr1. MAPT is the well-known gene, microtubule-associated protein tau, involved in fronto-temporal dementia and Alzheimer’s disease. Crhr1 codes for the Corticotropin Releasing Hormone Receptor 1 from the hypothalamic-pituitary-adrenal axis. It is associated with anxiety disorder and involved in the control of several physiological response including stress, behaviour, reproduction, immune and obesity. We have mutant allele for both genes that will be analysed in heterozygous condition.
Each task will last about 6 months and will combine genetics, behavioral and molecular analysis (based on the knowledge of the deletion model (Arbogast et al., in submission).

- WISHED SKILLS : The candidate should have a master degree in biology with knowledge in molecular biology, genetics neuroscience and mouse analysis. A good knowledge of English is also an advantage. In addition, good communication skills, enthusiasm and self-motivation are wanted to work in a dynamic and international team. The Team is provided with a fully equipped molecular and biochemistry laboratory, and is embedded in a highly collaborative and multidisciplinary

- EXPERTISES WHICH WILL BE ACQUIRED DURING THE TRAINING : The candidate will learn techniques in mouse genetics and phenotyping (maintenance of colonies, genotyping, Behavioral and physiological analyses), in molecular biology (DNA, RNA and protein extraction and analysis)
and cell biology (primary neuronal cells cultures, immunofluorescence, classical and confoncal microscopy). He or she will also benefit from a training in new techniques of genomic and transcriptional analyses (transcriptome, proteome and RNAseq) and will have the occasion to collaborate with French and European partners

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Application Deadline : Dec. 31, 2016

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