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Molecular mechanisms inderlying brain alterations in the CDKL5 variant of rett's syndrome

3 - Good health and well-being; Research Projects

Financed by Telethon

Rett's syndrome (RTT) is a neurodevelopmental disorder that mainly affects females, occurring with an incidence of up to 1:10,000. RTT is a genetic disorder that generally appears during the second year and within the first four years of patient's life. In the classic form, after a period of normal development, patients show growth retardation and regression of speech, appearance of stereotyped hand movements and severe mental retardation. Recent genetic studies have shown that RTT is often caused by mutations in the MeCP2 gene. However, not all RTT patients display mutations in this gene and it has been recently found that mutations in the CDKL5 gene may be also responsible for a variant of RTT resembling in many aspects the classical RTT. Besides, CDKL5 has been found to interact with MeCP2 and in part to affect the same pathways controlled by MeCP2, thus explaining why these two genes may give rise to similar phenotypes when mutated. However, while much has been discovered about the function and properties of MeCP2, very little is known about the role and function of the CDKL5 gene, particularly with respect to the development of the nervous system and the onset and evolution of RTT. To address this problem we have combined the expertise of four different research groups actively involved in different fields of neurosciences, to characterize the function of CDKL5 through distinct and complementary approaches. Precisely, we will design specific neuronal cell systems in order to identify both gene and protein targets of CDKL5 and will generate a mouse model carrying a CDKL5 loss of function mutation which should recapitulate many of RTT features. Our results will provide information on CDKL5 responsive genes and proteins that could be targets of novel and efficient treatments, aimed at slowing down/curing the disease.

Coordinated by Elisabetta Ciani from Biomedical and Neuromotor Sciences Department – DIBINEM with Laura Calzà and Giovanni Perini from Pharmacy and Biotechnology Department – FaBiT with Consiglio Nazionale delle Ricerche - CNR as external partner.

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