PhD Fellowship

Employeur Albert Ludwig University Medical Center Freiburg
Lieu Freiburg, Germany
Publié le 20. March 2014
Date d'expiration 30. April 2014
Numéro de référence PhD

Description du poste

Segmental Overgrowth syndromes – genetics and molecular biology
Segmental overgrowth syndromes are extremely rare genetic diseases. In some of them, only about 200 cases are known worldwide, such as for example the Proteus syndrome which presents with asymmetric and fast growth of extremities. Further overgrowth diseases are the SOLAMEN and the CLOVE syndrome with lipomatosis, vascular malformations and epidermal nevus as well as the type 2 segmental Cowden syndrome with multiple hamartomas. The patients with overgrowth syndromes all show close clinical overlap. Recently, genes of the PI3K/AKT/PTEN/mTOR signalling pathway have been identified to be causative for some of these syndromes. However, the genetic background in most of them remains currently unclear.
The overall objective of this project is to define the molecular pathophysiology of segmental overgrowth snydromes and related disorders, in particular Proteus, SOLAMEN, CLOVE, Cowden and Proteus-like syndromes, and to elucidate disease mechanisms that make this, and related disorders, amenable to targeted therapies. In consideration of the highly similar clinical presentation of PI3KCA, PTEN and AKT1-associated and PTEN/AKT1-negative cases, we assume that all forms of segemental overgrowth syndormes may have, at least in part, a common pathogenic genomic profile in diseased tissues. This may result either from mosaic somatic inactivation of AKT1 or PTEN proper, or alterations of other components of the PI3K/PTEN/AKT pathway, resulting in downstream mTOR activation. To achieve these objectives, specific aims within the time-frame of the proposal are:
• to analyse the already recruited segmental overgrowth patients (currently n=15) for germ-line PTEN mutations and somatic mosaic AKT1 and PI3K mutations and search for new mutations in candidate genes that interplay with the PI3K/PTEN/AKT/mTOR pathway
• to establish conditions for the molecular investigation mTOR activity in patient-derived PMBCs, skin fibroblasts, and biopsies

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