Unraveling the genetic architecture of peripheral nerves: A contribution from inherited peripheral neuropathies.

Charcot-Marie-Tooth neuropathies (CMT) are severe and incurable disorders, representing the most common genetic affliction of PNs. Autosomal recessive CMT forms (ARCMT) have an earlier onset and a more severe disease cause. Molecular genetics and biology of ARCMT, as CMT in general, is poorly understood due to the extensive genetic and pathophysiological heterogeneity. The diversity of gene functions known so far make CMT an ideal paradigm to study the mechanistic basis of peripheral neurons homeostasis and dysfunction. In this project, we will study a cohort of 135 ARCMT families using exome sequencing, positional cloning, bioinformatics and functional genomics in Drosophila models in order to identify new putative ARCMT genes and their interactions' patterns. Our findings will: i) pinpoint genes maintaining PNS homeostasis in health and disease; ii) highlight relationships between causal genes; iii) unravel novel pathomechanisms of neurodegeneration or strengthen the importance of known ones; iv) give clues to predict phenotypic outcome in response to different genetic background; v) deliver disease models suitable for therapeutic applications; vi) improve the molecular diagnosis, prognosis and prevention of CMT neuropathies. The knowledge gained will be relevant not only to CMT, but will potentially make a larger contribution in the understanding and treatment of other inherited or acquired neurodegenerative disorders.

Keywords:INHERITED PERIPHERAL NEUROPATHIES, EXOME SEQUENCING, CHARCOT-MARIE-TOOTH DISEASE

Disciplines:Genomics, Molecular and cell biology not elsewhere classified, Medical genomics, Genetics, Neurological and neuromuscular diseases

Project type:Collaboration project