At the origin of congenital muscular dystrophy: shedding light on the Tdark proteins DPM2 and DPM3

This project has been funded thanks to the Joint Call Fondazione Cariplo and Fondazione Telethon 2021

α-Dystroglycanopathy is a newly emerging subgroup of congenital muscular dystrophies caused by the aberrant glycosylation of α-Dystroglycan (αDG). Indeed, α-Dystroglycanopathieas are invariably caused by gene mutations associated with defective glycosylation of αDG. Glycosylation, i.e., the attachment of carbohydrates to molecules, is required for the correct function of αDG, that is to form a physical link between cells and the matrix in which they are embedded. This link is necessary for the proper organisation of tissues. Moreover, αDG protects muscle cells against contraction-induced damages. A defective glycosylation of αDG determines severe muscle damage/degeneration, intellectual disability, epilepsy, and cardiomyopathy.

Glycosylation is a complex process involving several proteins that work in synergy in a timely and functionally defined sequence. At the origin of glycosylation of αDG there are three proteins, named DPM1, 2 and 3, that form the enzyme dolichol-phosphate mannose (DPM) synthase. Mutations in the genes encoding for DPM2 and DPM3 are indeed associated with defective glycosylation of αDG, and thus with rare congenital muscular dystrophies combined with a complex spectrum of neurological disorders.

DPM synthase is a poorly studied enzyme, and even more obscure is the current state of knowledge concerning DPM2 and DPM3 subunits, which are indeed classified as Tdark proteins since their structure, function, interacting molecules and drugs are unknown. Consequently, the pathogenic role of DPM2 and DPM3 mutations remains unassigned.

 The aim of this project is to fill these gaps by describing, at molecular and cellular level, DPM synthase to exhaustively understand the link occurring between DPM2/3 mutations and the development of α- Dystroglycanopathieas. The results of this study will pose the necessary basis for novel therapies targeting this newly emerging subgroup of congenital muscular dystrophies