Deciphering the function(s) of SLC10A7 in Congenital Disorders of Glycosylation (CDG).

Congenital Disorders of Glycosylation (CDG) are a rapidly growing and heterogeneous group of rare metabolic diseases caused by inborn defects in glycosylation. Thanks to the use of Whole Exome Sequencing (WES), SLC10A7 has been identified as a candidate gene in CDG patients with a specific clinical phenotype of skeletal dysplasia. The function of SLC10A7 is absolutely not deciphered yet. This PhD project proposes to apply our combined knowledge in the field of genetics, cell biology and glycosylation as well as the availability of material from patients with specific mutations and a unique phenotype, to fully understand the molecular function of the SLC10A7 protein.  The underlying concept of this project is built on the fact that mutations identified in genes encoding transporters or ion binding proteins, such as SLC10A7, lead to impaired Golgi ion homeostasis. This results in Golgi glycosylation and specific GAG synthesis defects. The work will consist of the generation of specific cellular tools for the study of SLC10A7, the elucidation of the mechanism by which mutants cause disruption of Golgi ion homeostasis, with a focus on Ca2+ and Mn2+, two cations that play a key role in Golgi glycosylation and recently previously been implicated in the pathophysiology of CDG.   As such, it is ambitious to hypothesize that the restoration of Golgi ion homeostasis and modulation of Ca2+ and Mn2+  fluxes and concentrations will lead to a normalization of the GAG biosynthesis process, and will open the field of novel therapies for CDG patients with skeletal dysplasia.