Project Details
Projekt
Anaylsis of the pathophysiology of GMPPA- and GMPPB-associated diseases
Subject Area
Human Genetics
Term
since 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 504986145
A few years ago, we were able to identify mutations in the GMPPA gene as the cause of the AAMR syndrome, which is characterized by alacrimia, achalasia and mental retardation with myopathy. With the help of a knockout (KO) mouse model, we were subsequently able to confirm our hypothesis that GMPPA, as an allosteric inhibitor of GDP-mannose-pyrophosphorylase-B (GMPPB), regulates the availability of activated mannose. The loss of function of GMPPA leads to increased GDP-mannose levels and an increased incorporation of mannose into glycans. In the case of alpha-dystroglycan, this leads to an accelerated turnover and an overall reduced amount of protein. Notably, the glycosylation and the amount of alpha-dystroglycan normalized on a mannose-depleted diet. In addition, mannose restriction prevented the occurrence of a myopathy in Gmppa-KO mice. Within the current application, we will assess the consequences of the Gmppa defect on the central nervous system and behavior. To this end, we will analyze the consequences of a Gmppa defect on brain development and on brain function. For this purpose, we will exploit morphological, biochemical and electrophysiological approaches. In addition, we already established mouse models for GMPPB-associated syndromic disorders. We will characterize these mouse models and study the possible therapeutic effect of mannose supplementation on disease outcome. These studies will also include the analysis of the possible conseqeunces of dietary interventions for WT mice. While the functional and morphological analysis is primarily carried out by the Hübner group, the biochemical analysis of glycan structures will be carried out by the Blanchard group.
DFG Programme
Research Grants
