Periodic Reporting for period 1 - REsolution (Add medical genetic solutions to RESOLUTE (REsolution))
Reporting period: 2021-06-01 to 2022-05-31
Solute carriers (SLCs) are the largest family of membrane transporters encoded in the human genome and their role in trafficking nutrients, ions, vitamins and cofactors is vital for maintaining homeostasis in individual cells, organs and tissues. Their misfunction is associated with a variety of diseases. Despite their importance, the majority of SLCs remain understudied and only a small number of them are successful drug targets. While the RESOLUTE consortium is working on the basic aspects of SLC biochemistry and biology of the SLC family, REsolution wants to maximize the chances that SLC transporters will become successful drug targets and use the growing amount of data becoming available on genetic variations and disease association to assign pathophysiological relevance to individual transporters.
Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far
Within the first year, REsolution compiled publicly available evidence on genetic variation in SLC genes and their association to diseases. Respective information was combined into genetic assessments for the entire SLC family and visualized in the web portal (https://re-solute.eu/knowledgebase/gene). A flexible scoring algorithm allows to quantify and compare the variants across all SLCs, which should assist researchers in a tailored exploration of human SLC genetics (https://re-solute.eu/resources/dashboards/genetic-score). Furthermore, REsolution investigated the consequence of 61 genetic variants experimentally in functional assays for three different SLCs. Respective results are combined with structural, stability and evolutionary conservation analyses. Lastly, REsolution carried out a benchmark for available variant effect predictors which may be further improved based on the experimental data from REsolution.
Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)
Continued work will result in target-focused analyses on a subset of therapeutically relevant SLCs and their genetic variants observed in the population from a structure-function perspective. Investigating all possible variation by mutational scanning in few selected SLCs may allow to improve current variant effect predictors in a SLC-specific manner, which in turn may lead to a benefit for patient diagnosis for variants of unknown significance for transporters and other membrane proteins. REsolution together with RESOLUTE aim to create a SLC prioritization rationale and a resource of the whole SLC family for the pharmaceutical industry valid for years to come.