Research Progress Report by Bruno Gasnier, PhD, Paris University/CNRS)

CRF has provided over $1 million in research funding to Dr. Gasnier since 2007. In the fall of 2021, Dr. Gasnier was awarded a new grant to research the critical role of cystinosin during embryo development. This is the first progress report for this important project.

A Critical Role for Cystinosin During Embryo Development. 

Cystinosis is caused by genetic inactivation of the lysosomal membrane protein cystinosin. In a mouse model of cystinosis, we discovered a strong, unexpected genetic interaction between cystinosin and another lysosomal protein, which manifests as an embryonic lethality when both genes are inactivated. The aim of this project is to identify the underlying mechanism, thereby unveiling a novel biological function of cystinosin and, potentially, novel mechanisms at work in cystinosis.

Our preliminary studies had implicated an extra-embryonic tissue, the yolk sac, as a critical site for the synergy between cystinosin and its genetic interactor. Transgenic re-expression of cystinosin under control of a cell-type specific promoter confirmed this role of cystinosin in the yolk sac. However, it also suggested its implication in an embryonic organ, with a positive feedback loop between the extra-embryonic and embryonic defects leading to a toxic metabolic cascade.

During the past months, we confirmed the rescue of the embryonic lethality by the cystinosin transgene, with the production of >25 rescued double mutant mice. We also characterized the growth and health of the rescued mice. In another research line, we confirmed the specific expression of transgenic cystinosin in the yolk sac during embryogenesis, as expected from the choice of the transgene promoter, and we characterized its expression profile in other organs from embryogenesis to adulthood.

This expression profile validated our working hypothesis. We thus initiated biochemical measurements in mutant embryos to test our model of cooperation between cystinosin and another protein in a metabolic pathway hitherto unrelated to cystinosis. The first measurements validated a key feature of our model. Measurement of a larger set of metabolites is in progress.