Endoplasmic reticulum (ER) membrane contact sites (MCSs) are crucial regulatory hubs in cells, playing roles in signaling, organelle dynamics, and ion and lipid homeostasis. Previous work demonstrated that the highly conserved yeast Ltc/Lam sterol transporters localize and function at ER MCSs. Our analysis of the human family members, GRAMD1a and GRAMD2a, demonstrates that they are ER-PM MCS proteins, which mark separate regions of the plasma membrane (PM) and perform distinct functions in vivo. GRAMD2a, but not GRAMD1a, co-localizes with the E-Syt2/3 tethers at ER-PM contacts in a PIP lipid-dependent manner and pre-marks the subset of PI(4,5)P2-enriched ER-PM MCSs utilized for STIM1 recruitment. Data from an analysis of cells lacking GRAMD2a suggest that it is an organizer of ER-PM MCSs with pleiotropic functions including calcium homeostasis. Thus, our data demonstrate the existence of multiple ER-PM domains in human cells that are functionally specialized by GRAM-domain containing proteins.

Graphical Abstract Highlights d PUM2, and its ortholog in C. elegans, PUF-8, are upregulated upon aging d PUM2 represses Mff translation and impairs mitochondrial fission d The PUM2/MFF axis regulates mitophagy and mitochondrial function d Depletion of puf-8 and Pum2 in old worms and mice improves mitochondrial homeostasis

Mouse models have been instrumental in understanding human disease biology and proposing possible new treatments. The precise control of the environment and genetic composition of mice allows more rigorous observations, but limits the generalizability and translatability of the results into human applications. In the era of precision medicine, strategies using mouse models have to be revisited to effectively emulate human populations. Systems genetics is one promising paradigm that may promote the transition to novel precision medicine strategies. Here, we review the state-of-the-art resources and discuss how mouse systems genetics helps to understand human diseases and to advance the development of precision medicine, with an emphasis on the existing resources and strategies. Promises and Problems with Precision Medicine Most complex traits and diseases, such as height, longevity, and diabetes, are heritable and influenced by various genetic factors [1], while being modulated by environmental stimuli. Due every individual's unique genetic makeup, response to drugs [2], nutrition [3], and lifestyle [4] vary considerably from person to person. This uniqueness of every human being underpins the purpose of precision medicine, which posits that disease prediction, diagnosis, and treatment for each individual is based on personal genomic variations and external environments [5]. Precision medicine is an innovative approach that takes the variability in genetics, environment, and lifestyle of each individual into account in disease prevention and treatment, and provides better prediction of effective treatments, while concurrently minimizing the possibility of drug side effects [6]. Therefore, precision medicine requires a good understanding of the genetic bases of variation in phenotypes and their interaction with the environment in health and disease. Highlights The mouse is the premier model organism for human biomedical research. So far, most of the research studies involving mouse models rely on a single or few genetic backgrounds and controlled external factors that limit the generalizability of the results. Systems genetics improves the translational potential of mouse studies in human. Systems genetics approaches in mouse panels could serve as the prototype and provide valuable insights for human precision medicine.