Updated project metadata. Patients with Marinesco-Sjögren syndrome and gene targeting in mice revealed an essential role for the SIL1/Sil1 gene in maintenance of central nervous tissue and skeletal muscle. SIL1/Sil1 expression is not restricted to a certain tissue, and the gene product, SIL1/Sil1, localizes to the (sarco)endoplasmic reticulum. Due to the ADP/ATP exchange activity of SIL1/Sil1 for the major chaperone BiP (GRP78) it functions as a co-chaperone. It is still an enigma how loss of functional SIL1/Sil1 can lead to selective vulnerability of the nervous system and skeletal muscle whereas other cellular populations like lymphoblastoid cells (LCs) are protected against clinical manifestation of SIL1/Sil1 deficiency. In this study we address this issue in order to identify compensatory strategies and to gain a deeper understanding of the selective vulnerability in SIL1 pathology. By studying the morphology of SIL1-deficient LCs, we demonstrate that they present with altered organelle structures indicating subclinical vulnerability and once more the assumed presence of cellular strategies antagonizing phenotypical manifestation of loss of this co-chaperone. Proteomic profiling of MSS-derived LCs revealed affection of nuclear and mitochondrial integrity, cytoskeleton and cellular viability. Apart from that proteins, known to be causative for hereditary neuromuscular disorders or to be involved in development and function of the nervous system were altered in expression. Paradigmatic findings were confirmed in spleen of Sil1 deficient mice in comparison to appropriate controls. These findings along with the results of viability assays and the identification of activation of pro-survival mechanisms provide insights into cellular strategies antagonizing SIL1/Sil1 deficiency and on a more general note into the molecular cause of selective vulnerability defining the SIL1/Sil1-phenotype, in both man and mouse.