RNA-binding proteins in disease etiology: Fragile X Syndrome and Spinal Muscular Atrophy

Abstract

All RNAs exist in complexes (RNPs) with RNA-binding proteins (RBPs). Studies in my lab since the 1980s, identified, sequenced and characterized the major pre-mRNA- and mRNA-RBPs (hnRNPs/mRNPs), revealing RNA-binding domains and common features of numerous RBPs and their central roles in post-transcriptional gene regulation. The first links between RBPs and RNPs to diseases emerged serendipitously for fragile X syndrome, as its gene (FMR1) encoded RBP (FMRP), and spinal muscular atrophy (SMA), caused by deficits in survival motor neurons (SMN). Discoveries of the SMN complex and its unanticipated function in RNP assembly, essential for spliceosomal snRNPs biogenesis, advanced understanding of RNA biology and pathogenesis. I reflect on how these and other contributions (e.g., nucleo-cytoplasmic shuttling; telescripting) originated from curiosity-driven exploration and highly collaborative lab culture. The vast RNA and RBP assortments are beneficial, but increase complexity and chances of disorders, making the RNP sphere a rich source for future discoveries.