Connecting genotype and phenotype in minor spliceosome diseases.

Minor spliceosome is responsible for recognizing and excising a specific subset of divergent introns during the pre-mRNA splicing process. Mutations in the unique snRNA and protein components of the minor spliceosome are increasingly being associated with a variety of germline and somatic human disorders, collectively termed as minor spliceosomopathies. Understanding the mechanistic basis of these diseases has been challenging due to limited functional information on many minor spliceosome components. However, recently published cryo-electron microscopy (cryo-EM) structures of various minor spliceosome assembly intermediates have marked a significant advancement in elucidating the roles of these components during splicing. These structural breakthroughs have not only enhanced our comprehension of the minor spliceosome's functionality but also shed light on how disease-associated mutations disrupt its functions. Consequently, research focus is now shifting toward investigating how these splicing defects translate into broader pathological processes within gene expression pathways. Here we outline the current structural and functional knowledge of the minor spliceosome, explore the mechanistic consequences of its mutations, and discuss emerging challenges in connecting molecular dysfunctions to clinical phenotypes.