Mutational spectrum of minor spliceosomopathies. (A) Secondary structure of the U4atac/U6atac snRNA duplex, with mutations causing various RNUATAC-opathies indicated. The mutated nucleotides are colored according to the disorder they were first described in. If the same mutation has subsequently been reported in additional disorders, these are indicated by colored squares next to the mutation. The “Other” category includes phenotypes that fall in between or outside clinically defined disorders (McMillan et al. 2021; Tabib et al. 2023). (B) U4atac snRNA mutations in their structural context. The main image shows the cryo-EM structure of the U4atac/U6atac di-snRNP and U11 snRNP in the minor spliceosome pre-B complex (Protein Data Bank ID: 8Y6O). Insets show close-up views of the 5′ SL, stem II, Sm site, and 3′ SL regions. Mutated U4atac nucleotides are colored red and numbered by their position in the insets. Sm site mutations are shown for illustrative purposes as Sm-mutant snRNAs are not expected to assemble into snRNPs. Except for PRPF6, U5 snRNP components and tri-snRNP-specific proteins are grayed out for clarity. Structure visualization was carried out using PyMOL. (C) Secondary structure of the U12 snRNA showing mutations underlying EOCA and CDAGS. Binding sites of the RNPC3, RBM41, and ZCRB1 proteins are indicated. (D) Domain structure of minor-spliceosome-specific proteins implicated in human disease. Locations of germline mutations are shown at the bottom of the domain structure, and for ZRSR2, somatic mutations are shown on top of the domain structure. Somatic ZRSR2 mutations were downloaded from the COSMIC database and filtered for Primary Tissue (Hematopoietic and lymphoid) and Histology (Hematopoietic neoplasm).
