SF3B2

Locally advanced rectal cancer (LARC) presents a challenge in identifying molecular markers linked to the response to neoadjuvant chemoradiotherapy (nCRT). This study aimed to utilize a sensitive proteomic method, data-independent mass spectrometry (DIA-MS), to extensively analyze the LARC proteome, seeking individuals with favorable initial responses suitable for a watch-and-wait approach. This research addresses the unmet need to understand the response to treatment, potentially guiding personalized strategies for LARC patients. Post-treatment assessment included MRI scans and proctoscopy. This research involved 97 LARC patients treated with intense chemoradiotherapy, comprising radiation and chemotherapy. Out of 97 LARC included in this study, we selected 20 samples with the most different responses to nCRT for proteome profiling (responders vs. non-responders). This proteomic approach shows extensive proteome coverage in LARC samples. The analysis identified a significant number of proteins compared to a prior study. A total of 915 proteins exhibited differential expression between the two groups, with certain signaling pathways associated with response mechanisms, while top candidates had good predictive potential. Proteins encoded by genes SMPDL3A, PCTP, LGMN, SYNJ2, NHLRC3, GLB1, and RAB43 showed high predictive potential of unfavorable treatment outcome, while RPA2, SARNP, PCBP2, SF3B2, HNRNPF, RBBP4, MAGOHB, DUT, ERG28, and BUB3 were good predictive biomarkers of favorable treatment outcome. The identified proteins and related biological processes provide promising insights that could enhance the management and care of LARC patients.

Craniofacial microsomia (CFM) is a common congenital malformation with unknown pathogenesis. Although few cases have been reported, it is suggested that variants of the SF3B2 gene may lead to CFM. We herein report the case of a neonate with CFM exhibiting rare features of airway obstruction.

Trio whole-exome sequencing and Sanger validation were performed on the proband and her parents. Candidate gene mutations were analyzed using the Genome Aggregation Database (gnomAD) for normal frequency distributions. The Human Splicing Finder (HSF) and Rare Disease Data Center (RDDC) RNA splicer algorithms predicted the variant's harmfulness, verified by a Minigene assay.

The proband had a heterozygous SF3B2 variant, NM_006842.3:c.777+1G>A. The patient's father also carried this variant and exhibited facial abnormalities. The variant was not in gnomAD, and HSF and RDDC RNA splicers indicated donor site disruption. The minigene assay suggested that two mRNA products were produced, leading to a premature termination codon.

For this family, the pathogenesis of CFM may have been caused by an SF3B2 splicing variant. Affected family members exhibited varying degrees of malformation, indicating that CFM has phenotypic heterogeneity. This finding expands the phenotype and variant spectrum of SF3B2, enriches neonatal CFM research, and provides a possible guide to genetic counseling.

FRA10AC1, the causative gene for the manifestation of the FRA10A fragile site, encodes a well-conserved nuclear protein characterized as a non-core spliceosomal component. Pre-mRNA splicing perturbations have been linked with neurodevelopmental diseases. FRA10AC1 variants have been, recently, causally linked with severe neuropathological and growth retardation phenotypes. To further elucidate the participation of FRA10AC1 in spliceosomal multiprotein complexes and its involvement in neurological phenotypes related to splicing, we exploited protein-protein interaction experimental data and explored network information and information deduced from transcriptomics. We confirmed the direct interaction of FRA10AC1with ESS2, a non-core spliceosomal protein, mapped their interacting domains, and documented their tissue co-localization and physical interaction at the level of intracellular protein stoichiometries. Although FRA10AC1 and SF3B2, a major core spliceosomal protein, were shown to interact under in vitro conditions, the endogenous proteins failed to co-immunoprecipitate. A reconstruction of a comprehensive, strictly binary, protein-protein interaction network of FRA10AC1 revealed dense interconnectivity with many disease-associated spliceosomal components and several non-spliceosomal regulatory proteins. The topological neighborhood of FRA10AC1 depicts an interactome associated with multiple severe monogenic and multifactorial neurodevelopmental diseases mainly referring to spliceosomopathies. Our results suggest that FRA10AC1 involvement in pre-mRNA processing might be strengthened by interconnecting splicing with transcription and mRNA export, and they propose the broader role(s) of FRA10AC1 in cell pathophysiology.