Developmental pleiotropy revealed by mosaic heterozygous Snrpb deletion underlies CCMS-like axial skeletal defects

Abstract

Cerebro-Costo-Mandibular Syndrome (CCMS) is a rare congenital disorder due to pathogenic variants in the core spliceosomal gene SNRPB. Affected individuals present with axial skeletal abnormalities, including cleft palate, micrognathia, posterior rib gaps, and a bell-shaped thorax. The molecular basis of these axial defects remains poorly understood, limiting the development of targeted interventions. To study the temporal and molecular requirements of SNRPB during axial development, we generated a mouse model of CCMS using an inducible Cre-lox system to conditionally delete Snrpb. Mosaic deletion of exons 2-3 of Snrpb after gastrulation resulted in the full spectrum of CCMS-like abnormalities, including micrognathia, posterior rib gaps and a reduced thoracic cavity. Despite normal somite morphology and patterning, transcriptomic analysis of E9.5 mutant somites revealed upregulation of p53 pathway genes and mis-expression of retinoic acid (RA) signaling components, consistent with reduced RA signaling. Alternatively spliced genes in Snrpb mutant somites were associated with post-transcriptional regulation, including chromatin modifiers. To test if RA pathway supplementation can rescue axial defects, we performed dietary RA supplementation; however, this failed to rescue mutant phenotypes, suggesting that p53 activation and chromatin dysregulation additionally contribute to disease pathogenesis. Together, these findings establish the first in vivo model of CCMS-associated axial skeletal abnormalities and indicate that Snrpb dysfunction disrupts the early specification of axial skeletal identity without overtly altering somite patterning.