BMS1 Is Mutated in Aplasia Cutis Congenita

Aplasia cutis congenita (acc) manifests with localized skin defects at birth of unknown cause,mostly affecting the scalp vertex. here,genome-wide linkage analysis and exome sequencing was used to identify the causative mutation in autosomal dominant acc. a heterozygous arg-to-his missense mutation (p.r930h) in the ribosomal gtpase bms1 is identified in acc that is associated with a delay in 18s rrna maturation,consistent with a role of bms1 in processing of pre-rrnas of the small ribosomal subunit. mutations that affect ribosomal function can result in a cell cycle defect and acc skin fibroblasts with the bms1 p.r930h mutation show a reduced cell proliferation rate due to a p21-mediated g1/s phase transition delay. unbiased comparative global transcript and proteomic analyses of acc fibroblasts with this mutation confirm a central role of increased p21 levels for the acc phenotype,which are associated with downregulation of heterogenous nuclear ribonucleoproteins (hnrnps) and serine/arginine-rich splicing factors (srsfs). functional enrichment analysis of the proteomic data confirmed a defect in rna post-transcriptional modification as the top-ranked cellular process altered in acc fibroblasts. the data provide a novel link between bms1,the cell cycle,and skin morphogenesis. © 2013 alexander g.