title: BMS1 is mutated in aplasia cutis congenita.
abstract: 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.
authors.affiliation: Cutaneous Biology Research Center, Massachusetts General Hospital, Department of Dermatology, Harvard Medical School, Charlestown, Massachusetts, USA. amarneros@partners.org
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Marneros
mesh_terms: D049109:Cell Proliferation; D002874:Chromosome Mapping; D004476:Ectodermal Dysplasia / Q000235:genetics* / Q000473:pathology; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics*; D008040:Genetic Linkage; D015894:Genome, Human; D006801:Humans; D008297:Male; D009024:Morphogenesis / Q000235:genetics*; D020125:Mutation, Missense; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D040901:Proteomics; D012323:RNA Processing, Post-Transcriptional; D012337:RNA, Ribosomal, 18S / Q000235:genetics*; D012270:Ribosomes / Q000235:genetics / Q000378:metabolism; D012535:Scalp / Q000254:growth & development / Q000473:pathology
chemical_list: D012337:RNA, Ribosomal, 18S; D020558:GTP Phosphohydrolases