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.
Highlights
Aplasia cutis congenita (ACC [MIM 107600]) manifests at birth as a localized skin defect that usually heals with a hypertrophic scar
A mutation in the ribosomal GTPase BMS1 is identified in ACC that affects 18S rRNA maturation
Mutations in genes for structural proteins of the ribosome or in other genes involved in ribosome biogenesis or function have been found in rare congenital diseases termed ribosomopathies, including Diamond Blackfan anemia (e.g. RPS19 and RPS24), Shwachman-Diamond syndrome (SBDS), X-linked dyskeratosis congenita (DKC1), cartilage hair hypoplasia (RMRP) and Treacher Collins syndrome (TCOF1, POLR1C and POLR1D) [14,15,16,17,18]
Summary
Aplasia cutis congenita (ACC [MIM 107600]) manifests at birth as a localized skin defect that usually heals with a hypertrophic scar. Some patients with Johanson-Blizzard syndrome [MIM 243800] have been reported to have aplasia cutis of the scalp skin. This syndrome is characterized by nasal alar hypoplasia, hypothyroidism, pancreatic achylia and congenital deafness and is caused by a mutation in the UBR1 gene [2]. Adams-Oliver syndrome (AOS [MIM 100300]) is characterized by ACC and transverse limb defects, but a wide range of additional congenital anomalies have been reported in patients with AOS, including congenital heart defects. The majority of individuals with aplasia cutis have no other congenital anomalies, suggesting a distinct pathomechanism between non-syndromic ACC and syndromic cases as in AOS or other syndromes in which aplasia cutis has been described
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