Human Craniofacial Spliceosomopathies

Abstract

Germline mutation of core components of the spliceosomes have been associated with a range of clinical disorders from isolated retinitis pigmentosa (RP) to developmental syndromes, while somatic mutations of spliceosome components are linked to cell cycle dysregulation and cancer. Recently a group of craniofacial and skeletal disorders caused by dominant mutations in spliceosomal genes has emerged. The first of these to be identified is mandibulofacial dysostosis type Guion‐Almeida (MFDGA), caused by haploinsufficiency of the U5 snRNP component EFTUD2. We recently identified haploinsufficiency of SF3B4 as the cause of Nager syndrome, an acrofacial dysostosis (AFD), although only in 60% of cases suggesting genetic heterogeneity. Mutation of SF3B4 was subsequently reported in AFD Rodriquez type. SF3B4 is part of the U2 snRNP of the major spliceosome. We also identified heterozygous mutations in a highly conserved regulatory exon of SNRPBas the cause of cerebro‐costo‐mandibular syndrome (CCMS). Our experimental data show that these mutations disturb highly conserved exonic splicing silencer sequences crucial to the regulation of the gene's expression. SNRPB encodes a component of the Sm complex of the spliceosome. Additional craniofacial spliceosomopathies result from mutations in splicing factors TXNL4A, RBM8A and CWC27. The frequent involvement of craniofacial structures invite questions on the sensitivity of craniofacial and in particular pharyngeal arch development to spliceosomal defects, and on the role of the spliceosome in the regulation of development. The report of a young patient with Nager syndrome with bilateral synchronous breast cancer raises the possibility of a link between germline mutation of splicing factors and cancer predisposition. We also have a patient with a pathogenic SNRPB mutation who is non‐penetrant for CCMS syndrome but was diagnosed with early onset breast cancer, further linking heritable splicing mutations with cancer predisposition.Many of the craniofacial spliceosomopathies share overlapping features with Treacher‐Collins syndrome (TCS), a ribosomopathy. We are currently validating mutations in a ribosomal gene in two patients with typical Nager syndrome. This finding may provide unique insight into the overlapping roles of transcription and translation in craniofacial development. A combination of human genetics and model systems research will be required to further unravel the role of the spliceosome and the ribosome in craniofacial and skeletal development.Support or Funding InformationGenome Canada, Alberta Children's Hospital Research Institute, Genome AlbertaThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.