Altered mRNA Splicing, Chondrocyte Gene Expression and Abnormal Skeletal Development due to SF3B4 Mutations in Rodriguez Acrofacial Dysostosis

• Published in: PLoS genetics Vol. 12; no. 9; p. e1006307
• Main Authors: Marques, Felipe, Tenney, Jessica, Duran, Ivan, Martin, Jorge, Nevarez, Lisette, Pogue, Robert, Krakow, Deborah, Cohn, Daniel H, Li, Bing
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 13-09-2016; Public Library of Science (PLoS)
• Subjects: Adult; Biology and Life Sciences; Cells, Cultured; Chondrocytes - metabolism; Colleges & universities; Defects; Developmental biology; Dysostosis; Female; Funding; Gene expression; Genetic aspects; Genotype & phenotype; Grants; Hand Deformities, Congenital - diagnostic imaging; Hand Deformities, Congenital - genetics; Hand Deformities, Congenital - pathology; Health aspects; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Humans; Infant, Newborn; Male; Mandibulofacial Dysostosis - diagnostic imaging; Mandibulofacial Dysostosis - genetics; Mandibulofacial Dysostosis - pathology; Medicine and Health Sciences; Messenger RNA; Mutation; Pedigree; Phenotype; Research and Analysis Methods; RNA Splicing; RNA Splicing Factors - genetics; RNA Splicing Factors - metabolism; SOXD Transcription Factors - genetics; SOXD Transcription Factors - metabolism; Surgery; Transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism; Brazil; Los Angeles California; California; United States > US
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1006307

The acrofacial dysostoses (AFD) are a genetically heterogeneous group of inherited disorders with craniofacial and limb abnormalities. Rodriguez syndrome is a severe, usually perinatal lethal AFD, characterized by severe retrognathia, oligodactyly and lower limb abnormalities. Rodriguez syndrome has been proposed to be a severe form of Nager syndrome, a non-lethal AFD that results from mutations in SF3B4, a component of the U2 small nuclear ribonucleoprotein particle (U2 snRNP). Furthermore, a case with a phenotype intermediate between Rodriguez and Nager syndromes has been shown to have an SF3B4 mutation. We identified heterozygosity for SF3B4 mutations in Rodriguez syndrome, confirming that the phenotype is a dominant disorder that is allelic with Nager syndrome. The mutations led to reduced SF3B4 synthesis and defects in mRNA splicing, primarily exon skipping. The mutations also led to reduced expression in growth plate chondrocytes of target genes, including the DLX5, DLX6, SOX9, and SOX6 transcription factor genes, which are known to be important for skeletal development. These data provide mechanistic insight toward understanding how SF3B4 mutations lead to the skeletal abnormalities observed in the acrofacial dysostoses.