Abstract
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.
Highlights
The acrofacial dysostoses (AFD) are a genetically heterogeneous group of inherited disorders unified by craniofacial and limb abnormalities
Rodriguez syndrome is a severe type of AFD that is usually lethal in the immediate perinatal period
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 mRNA splicing machinery needed for proper maturation of primary transcripts
Summary
The acrofacial dysostoses (AFD) are a genetically heterogeneous group of inherited disorders unified by craniofacial and limb abnormalities. Identification of EFTUD2 mutations in mandibulofacial dysostosis of the Guion-Almeida type (OMIM 610536) demonstrated that pre-mRNA splicing abnormalities could produce an AFD [7]. Demonstrating a link with pre-mRNA splicing, mutations in EIF4A3 which affect the activity of the exon junction complex have been characterized in Richieri-Costa-Pereira syndrome (OMIM 268305) [8]. Mutations in the gene encoding the SF3B4 protein ( known as SAP49), a component of the U2 snRNP, have been found to produce Nager syndrome (OMIM 154400) [9,10,11,12]. While the genes involved in the characterized AFDs demonstrate that defects in a variety of basic biochemical processes can lead to these phenotypes, the underlying reasons for the distinct distribution of abnormalities in the craniofacies and distal limbs are not well understood
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