期刊
PLOS GENETICS
卷 12, 期 9, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.1006307
关键词
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资金
- National Institutes of Health (NIAMS) [R01 AR062651, RO1 AR066124]
- March of Dimes
- Joseph Drown Foundation
- National Institutes of Health UCLA Intercampus Medical Genetics Training Grant [5T32 GM008243]
- Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES, Brazil) [PVE-A120/2013]
- Rede Pro-Centro-Oeste through the Brazilian Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)
- CAPES
- Fundacao de Apoio a Pesquisa do Distrito Federal (FAP-DF) [564537/2010]
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.
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