Altered mRNA Splicing, Chondrocyte Gene Expression and Abnormal Skeletal Development due to SF3B4 Mutations in Rodriguez Acrofacial Dysostosis.
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.
Programa de Pós-Graduação em Ciências Genômicas e Biotecnologia, Universidade Católica de Brasília, Brasília, Brazil.|Laboratório de Biotecnologia, Universidade CEUMA, Campus Renascença, São Luís-MA, Brazil.
Felipe
F
Marques
Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.|Department of Pediatrics, Division of Genetics, University of California Los Angeles, Los Angeles, California, United States of America.
Jessica
J
Tenney
Department of Orthopaedic Surgery, University of California Los Angeles, Los Angeles, California, United States of America.
Ivan
0000-0001-6097-0402
I
Duran
Department of Orthopaedic Surgery, University of California Los Angeles, Los Angeles, California, United States of America.
Jorge
0000-0002-6312-7637
J
Martin
Department of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles, California, United States of America.
Lisette
L
Nevarez
Programa de Pós-Graduação em Ciências Genômicas e Biotecnologia, Universidade Católica de Brasília, Brasília, Brazil.
Robert
R
Pogue
Department of Orthopaedic Surgery, University of California Los Angeles, Los Angeles, California, United States of America.|Department of Obstetrics and Gynecology, University of California at Los Angeles, Los Angeles, California, United States of America.|Department of Human Genetics, University of California Los Angeles, Los Angeles, California, United States of America.
Deborah
D
Krakow
Department of Orthopaedic Surgery, University of California Los Angeles, Los Angeles, California, United States of America.|Department of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles, California, United States of America.
Daniel H
DH
Cohn
Department of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles, California, United States of America.
Bing
0000-0003-3683-8414
B
Li
D000328:Adult; D002478:Cells, Cultured; D019902:Chondrocytes / Q000378:metabolism*; D005260:Female; D006228:Hand Deformities, Congenital / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008342:Mandibulofacial Dysostosis / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D012326:RNA Splicing; D000072260:RNA Splicing Factors / Q000235:genetics* / Q000378:metabolism; D055755:SOXD Transcription Factors / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
C100596:DLX5 protein, human; C491014:DLX6 protein, human; D018398:Homeodomain Proteins; D000072260:RNA Splicing Factors; C486347:SF3B4 protein, human; C486270:SOX6 protein, human; D055755:SOXD Transcription Factors; D014157:Transcription Factors