A cis-regulatory site downregulates PTHLH in translocation t(8;12)(q13;p11.2) and leads to Brachydactyly Type E
Autor: | Sigrid Tinschert, Andreas Rump, Miguel Otero, Sigmar Stricker, Philipp G. Maass, J. Wirth, Kaneyuki Tsuchimochi, Sylvia Bähring, Atakan Aydin, Friedrich C. Luft, Mary B. Goldring |
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Jazyk: | angličtina |
Rok vydání: | 2010 |
Předmět: |
dna topoisomerase-ii
Derivative chromosome Foot Deformities Congenital ADAMTS7 Protein mesenchymal stem-cells Down-Regulation Chromosomal translocation Regulatory site Biology Regulatory Sequences Nucleic Acid hormone-related peptide in-vitro Translocation Genetic Fingers Behavioral Ecology Mice Downregulation and upregulation Gene expression Genetics medicine Animals Humans chondrogenic differentiation Molecular Biology Gene Genetics (clinical) chondrocyte differentiation indian hedgehog Chromosomes Human Pair 12 Parathyroid hormone-related protein Brachydactyly ets transcription factors Parathyroid Hormone-Related Protein autosomal-dominant hypertension General Medicine Articles Toes medicine.disease Molecular biology gene-expression Gedragsecologie ADAM Proteins Hand Deformities Congenital Chromosomes Human Pair 8 |
Zdroj: | Human Molecular Genetics 19 (2010) 5 Human Molecular Genetics, 19(5), 848-860 |
ISSN: | 0964-6906 |
Popis: | Parathyroid hormone-like hormone (PTHLH) is an important chondrogenic regulator; however, the gene has not been directly linked to human disease. We studied a family with autosomal-dominant Brachydactyly Type E (BDE) and identified a t(8;12)(q13;p11.2) translocation with breakpoints (BPs) upstream of PTHLH on chromosome 12p11.2 and a disrupted KCNB2 on 8q13. We sequenced the BPs and identified a highly conserved Activator protein 1 (AP-1) motif on 12p11.2, together with a C-ets-1 motif translocated from 8q13. AP-1 and C-ets-1 bound in vitro and in vivo at the derivative chromosome 8 breakpoint [der(8) BP], but were differently enriched between the wild-type and BP allele. We differentiated fibroblasts from BDE patients into chondrogenic cells and found that PTHLH and its targets, ADAMTS-7 and ADAMTS-12 were downregulated along with impaired chondrogenic differentiation. We next used human and murine chondrocytes and observed that the AP-1 motif stimulated, whereas der(8) BP or C-ets-1 decreased, PTHLH promoter activity. These results are the first to identify a cis-directed PTHLH downregulation as primary cause of human chondrodysplasia. |
Databáze: | OpenAIRE |
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