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
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
Externí odkaz: