Staff Publications

Staff Publications

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    'Staff publications' is the digital repository of Wageningen University & Research

    'Staff publications' contains references to publications authored by Wageningen University staff from 1976 onward.

    Publications authored by the staff of the Research Institutes are available from 1995 onwards.

    Full text documents are added when available. The database is updated daily and currently holds about 240,000 items, of which 72,000 in open access.

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Record number 406884
Title A cis-regulatory site downregulates PTHLH in translocation t(8;12)(q13;p11.2) and leads to Brachydactyly Type E
Author(s) Maass, P.G.; Wirth, J.; Aydin, A.; Rump, A.; Stricker, S.; Tinschert, S.; Otero, M.; Tsuchimochi, K.; Goldring, M.B.; Luft, F.C.; Bahring, S.
Source Human Molecular Genetics 19 (2010)5. - ISSN 0964-6906 - p. 848 - 860.
Department(s) Behavioural Ecology
Publication type Refereed Article in a scientific journal
Publication year 2010
Keyword(s) hormone-related peptide - autosomal-dominant hypertension - ets transcription factors - mesenchymal stem-cells - dna topoisomerase-ii - chondrocyte differentiation - in-vitro - chondrogenic differentiation - gene-expression - indian hedgehog
Abstract 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.
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