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A cis-regulatory site downregulates PTHLH in translocation t(8;12)(q13;p11.2) and leads to Brachydactyly Type E

Item Type:Article
Title:A cis-regulatory site downregulates PTHLH in translocation t(8;12)(q13;p11.2) and leads to Brachydactyly Type E
Creators Name:Maass, P.G. and Wirth, J. and Aydin, A. and Rump, A. and Stricker, S. and Tinschert, S. and Otero, M. and Tsuchimochi, K. and Goldring, M.B. and Luft, F.C. and Baehring, S.
Abstract:PTHLH (parathyroid hormone-like hormone) 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 upstream of PTHLH on chromosome 12p11.2 and a disrupted KCNB2 on 8q13. We sequenced the breakpoints (BP) and identified a highly conserved 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 der(8) breakpoint (BP), but were differently enriched between the wild-type and breakpoint 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, while 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.
Keywords:ADAM Proteins, Human Pair 12 Chromosomes, Human Pair 8 Chromosomes, Down-Regulation, Fingers, Congenital Foot Deformities, Congenital Hand Deformities, Parathyroid Hormone-Related Protein, Nucleic Acid Regulatory Sequences, Toes, Genetic Translocation, Animals, Mice
Source:Human Molecular Genetics
ISSN:0964-6906
Publisher:Oxford University Press (U.K.)
Volume:19
Number:5
Page Range:848-860
Date:1 March 2010
Official Publication:https://doi.org/10.1093/hmg/ddp553
PubMed:View item in PubMed

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