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

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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., Wirth, J., Aydin, A., Rump, A., Stricker, S., Tinschert, S., Otero, M., Tsuchimochi, K., Goldring, M.B., Luft, F.C. and Bähring, 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
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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