A Cis-regulatory Site Downregulates PTHLH in Translocation T(8;12)(q13;p11.2) and Leads to Brachydactyly Type E

Overview

Journal Hum Mol Genet

Specialties Genetics
Molecular Biology

Date 2009 Dec 18

PMID 20015959

Citations 30

Authors

Philipp G Maass

Jutta Wirth

Atakan Aydin

Andreas Rump

Sigmar Stricker

Sigrid Tinschert

Miguel Otero

Kaneyuki Tsuchimochi

Mary B Goldring

Friedrich C Luft

Sylvia Bahring

Affiliations

Soon will be listed here.

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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