title: A cis-regulatory site downregulates PTHLH in translocation t(8;12)(q13;p11.2) and leads to Brachydactyly Type E.
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.
authors.affiliation: Department of Genetics, Nephrology, Hypertension, and Vascular Injury, Max-Delbrück Center for Molecular Medicine (MDC), Robert-Rössle Strasse 10, 13125 Berlin, Germany.
authors.forename: Philipp G
authors.initials: PG
authors.lastname: Maass
authors.forename: Jutta
authors.initials: J
authors.lastname: Wirth
authors.forename: Atakan
authors.initials: A
authors.lastname: Aydin
authors.forename: Andreas
authors.initials: A
authors.lastname: Rump
authors.forename: Sigmar
authors.initials: S
authors.lastname: Stricker
authors.forename: Sigrid
authors.initials: S
authors.lastname: Tinschert
authors.forename: Miguel
authors.initials: M
authors.lastname: Otero
authors.forename: Kaneyuki
authors.initials: K
authors.lastname: Tsuchimochi
authors.forename: Mary B
authors.initials: MB
authors.lastname: Goldring
authors.forename: Friedrich C
authors.initials: FC
authors.lastname: Luft
authors.forename: Sylvia
authors.initials: S
authors.lastname: Bähring
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism; D000071118:ADAMTS7 Protein; D000818:Animals; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics*; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics*; D015536:Down-Regulation; D005385:Fingers / Q000002:abnormalities*; D005532:Foot Deformities, Congenital / Q000235:genetics; D006228:Hand Deformities, Congenital / Q000235:genetics; D006801:Humans; D051379:Mice; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics*; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D014034:Toes / Q000002:abnormalities*; D014178:Translocation, Genetic
chemical_list: C470121:PTHLH protein, human; D044162:Parathyroid Hormone-Related Protein; D051722:ADAM Proteins; D000071118:ADAMTS7 Protein; C121534:ADAMTS7 protein, human