A cis-regulatory site downregulates PTHLH in translocation t(8;12)(q13;p11.2) and leads to Brachydactyly Type E.
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.
Maass
Philipp G
PG
Department of Genetics, Nephrology, Hypertension, and Vascular Injury, Max-Delbrück Center for Molecular Medicine (MDC), Robert-Rössle Strasse 10, 13125 Berlin, Germany.
Wirth
Jutta
J
Aydin
Atakan
A
Rump
Andreas
A
Stricker
Sigmar
S
Tinschert
Sigrid
S
Otero
Miguel
M
Tsuchimochi
Kaneyuki
K
Goldring
Mary B
MB
Luft
Friedrich C
FC
Bähring
Sylvia
S
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
C470121:PTHLH protein, human; D044162:Parathyroid Hormone-Related Protein; D051722:ADAM Proteins; D000071118:ADAMTS7 Protein; C121534:ADAMTS7 protein, human