PMID- 20015959
OWN - NLM
STAT- MEDLINE
DCOM- 20100629
LR  - 20211020
IS  - 1460-2083 (Electronic)
IS  - 0964-6906 (Print)
IS  - 0964-6906 (Linking)
VI  - 19
IP  - 5
DP  - 2010 Mar 1
TI  - A cis-regulatory site downregulates PTHLH in translocation t(8;12)(q13;p11.2) and 
      leads to Brachydactyly Type E.
PG  - 848-60
LID - 10.1093/hmg/ddp553 [doi]
AB  - 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.
FAU - Maass, Philipp G
AU  - Maass PG
AD  - Department of Genetics, Nephrology, Hypertension, and Vascular Injury, 
      Max-Delbruck Center for Molecular Medicine (MDC), Robert-Rossle Strasse 10, 13125 
      Berlin, Germany.
FAU - Wirth, Jutta
AU  - Wirth J
FAU - Aydin, Atakan
AU  - Aydin A
FAU - Rump, Andreas
AU  - Rump A
FAU - Stricker, Sigmar
AU  - Stricker S
FAU - Tinschert, Sigrid
AU  - Tinschert S
FAU - Otero, Miguel
AU  - Otero M
FAU - Tsuchimochi, Kaneyuki
AU  - Tsuchimochi K
FAU - Goldring, Mary B
AU  - Goldring MB
FAU - Luft, Friedrich C
AU  - Luft FC
FAU - Bahring, Sylvia
AU  - Bahring S
LA  - eng
GR  - R01 AG022021/AG/NIA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20091216
PL  - England
TA  - Hum Mol Genet
JT  - Human molecular genetics
JID - 9208958
RN  - 0 (PTHLH protein, human)
RN  - 0 (Parathyroid Hormone-Related Protein)
RN  - EC 3.4.24.- (ADAM Proteins)
RN  - EC 3.4.24.- (ADAMTS7 Protein)
RN  - EC 3.4.24.- (ADAMTS7 protein, human)
SB  - IM
MH  - ADAM Proteins/genetics/metabolism
MH  - ADAMTS7 Protein
MH  - Animals
MH  - Chromosomes, Human, Pair 12/*genetics
MH  - Chromosomes, Human, Pair 8/*genetics
MH  - *Down-Regulation
MH  - Fingers/*abnormalities
MH  - Foot Deformities, Congenital/genetics
MH  - Hand Deformities, Congenital/genetics
MH  - Humans
MH  - Mice
MH  - Parathyroid Hormone-Related Protein/*genetics
MH  - Regulatory Sequences, Nucleic Acid/*genetics
MH  - Toes/*abnormalities
MH  - *Translocation, Genetic
PMC - PMC3031338
EDAT- 2009/12/18 06:00
MHDA- 2010/06/30 06:00
PMCR- 2011/03/01
CRDT- 2009/12/18 06:00
PHST- 2009/12/18 06:00 [entrez]
PHST- 2009/12/18 06:00 [pubmed]
PHST- 2010/06/30 06:00 [medline]
PHST- 2011/03/01 00:00 [pmc-release]
AID - ddp553 [pii]
AID - 10.1093/hmg/ddp553 [doi]
PST - ppublish
SO  - Hum Mol Genet. 2010 Mar 1;19(5):848-60. doi: 10.1093/hmg/ddp553. Epub 2009 Dec 
      16.