Differences in fat and muscle mass associated with a functional human polymorphism in a post-transcriptional BMP2 gene regulatory element.
A classic morphogen, bone morphogenetic protein 2 (BMP2) regulates the differentiation of pluripotent mesenchymal cells. High BMP2 levels promote osteogenesis or chondrogenesis and low levels promote adipogenesis. BMP2 inhibits myogenesis. Thus, BMP2 synthesis is tightly controlled. Several hundred nucleotides within the 3' untranslated regions of BMP2 genes are conserved from mammals to fishes indicating that the region is under stringent selective pressure. Our analyses indicate that this region controls BMP2 synthesis by post-transcriptional mechanisms. A common A to C single nucleotide polymorphism (SNP) in the BMP2 gene (rs15705, +A1123C) disrupts a putative post-transcriptional regulatory motif within the human ultra-conserved sequence. In vitro studies indicate that RNAs bearing the A or C alleles have different protein binding characteristics in extracts from mesenchymal cells. Reporter genes with the C allele of the ultra-conserved sequence were differentially expressed in mesenchymal cells. Finally, we analyzed MRI data from the upper arm of 517 healthy individuals aged 18-41 years. Individuals with the C/C genotype were associated with lower baseline subcutaneous fat volumes (P = 0.0030) and an increased gain in skeletal muscle volume (P = 0.0060) following resistance training in a cohort of young males. The rs15705 SNP explained 2-4% of inter-individual variability in the measured parameters. The rs15705 variant is one of the first genetic markers that may be exploited to facilitate early diagnosis, treatment, and/or prevention of diseases associated with poor fitness. Furthermore, understanding the mechanisms by which regulatory polymorphisms influence BMP2 synthesis will reveal novel pharmaceutical targets for these disabling conditions.
Devaney
Joseph M
JM
Research Center for Genetic Medicine, Children's National Medical Center, Washington, District of Columbia 20010, USA.
Tosi
Laura L
LL
Fritz
David T
DT
Gordish-Dressman
Heather A
HA
Jiang
Shan
S
Orkunoglu-Suer
Funda E
FE
Gordon
Andrew H
AH
Harmon
Brennan T
BT
Thompson
Paul D
PD
Clarkson
Priscilla M
PM
Angelopoulos
Theodore J
TJ
Gordon
Paul M
PM
Moyna
Niall M
NM
Pescatello
Linda S
LS
Visich
Paul S
PS
Zoeller
Robert F
RF
Brandoli
Cinzia
C
Hoffman
Eric P
EP
Rogers
Melissa B
MB
D000273:Adipose Tissue / Q000254:growth & development* / Q000502:physiology; D000293:Adolescent; D000328:Adult; D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics*; D002460:Cell Line; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000254:growth & development* / Q000502:physiology; D010809:Physical Fitness; D020641:Polymorphism, Single Nucleotide; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D055070:Resistance Training; D055815:Young Adult
C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2