P518/Qrfp sequence polymorphisms in SAMP6 osteopenic mouse.
Mice lacking GPR103A expression display osteopenia. Analysis of mouse quantitative trait loci literature associated with bone mineral density suggested GPR103A ligand P518/Qrfp (chromosome 2qB) as a candidate osteoporosis gene. Promoter and coding regions of mouse P518/Qrfp were sequenced from genomic DNA obtained from the osteoporosis-prone strain SAMP6 and control strains SAMR1, A/J, AKR/J, BALB/c, C3H/HeJ, C57BL/6J, and DBA/2J. Four single-nucleotide polymorphisms (SNPs) were identified in only SAMP6 genomic DNA, g.-1773 T-->C, g.110 A-->G (N37S), g.188 G-->A (R63K), and g.135 T-->C (H45H). The promoter SNP generated a novel neuron-restrictive silencing factor binding site, a repressor that decreases gene expression in nonneuronal tissues. TaqMan analysis demonstrated fivefold lower P518/Qrfp liver expression in SAMP6 versus SAMR1 or C57BL/6J control strains. Tissue distribution of human, mouse, and rat P518/Qrfp and its receptors showed expression in bone and spinal cord. A direct role for P518/Qrfp function in maintaining bone mineral density is suggested.
Zhang
Qing
Q
Department of Discovery Technologies, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Qiu
Ping
P
Arreaza
M Gladys
MG
Simon
Jason S
JS
Golovko
Andrei
A
Laverty
Maureen
M
Vassileva
Galya
G
Gustafson
Eric L
EL
Rojas-Triana
Alberto
A
Bober
Loretta A
LA
Hedrick
Joseph A
JA
Monsma
Frederick J
FJ
Greene
Jonathan R
JR
Bayne
Marvin L
ML
Murgolo
Nicholas J
NJ
D000595:Amino Acid Sequence; D000818:Animals; D015519:Bone Density; D001851:Bone Diseases, Metabolic / Q000235:genetics*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D016366:Open Reading Frames / Q000235:genetics*; D010455:Peptides / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D019655:Quantitative Trait, Heritable; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D014018:Tissue Distribution
D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D010455:Peptides; C511787:QRFP peptide; C476583:Qrfpr protein, mouse; D043562:Receptors, G-Protein-Coupled