Submitted on March 14, 2005
Accepted on September 11, 2005
Serum Alkaline Phosphatase Activity is Regulated by a Chromosomal Region Containing the Alkaline Phosphatase 2 (Akp2) Gene in C57BL/6J and DBA/2J Mice
Jennifer E Foreman1, David A Blizard2, Glenn Gerhard3, Holly A Mack4, Dean H Lang5, Kathryn L Van Nimwegen4, George P Vogler4, Joseph T Stout2, Zakariya K Shihabi6, James W Griffith7, Joan M Lakoski8, Gerald E McClearn4, and David J Vandenbergh9*
1 Center for Developmental and Health Genetics, The Pennsylvania State University, University Park, PA, USA; Intercollege Program in Genetics, The Pennsylvania State University, University Park, PA, USA
2 Center for Developmental and Health Genetics, The Pennsylvania State University, University Park, PA, USA
3 Weis Center for Research, Geisinger Clinic, Danville, PA, USA
4 Center for Developmental and Health Genetics, The Pennsylvania State University, University Park, PA, USA; Department of Biobehavioral Health, The Pennsylvania State University, University Park, PA, USA
5 Center for Developmental and Health Genetics, The Pennsylvania State University, University Park, PA, USA; Department of Kinesiology, The Pennsylvania State University, University Park, PA, USA
6 Department of Pathology, Wake Forest University Medical Center, Winston-Salem, NC, USA
7 Department of Comparative Medicine, The Pennsylvania State University College of Medicine, Hershey, PA, USA
8 Department of Pharmacology, University of Pittsburgh, Pittsburgh, PA, USA
9 Center for Developmental and Health Genetics, The Pennsylvania State University, University Park, PA, USA; Intercollege Program in Genetics, The Pennsylvania State University, University Park, PA, USA; Department of Biobehavioral Health, The Pennsylvania State University, University Park, PA, USA
* To whom correspondence should be addressed. E-mail: djv4{at}psu.edu.
Quantitative Trait Locus (QTL) analyses were conducted to identify chromosomal regions that contribute to variability in serum alkaline phosphatase (AP) enzyme activity in mice derived from the C57BL/6J (B6) and DBA/2J (D2) inbred strains. Serum AP was measured in 400 B6D2 F2 mice at 5 months and 400 B6D2 F2 mice at 15 months of age that were genotyped at 96 microsatellite markers, and in 19 BXD RI strains at 5 months of age. A QTL on the distal end of chromosome 4 was present in all sex- and age-specific analyses with a peak LOD score of 20.36 at 58.51 centimorgans (cM). The Akp2 gene, which encodes the major serum AP isozyme, falls within this QTL region at 70.2 cM where the LOD score reached 13.2 (LOD significance level set at 4.3). Serum AP activity was directly related to the number of D2 alleles of a single nucleotide polymorphism in the 5' flanking region of the Akp2 gene, although no strain-related differences in hepatic expression of Akp2 RNA were found. A variety of sequence polymorphisms in this chromosomal region could be responsible for the differences in serum AP activity, the Akp2 gene, however, with several known amino acid substitutions between protein sequences of the B6 and D2 strains, is a leading candidate.
