Mammalian Genome

, Volume 16, Issue 12, pp 955–962 | Cite as

Linkage analysis and gene expression profile of pancreatic acinar atrophy in the German Shepherd Dog

  • Leigh Anne Clark
  • Jacquelyn M. Wahl
  • Jörg M. Steiner
  • Wenli Zhou
  • Wan Ji
  • Thomas R. Famula
  • David A. Williams
  • Keith E. MurphyEmail author


Pancreatic acinar atrophy (PAA) is a degenerative disease of the exocrine pancreas and is the most common cause of exocrine pancreatic insufficiency in the German Shepherd Dog. Analyses of inheritance have shown that a single gene segregating in an autosomal recessive fashion is causative for PAA. To date the gene and causative mutation have not been determined. To identify a region of interest and/or candidate genes, we conducted linkage and gene expression studies. Analysis of 384 microsatellite markers resulted in a maximum two-point LOD score of 2.5 for FH2107 on CFA03. We used an oligonucleotide array to generate gene expression profiles for normal and affected pancreata. It revealed 244 genes with greater than two-fold difference in expression levels. Five genes of interest were further assessed by TaqMan quantitative real-time RT-PCR that confirmed trends observed using the microarray. One gene, gp25L, located on CFA03, was found to be downregulated by more than 500-fold in affected pancreata and was further investigated as a candidate gene. Sequence data did not reveal a mutation in the coding sequence that segregates with PAA.


Exocrine Pancreatic Insufficiency Exocrine Pancreatic Insufficiency Multipoint Linkage Analysis Pedigree Member Sequential Oligogenic Linkage Analysis Routine 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This work was supported by grants from the Canine Health Foundation. The authors thank the GSD owners that generously participated in this study. The authors also thank Catherine André for providing assistance with RH mapping.


  1. Almasy, L, Blangero, J 1998 Multipoint quantitative trait linkage analysis in general pedigreesAm J Hum Genet6211981211CrossRefPubMedGoogle Scholar
  2. Blum, R, Feick, P, Puype, M, Vandekerckhove, J, Klengel, R,  et al. 1996Tmp21 and p24A, two type I proteins enriched in pancreatic microsomal membranes, are members of a protein family involved in vesicular traffickingJ Biol Chem2711718317189CrossRefPubMedGoogle Scholar
  3. Cargill, EJ, Clark, LA, Steiner, JM, Murphy, KE 2002Multiplexing of canine microsatellite markers for whole-genome screensGenomics80250253CrossRefPubMedGoogle Scholar
  4. Clark, LA, Tsai, KL, Steiner, JM, Williams, DA, Guerra, T,  et al. 2004Chromosome-specific microsatellite multiplex sets for linkage studies in the domestic dogGenomics84550554CrossRefPubMedGoogle Scholar
  5. Dimagno, E, Go, VL, Summerskill, W 1973Relations between pancreatic enzyme outputs and malabsorption in severe pancreatic insufficiencyN Engl J Med288813815PubMedCrossRefGoogle Scholar
  6. Durie, P 2000Pancreatic aspects of cystic fibrosis and other inherited causes of pancreatic dysfunctionMed Clin North Am84609620CrossRefPubMedGoogle Scholar
  7. Friess, H, Ding, J, Kleeff, J, Fenkell, L, Rosinski, JA,  et al. 2003Microarray-based identification of differentially expressed growth- and metastasis-associated genes in pancreatic cancerCell Mol Life Sci6011801199PubMedGoogle Scholar
  8. Gauthier, ER, Madison, SD, Michel, RN 1997Rapid RNA isolation without the use of commercial kits: application to small tissue samplesPflugers Arch433664668CrossRefPubMedGoogle Scholar
  9. Guyon, R, Lorentzen, TD, Hitte, C, Kim, L, Cadieu, E,  et al. 2003A 1-Mb resolution radiation hybrid map of the canine genomeProc Natl Acad Sci USA10052965301CrossRefPubMedGoogle Scholar
  10. Hamajima, N, Matsuda, K, Sakata, S, Tamaki, N, Sasaki, M,  et al. 1996A novel gene family defined by human dihydropyrimidinase and three related proteins with differential tissue distributionGene180157163CrossRefPubMedGoogle Scholar
  11. Han, H, Bearss, D, Browne, W, Calaluce, R, Nagle, RB,  et al. 2002Identification of differentially expressed genes in pancreatic cancer cells using cDNA microarrayCancer Res6228902896PubMedGoogle Scholar
  12. Ji, B, Chen, X, Misek, D, Kuick, R, Hanash, S,  et al. 2003Pancreatic gene expression during the initiation of acute pancreatitis: identification of EGR-1 as a key regulatorPhysiol Genomics145972PubMedGoogle Scholar
  13. Ji, W, Zhou, W, Gregg, K, Yu, N, Davis, S,  et al. 2004A method for cross-species gene expression analysis with high-density oligonucleotideNucleic Acids Res32e93CrossRefPubMedGoogle Scholar
  14. Jones, L, Humphreys, M, Campbell, F, Neoptolemos, JP, Boyd, MT 2004Comprehensive analysis of matrix metalloproteinase and tissue inhibitor expression in pancreatic cancer: increased expression of matrix metalloproteinase-7 predicts poor survivalClin Cancer Res1028322845PubMedCrossRefGoogle Scholar
  15. Kaur, S, Norkina, O, Ziemer, D, Samuelson, LC, Lisle, RC 2004Acidic duodenal pH alters gene expression in the cystic fibrosis mouse pancreasAm J Physiol Gastrointest Liver Physiol287G480490CrossRefPubMedGoogle Scholar
  16. Logsdon, C, Simeone, D, Binkley, C, Arumugam, T, Greenson, JK,  et al. 2003Molecular profiling of pancreatic adenocarcinoma and chronic pancreatitis identifies multiple genes differentially regulated in pancreatic cancerCancer Res6326492657PubMedGoogle Scholar
  17. Moeller, EM, Steiner, JS, Clark, LA, Murphy, KE, Famula, TR,  et al. 2002Inheritance of pancreatic acinar atrophy in German Shepherd DogsAm J Vet Res6314291434PubMedCrossRefGoogle Scholar
  18. Nakamura, T, Furukawa, Y, Nakagawa, H, Tsunoda, T, Ohigashi, H,  et al. 2004Genome-wide cDNA microarray analysis of gene expression profiles in pancreatic cancers using populations of tumor cells and normal ductal epithelial cells selected for purity by laser microdissectionOncogene2323852400CrossRefPubMedGoogle Scholar
  19. Orelle, B, Keim, V, Masciotra, L, Dagorn, JC, Iovanna, JL 1992Human pancreatitis-associated protein. Messenger RNA cloning and expression in pancreatic diseasesJ Clin Invest9022842291PubMedCrossRefGoogle Scholar
  20. Raiha, M, Westermarck, E 1989The signs of pancreatic degenerative atrophy in dogs and the role of external factors in the etiology of the diseasesActa Vet Scand30447452PubMedGoogle Scholar
  21. Richman, M, Mellersh, CS, André, C, Galibert, F, Ostrander, EA 2001Characterization of a minimal screening set of 172 microsatellite markers for genome-wide screens of the canine genomeJ Biochem Biophys Methods47137149CrossRefPubMedGoogle Scholar
  22. Rogers, WA, O’Dorisio, TM, Johnson, SE, Cataland, S, Stradley, RP,  et al. 1983Postprandial release of gastric inhibitory polypeptide (GIP) and pancreatic polypeptide in dogs with pancreatic acinar atrophyDig Dis Sci28345349CrossRefPubMedGoogle Scholar
  23. Rötter, J, Kuiper, R, Bouw, G, Martens, J 2002Cell-type-specific and selectively induced expression of members of the p24 family of putative cargo receptorsJ Cell Sci11510491058PubMedGoogle Scholar
  24. Stamnes, M, Craighead, M, Hoe, M, Lampen, N 1995An integral membrane component of coatemer-coated transport vesicles defines a family of proteins involved in buddingProc Natl Acad Sci USA928011 8015PubMedCrossRefGoogle Scholar
  25. Wada, I, Rindress, D, Cameron, P, Ou, WJ, Doherty, JJ,2nd,  et al. 1991SSRα and associated calnexin are major calcium binding proteins of the endoplasmic reticulum membraneJ Biol Chem2661959919610PubMedGoogle Scholar
  26. Westermarck, E, Wiberg, M 2003Exocrine pancreatic insufficiency in dogsVet Clin Small Anim3311651179CrossRefGoogle Scholar
  27. Westermarck, E, Batt, RM, Vaillant, C, Wiberg, M 1993Sequential study of pancreatic structure and function during development of pancreatic acinar atrophy in a German Shepherd DogAm J Vet Res5410881094PubMedGoogle Scholar
  28. Wiberg, M, Saari, S, Westermarck, E 1999Exocrine pancreatic atrophy in German Shepherd Dogs and Rough-coated Collies: an end result of lymphocytic pancreatitisVet Pathol36530541CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2005

Authors and Affiliations

  • Leigh Anne Clark
    • 1
  • Jacquelyn M. Wahl
    • 1
  • Jörg M. Steiner
    • 2
  • Wenli Zhou
    • 3
  • Wan Ji
    • 3
  • Thomas R. Famula
    • 4
  • David A. Williams
    • 2
  • Keith E. Murphy
    • 1
    Email author
  1. 1.Department of Pathobiology, College of Veterinary Medicine and Biomedical SciencesTexas A&M UniversityUSA
  2. 2.Gastrointestinal Laboratory, Department of Small Animal Clinical Sciences, College of Veterinary Medicine and Biomedical SciencesTexas A&M UniversityUSA
  3. 3.ViaGen, Inc.AustinUSA
  4. 4.Department of Animal ScienceUniversity of California DavisDavisUSA

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