Inheritance of pancreatic acinar atrophy in German Shepherd Dogs

Moeller, Erik M.; Steiner, Jörg M.; Clark, Leigh Anne; Murphy, Keith E.; Famula, Thomas R.; Williams, David A.; Stankovics, Mary E.; Vose, Amy S.

doi:10.2460/ajvr.2002.63.1429

Cited by 27 publications

(22 citation statements)

References 10 publications

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“…Although PAA was thought to be a simple autosomal recessive disorder (Moeller et al 2002; Westermarck 1980), the results of a recent test mating between two GSDs with PAA indicate more complex genetic underpinnings (Westermarck et al 2010). The study monitored the cTLI scores for the resulting litter of six over the course of the dogs’ lives (8–13 years) and the pancreas for each dog was examined at necropsy.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide association studies for multiple diseases of the German Shepherd Dog

et al. 2011

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The German Shepherd Dog (GSD) is a popular working and companion breed for which over 50 hereditary diseases have been documented. Herein, SNP profiles for 197 GSDs were generated using the Affymetrix v2 canine SNP array for a genome-wide association study to identify loci associated with four diseases: pituitary dwarfism, degenerative myelopathy (DM), congenital megaesophagus (ME), and pancreatic acinar atrophy (PAA). A locus on Chr 9 is strongly associated with pituitary dwarfism and is proximal to a plausible candidate gene, LHX3. Results for DM confirm a major locus encompassing SOD1, in which an associated point mutation was previously identified, but do not suggest modifier loci. Several SNPs on Chr 12 are associated with ME and a 4.7 Mb haplotype block is present in affected dogs. Analysis of additional ME cases for a SNP within the haplotype provides further support for this association. Results for PAA indicate more complex genetic underpinnings. Several regions on multiple chromosomes reach genome-wide significance. However, no major locus is apparent and only two associated haplotype blocks, on Chrs 7 and 12 are observed. These data suggest that PAA may be governed by multiple loci with small effects, or it may be a heterogeneous disorder.

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Section: Discussionmentioning

confidence: 99%

Genome-wide association studies for multiple diseases of the German Shepherd Dog

et al. 2011

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“…Although previous inheritance analyses suggested an autosomal recessive mode of inheritance, a test breeding of two affected GSDs failed to produce an entirely affected litter, contradicting predicted Mendelian ratios and suggesting a more complex mode of inheritance (Moeller et al 2002; Westermarck et al 2010). Classical linkage studies using multigenerational families of GSDs segregating EPI did not detect significant linkage with microsatellite markers across 39 canine chromosomes (Clark et al 2005).…”

Section: Introductionmentioning

confidence: 67%

Alleles of the major histocompatibility complex play a role in the pathogenesis of pancreatic acinar atrophy in dogs

et al. 2013

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Exocrine pancreatic insufficiency (EPI) is a disease wherein pancreatic acinar cells fail to synthesize and secrete sufficient amounts of digestive enzymes for normal digestion of food. EPI affects many dog breeds, with a dramatically higher prevalence in the German shepherd dog (GSD) population. In this breed and perhaps others, EPI most often results from degeneration of the acinar cells of the pancreas, a hereditary disorder termed pancreatic acinar atrophy (PAA). Evidence of lymphocytic infiltration indicates that PAA is an autoimmune disease, but the genetic etiology remains unclear. Data from global gene expression and single nucleotide polymorphism profiles in the GSD suggest the involvement of the major histocompatibility complex [MHC; dog leukocyte antigen (DLA)]. To determine if alleles of the MHC influence development of EPI, genotyping of polymorphic class I (DLA-88) and II loci (DLA-DRB1, DLA-DQA1, and DLA- DQB1) was carried out for 70 affected and 63 control GSDs, and four-locus haplotypes were determined. One haplotype containing a novel allele of DLA-88 is very highly associated with EPI (OR>17; P=0.000125), while two haplotypes were found to confer protection from EPI (P=0.00087 and 0.0115). Described herein is the genotyping of MHC class I and II loci in a GSD cohort, establishment of four-locus haplotypes, and association of alleles/haplotypes with EPI.

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“…The diagnosis of pancreatitis was based on one or more of the following criteria: appropriate historic and physical findings, elevations in one or more serum markers of pancreatitis (pancreatic lipase immunoreactivity or lipase or amylase activities), and characteristic radiographic or ultrasonographic abnormalities. PAA is a degenerative recessive genetic disease of the exocrine pancreas that causes EPI in the homozygous state (14). Clinical EPI diagnosis was made in an animal with a family history of PAA and serum canine trypsinlike immunoreactivity (cTLI) levels Յ2.5 g/l.…”

Section: Methodsmentioning

confidence: 99%

“…Unfortunately, neither of these groups reported finding a disease-causing CFTR mutation. We recently considered that domestic dogs might carry CF-causing CFTR mutations because these animals are known to have diseases that in humans harbor relatively high frequencies of CFTR mutations: bronchiectasis (9), pancreatic insufficiency (14), pancreatitis (24), and atresia of the vas deferens (6). Because dogs are popular pets and commonly receive medical treatment, we reasoned that animals afflicted with these various disorders could be identified through veterinary hospitals and screened for CFTR mutations.…”

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Naturally occurring mutations in the canine CFTR gene

Spadafora

Hawkins

Murphy

et al. 2010

Physiological Genomics

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Naturally occurring cystic fibrosis (CF)-causing mutations in the CFTR gene have not been identified in any nonhuman animal species. Since domestic dogs are known to develop medical conditions associated with atypical CF in humans (e.g., bronchiectasis and pancreatitis), we hypothesized that dogs with these disorders likely have a higher expression rate of CFTR mutations than the at-large population. Temporal temperature-gradient gel electrophoresis (TTGE) was used to screen canine CFTR in 400 animals: 203 dogs diagnosed with pancreatitis, 23 dogs diagnosed with bronchiectasis, and 174 dogs admitted to clinics for any illness (at-large dogs). Twenty-eight dogs were identified with one of four CFTR missense mutations. P1281T and P1464H mutations occur in relatively unconserved residues. R1456W is analogous to the human R1453W mutation, which has ∼20% of normal CFTR function and is associated with pancreatitis and panbronchiolitis. R812W disrupts a highly conserved protein kinase A recognition site within the regulatory domain. We conclude that naturally occurring CFTR mutations are relatively common in domestic dogs and can be detected with TTGE. No substantive differences in mutation frequency were observed between the at-large, pancreatitis, and bronchiectasis dogs.

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Inheritance of pancreatic acinar atrophy in German Shepherd Dogs

Abstract: Evaluation of data by complex segregation analysis is strongly suggestive of an autosomal recessive mode of inheritance for EPI in GSDs in the United States.

Cited by 27 publications

References 10 publications

Genome-wide association studies for multiple diseases of the German Shepherd Dog

Genome-wide association studies for multiple diseases of the German Shepherd Dog

Alleles of the major histocompatibility complex play a role in the pathogenesis of pancreatic acinar atrophy in dogs

Naturally occurring mutations in the canine CFTR gene

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