Hereditary Factor VII Deficiency in the Alaskan Klee Kai Dog

Abstract

Background: Hereditary factor VII (FVII) deficiency is characterized as a mild bleeding disorder in Beagles, caused by a missense mutation in exon 5 of the FVII gene. An Alaskan Klee Kai dog with severe bleeding after trauma was diagnosed with FVII deficiency based on coagulation testing. Molecular analyses were undertaken to identify the genetic basis of the defect in this breed. Hypothesis: FVII deficiency in Alaskan Klee Kai dogs is caused by a mutation in the FVII gene. Animals: Eighteen client‐owned Alaskan Klee Kai. Methods: Coagulation screening tests and factor assays were performed to characterize the coagulopathy. All coding regions of the propositus' FVII gene were sequenced. Amplification of exon 5, sequencing, and Mnl I restriction digest experiments were performed to screen for a point mutation in the remaining 17 dogs. Results: FVII deficiency was diagnosed in 6 dogs with a median FVII activity (FVII:C) of 5% (reference range, 50–150%). All FVII‐deficient Alaskan Klee Kai were homozygous for the same mutation as FVII‐deficient Beagles (ie, a G to A transition), resulting in substitution of glycine 96 by glutamic acid. An overlap in the FVII: C values obtained from heterozygote and wild‐type dogs precluded accurate detection of carriers without genetic screening. Conclusions and Clinical Importance: FVII deficiency may be associated with a bleeding tendency and should be considered in Alaskan Klee Kai dogs with prolonged prothrombin times. Plasma FVII:C accurately identifies affected dogs, but deoxyribonucleic acid testing is required for identification of carriers.

HEREDITARY FACTOR VII DEFICIENCY IN THE ASIAN ELEPHANT (ELEPHAS MAXIMUS) CAUSED BY AF7MISSENSE MUTATION

“…Variability in FVII activity between individual elephants was also observed in the present study and is seen in humans and dogs (Marder and Shulman 1964, Kaae et al 2007). In humans, plasma FVII activity is also known to be affected by a range of non-genetic factors including age, sleep deprivation, plasma triglycerides/cholesterol concentrations and components of the inflammatory response (Mariani et al 1999, Passaro et al 2008, Pinotti et al 2010).…”

“…An identical missense mutation has been identified in three humans (Giansily-Blaizot et al 2001, Herrmann et al 2009) but hereditary FVII deficiency in humans is also caused by mutations at many other locations on the F7 genome (Giansily-Blaizot et al 2001). In domestic dogs with FVII deficiency, another single missense mutation in the EGF-like domain has been found in all affected individuals thus far studied (Callan et al 2006, Kaae et al 2007). …”

“…As this factor resides in the extrinsic cascade, it affects the PT and not the PTT. In FVII deficient human patients several mutations in the F7 gene have been described, while the very same point missense mutation has been found in all affected domestic dog breeds including Beagles, Scottish deerhounds, Alaskan Klee Kai and others (Callan et al 2006, Daly and Giger 2007, Kaae et al 2007). …”

Protein Replacement Therapy and Gene Transfer in Canine Models of Hemophilia A, Hemophilia B, von Willebrand Disease, and Factor VII Deficiency

“…The protein sequence contains 406 amino acids and shares a 75% identity with mature human F.VII. The availability of the canine cDNA enabled the identification of a G to A missense mutation at nucleotide 6385 in exon 5 that substitutes glycine 96 for a glutamic acid as the causative molecular defect in dogs from research colonies in Switzerland, Canada, and the United States (Callan et al 2006) and in Alaskan Klee Kai dogs (Kaae et al 2007). …”

Missense mutation in PFKM associated with muscle-type phosphofructokinase deficiency in the Wachtelhund dog

“…As the above-cited breeds are phenotypically different but exhibited the same disease-causing mutation, a common ancestor appears likely to be responsible for transmission of the mutant allele to these breeds[10,12]. Similarly, in cases of ivermectin hypersensitivity [22] or factor VII deficiency [23,24] a single disease-causing mutation is observed in the multi-drug resistance 1 ( MDR1 ) gene [25,26] and factor VII ( FVII ) gene, respectively, for several closely related breeds. Conversely, different breed-specific mutations in the same gene can cause a single disease; examples include pyruvate kinase (PK) deficiency, a common erythroenzymoptathy affecting Basenjis [27], West Highland White Terriers [28], and most recently demonstrated in Labrador, Pug, Beagles and Cairn Terrier breeds [29] as well as von Willebrand disease, which is caused by several distinct mutations in the vWF gene in many different breeds [30].…”