Two novel missense mutations associated with hemophilia A in a family of Boxers, and a German Shepherd dog

Christopherson, Pete W.; Bacek, Lenore M.; King, Kevin B.; Boudreaux, Mary K.

doi:10.1111/vcp.12172

Cited by 13 publications

(20 citation statements)

References 12 publications

(29 reference statements)

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“…The other so far identified genetic variants in dogs carrying or suffering from hemophilia A lie further upstream of the SINE c.4824_25ins221; Pro471Arg in Boxers [8], Cys548Tyr in a German Shepherd [8], Arg577* in Old English sheepdog [7], and Trp33* in a German Shepherd [9]. These four variants are associated with a severe form of Hemophilia A with <1% FVIII activity.…”

Section: Discussionmentioning

confidence: 99%

“…Later, an intron 22 inversion similar to a genetic mutation commonly found in human patients, was identified in both the Chapel Hill colony and an unrelated dog colony at Queens Hospital, Canada [5,6]. Other breed-specific genetic variants causing Hemophilia A are later described in the breeds Old English Sheepdog [7], Boxer [8], German Shepherd [8,9], and Havanese [10].…”

Section: Introductionmentioning

confidence: 99%

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A SINE Insertion in F8 Gene Leads to Severe Form of Hemophilia A in a Family of Rhodesian Ridgebacks

Kehl

Haaland

Langbein-Detsch

et al. 2021

Genes

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Hemophilia A is the most common coagulation factor disorder in humans and dogs. The disease is characterized by the lack or diminished activity of Factor VIII (FVIII), caused by variants in the F8 gene and inherited as an X chromosomal trait. Two related male Rhodesian Ridgebacks were diagnosed with Hemophilia A due to reduced FVIII activity. The purpose of the study was to determine the genetic cause and give breeding advice for the remaining family members in order to eradicate the variant. By Sanger sequencing a short interspersed nuclear element (SINE) insertion in exon 14 of the F8 gene was found. Perfect correlation of this genetic variant with clinical signs of hemophilia A in the family tree, and the lack of this genetic variant in more than 500 unrelated dogs of the same and other breeds, confirms the hypothesis of this SINE being the underlying genetic cause of Hemophilia A in this family. The identification of clinically unaffected female carriers allows subsequent exclusion of these animals from breeding, to avoid future production of clinically affected male offspring and more subclinical female carriers.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A SINE Insertion in F8 Gene Leads to Severe Form of Hemophilia A in a Family of Rhodesian Ridgebacks

Kehl

Haaland

Langbein-Detsch

et al. 2021

Genes

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“…It is still possible that males in the study experienced an X-linked bleeding disorder; none of the case cohort dogs were genotyped for any hemophilia A or B variants. Interestingly, although 2 different hemophilia A variants have been described in German Shepherds, 9,26 and our sample cohort contained 6 German Shepherd cases, 5 of the 6 were female. Although this finding does not rule out hemophilia A in these cases, the sex pattern is not consistent with an X-linked disease.…”

Section: Discussionmentioning

confidence: 96%

Investigation of a common canine factor VII deficiency variant in dogs with unexplained bleeding on autopsy

et al. 2022

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The factor VII (FVII) protein is an integral component of the extrinsic coagulation pathway. Deleterious variants in the gene encoding this protein can result in factor VII deficiency (FVIID), a bleeding disorder characterized by abnormal (slowed) clotting with a wide range of severity, from asymptomatic to life-threatening. In canids, a single FVIID-associated variant, first described in Beagles, has been observed in 24 breeds and mixed-breed dogs. Because this variant is present in breeds of diverse backgrounds, we hypothesized that it could be a contributing factor to unexplained bleeding observed in some canine autopsy cases. DNA was extracted from paraffin-embedded tissue samples from 67 anticoagulant-negative autopsy cases with unexplained etiology for gross lesions of hemorrhage. Each dog was genotyped for the c.407G>A ( F71) variant. Experimental controls included 3 known heterozygotes and 2 known homozygotes for the F71 variant, 2 normal dogs with known homozygous wild-type genotypes ( F7W F7W), and 5 dogs with bleeding at autopsy that tested positive for anticoagulant rodenticide and were genotyped as F7W F7W. All 67 cases tested homozygous for the wild-type allele, indicating that the common FVIID variant was not responsible for the observed unexplained bleeding. Our work demonstrates the usefulness of retrospective studies utilizing veterinary diagnostic laboratory databases and tissue archives for genetic studies. In the case of FVIID, our results suggest that a singular molecular test for the F71 variant is not a high-yield addition to postmortem screening in these scenarios.

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“…Although FVIII mRNA is found in different human tissues such as liver, spleen, lymph nodes, and kidney , transplantation studies in hemophilic animal models and patients have demonstrated liver as the primary source of FVIII . Canine models have played an important role in the study and treatment of hemophilia A and in elucidating the central role played by the liver in this disease . The Chapel Hill colony of hemophilia A dogs was founded at the University of North Carolina in 1947 from a male Irish Setter with severe hemophilia A resulting from a gene inversion analogous to one commonly found in humans .…”

Section: Fviii Is Produced By Lsecsmentioning

confidence: 99%

Progress and challenges in the development of a cell‐based therapy for hemophilia A

Fomin

Togarrati

Muench

2014

Journal of Thrombosis and Haemostasis

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Hemophilia A results from an insufficiency of factor VIII (FVIII). Although replacement therapy with plasma-derived or recombinant FVIII is a life-saving therapy for hemophilia A patients, such therapy is a life-long treatment rather than a cure for the disease. In this review we discuss the possibilities, progress and challenges that remain in the development of a cell-based cure for hemophilia A. The success of cell therapy depends on the type and availability of donor cells, the age of the host and method of transplantation, and the levels of engraftment and production of FVIII by the graft. Early therapy, possibly even prenatal transplantation, may yield the highest levels of engraftment by avoiding immunological rejection of the graft. Potential cell sources of FVIII include a specialized subset of endothelial cells known as liver sinusoidal endothelial cells (LSECs) present in the adult and fetal liver, or patient-specific endothelial cells derived from induced pluripotent stem cells (iPSCs) that have undergone gene editing to produce FVIII. Achieving sufficient engraftment of transplanted LSECs is one of the obstacles to successful cell therapy for hemophilia A. We discuss recent results from transplants performed in animals that show production of functional and clinically relevant levels of FVIII obtained from donor LSECs. Hence, the possibility of treating hemophilia A can be envisioned through persistent production of FVIII from transplanted donor cells derived from a number of potential cell sources or through creation of donor endothelial cells from patient-specific iPSCs.

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Two novel missense mutations associated with hemophilia A in a family of Boxers, and a German Shepherd dog

Abstract: Here we document 2 mutations associated with canine hemophilia A associated with < 1% factor VIII activity, similar to that in people. Another related Boxer with the P471R mutation was later identified.

Cited by 13 publications

References 12 publications

A SINE Insertion in F8 Gene Leads to Severe Form of Hemophilia A in a Family of Rhodesian Ridgebacks

A SINE Insertion in F8 Gene Leads to Severe Form of Hemophilia A in a Family of Rhodesian Ridgebacks

Investigation of a common canine factor VII deficiency variant in dogs with unexplained bleeding on autopsy

Progress and challenges in the development of a cell‐based therapy for hemophilia A

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