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Title: A single codon insertion in PICALM is associated with development of familial subvalvular aortic stenosis in Newfoundland dogs

Author
item STERN, JOSHUA - North Carolina State University
item White, Stephen
item LEHMKUHL, LINDA - Medvet Medical Center Of Pets
item DORESTE-REINA, YAMIR - North Carolina State University
item FERGUSON, JORDAN - North Carolina State University
item NASCONE-YODER, NANETTE - North Carolina State University
item MEURS, KATHRYN - North Carolina State University

Submitted to: Human Genetics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/20/2014
Publication Date: 9/1/2014
Citation: Stern, J.A., White, S.N., Lehmkuhl, L.B., Doreste-Reina, Y., Ferguson, J.L., Nascone-Yoder, N.M., Meurs, K.M. 2014. A single codon insertion in PICALM is associated with development of familial subvalvular aortic stenosis in Newfoundland dogs. Human Genetics. 133(9):1139-1148.

Interpretive Summary: Among inherited heart defects in dogs and human beings, a type known as subvalvular aortic stenosis (SAS) is one of the most common. While it is known that some Newfoundland dogs develop SAS heart disease, the specific gene, mutation, and mode of inheritance have not been known. A systematic genome-wide scan for important genes identified the PICALM gene as highly associated with SAS. Within this gene, a specific 3-base-pair insertion that adds to the protein coding portion of the gene is highly associated with and appears to be responsible for the risk of developing SAS. In addition, a pedigree analysis supported dominant inheritance within individual families of Newfoundland dogs. These results advance the field by identifying a new gene that had previously not been known to play a role in SAS heart disease in any mammal species. Further, now that a specific mutation has been identified, it will be possible to selectively breed dogs to have dramatically lower chances of developing SAS heart disease.

Technical Abstract: Familial subvalvular aortic stenosis (SAS) is one of the most common congenital heart defects in dogs and is an inherited defect of Newfoundlands, golden retrievers and human children. Although SAS is known to be inherited, specific genes involved in Newfoundlands with SAS have not been defined. We hypothesized that SAS in Newfoundlands is inherited in an autosomal dominant pattern and a caused by a single genetic variant. We studied 93 prospectively recruited Newfoundland dogs, and 180 control dogs of 30 breeds. By providing cardiac screening evaluations for Newfoundlands we conducted a pedigree evaluation, genome wide association study and RNA sequence analysis to identify a proposed pattern of inheritance and genetic loci associated with the development of SAS. We identified a 3-nucleotide exonic insertion in phosphatidylinositol binding clathrin assembly protein (PICALM) that is associated with the development of SAS in Newfoundlands. Pedigree evaluation best supported an autosomal dominant pattern of inheritance and provided evidence that equivocally affected individuals may pass on SAS in their progeny. Immunohistochemistry demonstrated the presence of PICALM in the canine myocardium and area of the subvalvular ridge. Additionally, small molecule inhibition of clathrin-mediated endocytosis resulted in developmental abnormalities within the outflow tract (OFT) of Xenopus laevis embryos. The ability to test for presence of this PICALM insertion may impact dog-breeding decisions and facilitate reduction of SAS disease prevalence in Newfoundland dogs. Understanding the role of PICALM in OFT development may aid in future molecular and genetic investigations into other congenital heart defects of various species.