XB-ART-49131Hum Genet September 1, 2014; 133 (9): 1139-48.
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A single codon insertion in PICALM is associated with development of familial subvalvular aortic stenosis in Newfoundland dogs.
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 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 three-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.
PubMed ID: 24898977
PMC ID: PMC4148152
Article link: Hum Genet
Species referenced: Xenopus laevis
Genes referenced: cltc fbn1 gopc picalm picalml tspan31
Disease Ontology terms: subvalvular aortic stenosis
Article Images: [+] show captions
|Fig. 1 Pedigree representing an extended family of 53 newfound- lands evaluated for sas and depicted with the following key: circles represent females; squares represent males; open symbols are unaf- fected; blackened symbols are affected; striped symbols are equivo- cal; a diagonal line through the symbol represents sudden death; and symbols containing question marks have unknown phenotypes as they were not evaluated as part of this study|
|Fig. 7 Comparative immunohistochemical imaging of a stage 40 Xenopus laevis control embryo (DMSO) versus a 5uM treated Pitstop embryo. the top row a, b shows the full section while the middle row c, d and bottom row e, f are successive magnification of the squared region to better visualize the outflow tract. the neural tube (nt), outflow tract (OFT), and pharyngeal cavity (Ph) are visualized. The fluorescent staining represents fibrillin (green), beta-catenin (red) and DaPI nuclear stain (blue).|
References [+] :
Burton, Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. 2007, Pubmed