Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
A single codon insertion in PICALM is associated with development of familial subvalvular aortic stenosis in Newfoundland dogs.
Stern JA
,
White SN
,
Lehmkuhl LB
,
Reina-Doreste Y
,
Ferguson JL
,
Nascone-Yoder NM
,
Meurs KM
.
???displayArticle.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 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.
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).
Choi,
Predicting the functional effect of amino acid substitutions and indels.
2012, Pubmed
Choi,
Predicting the functional effect of amino acid substitutions and indels.
2012,
Pubmed
Combet,
NPS@: network protein sequence analysis.
2000,
Pubmed
D'Angelo,
A yeast model for amyloid-β aggregation exemplifies the role of membrane trafficking and PICALM in cytotoxicity.
2013,
Pubmed
Drögemüller,
A single codon insertion in the PICALM gene is not associated with subvalvular aortic stenosis in Newfoundland dogs.
2015,
Pubmed
Fagotto,
Beta-catenin localization during Xenopus embryogenesis: accumulation at tissue and somite boundaries.
1994,
Pubmed
,
Xenbase
Flicek,
Ensembl 2012.
2012,
Pubmed
Kienle,
The natural clinical history of canine congenital subaortic stenosis.
1994,
Pubmed
Maritzen,
Turning CALM into excitement: AP180 and CALM in endocytosis and disease.
2012,
Pubmed
Meurs,
Nine polymorphisms within the head and hinge region of the feline cardiac beta-myosin heavy chain gene.
2000,
Pubmed
Meurs,
Survival times in dogs with severe subvalvular aortic stenosis treated with balloon valvuloplasty or atenolol.
2005,
Pubmed
O'grady,
Canine congenital aortic stenosis: A review of the literature and commentary.
1989,
Pubmed
Petsas,
Familial discrete subaortic stenosis.
1998,
Pubmed
Purcell,
PLINK: a tool set for whole-genome association and population-based linkage analyses.
2007,
Pubmed
Pyle,
The genetics and pathology of discrete subaortic stenosis in the Newfoundland dog.
1976,
Pubmed
Reed,
Morphogenesis of the primitive gut tube is generated by Rho/ROCK/myosin II-mediated endoderm rearrangements.
2009,
Pubmed
,
Xenbase
Scotland,
The PICALM protein plays a key role in iron homeostasis and cell proliferation.
2012,
Pubmed
Stern,
Familial subvalvular aortic stenosis in golden retrievers: inheritance and echocardiographic findings.
2012,
Pubmed
Strilić,
Formation of cardiovascular tubes in invertebrates and vertebrates.
2010,
Pubmed
Tidholm,
Retrospective study of congenital heart defects in 151 dogs.
1997,
Pubmed
Valeske,
The dilemma of subaortic stenosis--a single center experience of 15 years with a review of the literature.
2011,
Pubmed
Wellcome Trust Case Control Consortium,
Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls.
2007,
Pubmed
Wessels,
Autosomal dominant inheritance of cardiac valves anomalies in two families: extended spectrum of left-ventricular outflow tract obstruction.
2009,
Pubmed
Yang,
Genomic inflation factors under polygenic inheritance.
2011,
Pubmed
Zhang,
I-TASSER server for protein 3D structure prediction.
2008,
Pubmed
