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...
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ftcdlib:oai:escholarship.org/ark:/13030/qt18r205td 2023-05-15T17:21:23+02:00 A single codon insertion in PICALM is associated with development of familial subvalvular aortic stenosis in Newfoundland dogs. Stern, Joshua A White, Stephen N Lehmkuhl, Linda B Reina-Doreste, Yamir Ferguson, Jordan L Nascone-Yoder, Nanette M Meurs, Kathryn M 1139 - 1148 2014-09-01 application/pdf https://escholarship.org/uc/item/18r205td unknown eScholarship, University of California qt18r205td https://escholarship.org/uc/item/18r205td public Human genetics, vol 133, iss 9 Animals Xenopus laevis Dogs Aortic Stenosis Subvalvular Dog Diseases Genetic Predisposition to Disease Phosphatidylinositols Monomeric Clathrin Assembly Proteins Clathrin Codon Case-Control Studies Prospective Studies Mutagenesis Insertional Pedigree Sequence Analysis RNA Sex Factors Base Sequence Protein Conformation Molecular Sequence Data Female Male Genome-Wide Association Study Genetics Complementary and Alternative Medicine Paediatrics and Reproductive Medicine Genetics & Heredity article 2014 ftcdlib 2020-10-13T16:03:38Z 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. Article in Journal/Newspaper Newfoundland University of California: eScholarship |
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University of California: eScholarship |
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language |
unknown |
topic |
Animals Xenopus laevis Dogs Aortic Stenosis Subvalvular Dog Diseases Genetic Predisposition to Disease Phosphatidylinositols Monomeric Clathrin Assembly Proteins Clathrin Codon Case-Control Studies Prospective Studies Mutagenesis Insertional Pedigree Sequence Analysis RNA Sex Factors Base Sequence Protein Conformation Molecular Sequence Data Female Male Genome-Wide Association Study Genetics Complementary and Alternative Medicine Paediatrics and Reproductive Medicine Genetics & Heredity |
spellingShingle |
Animals Xenopus laevis Dogs Aortic Stenosis Subvalvular Dog Diseases Genetic Predisposition to Disease Phosphatidylinositols Monomeric Clathrin Assembly Proteins Clathrin Codon Case-Control Studies Prospective Studies Mutagenesis Insertional Pedigree Sequence Analysis RNA Sex Factors Base Sequence Protein Conformation Molecular Sequence Data Female Male Genome-Wide Association Study Genetics Complementary and Alternative Medicine Paediatrics and Reproductive Medicine Genetics & Heredity Stern, Joshua A White, Stephen N Lehmkuhl, Linda B Reina-Doreste, Yamir Ferguson, Jordan L Nascone-Yoder, Nanette M Meurs, Kathryn M A single codon insertion in PICALM is associated with development of familial subvalvular aortic stenosis in Newfoundland dogs. |
topic_facet |
Animals Xenopus laevis Dogs Aortic Stenosis Subvalvular Dog Diseases Genetic Predisposition to Disease Phosphatidylinositols Monomeric Clathrin Assembly Proteins Clathrin Codon Case-Control Studies Prospective Studies Mutagenesis Insertional Pedigree Sequence Analysis RNA Sex Factors Base Sequence Protein Conformation Molecular Sequence Data Female Male Genome-Wide Association Study Genetics Complementary and Alternative Medicine Paediatrics and Reproductive Medicine Genetics & Heredity |
description |
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. |
format |
Article in Journal/Newspaper |
author |
Stern, Joshua A White, Stephen N Lehmkuhl, Linda B Reina-Doreste, Yamir Ferguson, Jordan L Nascone-Yoder, Nanette M Meurs, Kathryn M |
author_facet |
Stern, Joshua A White, Stephen N Lehmkuhl, Linda B Reina-Doreste, Yamir Ferguson, Jordan L Nascone-Yoder, Nanette M Meurs, Kathryn M |
author_sort |
Stern, Joshua A |
title |
A single codon insertion in PICALM is associated with development of familial subvalvular aortic stenosis in Newfoundland dogs. |
title_short |
A single codon insertion in PICALM is associated with development of familial subvalvular aortic stenosis in Newfoundland dogs. |
title_full |
A single codon insertion in PICALM is associated with development of familial subvalvular aortic stenosis in Newfoundland dogs. |
title_fullStr |
A single codon insertion in PICALM is associated with development of familial subvalvular aortic stenosis in Newfoundland dogs. |
title_full_unstemmed |
A single codon insertion in PICALM is associated with development of familial subvalvular aortic stenosis in Newfoundland dogs. |
title_sort |
single codon insertion in picalm is associated with development of familial subvalvular aortic stenosis in newfoundland dogs. |
publisher |
eScholarship, University of California |
publishDate |
2014 |
url |
https://escholarship.org/uc/item/18r205td |
op_coverage |
1139 - 1148 |
genre |
Newfoundland |
genre_facet |
Newfoundland |
op_source |
Human genetics, vol 133, iss 9 |
op_relation |
qt18r205td https://escholarship.org/uc/item/18r205td |
op_rights |
public |
_version_ |
1766105615079309312 |