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...
Published in: | Human Genetics |
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eScholarship, University of California
2014
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Online Access: | https://escholarship.org/uc/item/9887859c https://escholarship.org/content/qt9887859c/qt9887859c.pdf https://doi.org/10.1007/s00439-014-1454-0 |
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ftcdlib:oai:escholarship.org:ark:/13030/qt9887859c 2024-09-15T18:19:57+00:00 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/9887859c https://escholarship.org/content/qt9887859c/qt9887859c.pdf https://doi.org/10.1007/s00439-014-1454-0 unknown eScholarship, University of California qt9887859c https://escholarship.org/uc/item/9887859c https://escholarship.org/content/qt9887859c/qt9887859c.pdf doi:10.1007/s00439-014-1454-0 public Human Genetics, vol 133, iss 9 Pediatric Heart Disease Cardiovascular Genetics 2.1 Biological and endogenous factors Aetiology Animals Aortic Stenosis Subvalvular Base Sequence Case-Control Studies Clathrin Codon Dog Diseases Dogs Female Genetic Predisposition to Disease Genome-Wide Association Study Male Molecular Sequence Data Monomeric Clathrin Assembly Proteins Mutagenesis Insertional Pedigree Phosphatidylinositols Prospective Studies Protein Conformation Sequence Analysis RNA Sex Factors Xenopus laevis Complementary and Alternative Medicine Paediatrics and Reproductive Medicine Genetics & Heredity article 2014 ftcdlib https://doi.org/10.1007/s00439-014-1454-0 2024-06-28T06:28:20Z 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. © 2014 The Author(s). Article in Journal/Newspaper Newfoundland University of California: eScholarship Human Genetics 133 9 1139 1148 |
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University of California: eScholarship |
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unknown |
topic |
Pediatric Heart Disease Cardiovascular Genetics 2.1 Biological and endogenous factors Aetiology Animals Aortic Stenosis Subvalvular Base Sequence Case-Control Studies Clathrin Codon Dog Diseases Dogs Female Genetic Predisposition to Disease Genome-Wide Association Study Male Molecular Sequence Data Monomeric Clathrin Assembly Proteins Mutagenesis Insertional Pedigree Phosphatidylinositols Prospective Studies Protein Conformation Sequence Analysis RNA Sex Factors Xenopus laevis Complementary and Alternative Medicine Paediatrics and Reproductive Medicine Genetics & Heredity |
spellingShingle |
Pediatric Heart Disease Cardiovascular Genetics 2.1 Biological and endogenous factors Aetiology Animals Aortic Stenosis Subvalvular Base Sequence Case-Control Studies Clathrin Codon Dog Diseases Dogs Female Genetic Predisposition to Disease Genome-Wide Association Study Male Molecular Sequence Data Monomeric Clathrin Assembly Proteins Mutagenesis Insertional Pedigree Phosphatidylinositols Prospective Studies Protein Conformation Sequence Analysis RNA Sex Factors Xenopus laevis 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 |
Pediatric Heart Disease Cardiovascular Genetics 2.1 Biological and endogenous factors Aetiology Animals Aortic Stenosis Subvalvular Base Sequence Case-Control Studies Clathrin Codon Dog Diseases Dogs Female Genetic Predisposition to Disease Genome-Wide Association Study Male Molecular Sequence Data Monomeric Clathrin Assembly Proteins Mutagenesis Insertional Pedigree Phosphatidylinositols Prospective Studies Protein Conformation Sequence Analysis RNA Sex Factors Xenopus laevis 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. © 2014 The Author(s). |
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/9887859c https://escholarship.org/content/qt9887859c/qt9887859c.pdf https://doi.org/10.1007/s00439-014-1454-0 |
op_coverage |
1139 - 1148 |
genre |
Newfoundland |
genre_facet |
Newfoundland |
op_source |
Human Genetics, vol 133, iss 9 |
op_relation |
qt9887859c https://escholarship.org/uc/item/9887859c https://escholarship.org/content/qt9887859c/qt9887859c.pdf doi:10.1007/s00439-014-1454-0 |
op_rights |
public |
op_doi |
https://doi.org/10.1007/s00439-014-1454-0 |
container_title |
Human Genetics |
container_volume |
133 |
container_issue |
9 |
container_start_page |
1139 |
op_container_end_page |
1148 |
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1810458305044152320 |