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

Joshua A Stern, Stephen N. White, Linda B. Lehmkuhl, Yamir Reina-Doreste, Jordan L. Ferguson, Nanette M. Nascone-Yoder, Kathryn M. Meurs

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)1139-1148
Number of pages10
JournalHuman Genetics
Volume133
Issue number9
DOIs
StatePublished - 2014

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Subvalvular Aortic Stenosis
Newfoundland and Labrador
Codon
Dogs
Inheritance Patterns
Congenital Heart Defects
Pedigree
Vesicular Transport Adaptor Proteins
RNA Sequence Analysis
Aortic Diseases
Clathrin
Genetic Loci
Genome-Wide Association Study
Xenopus laevis
Phosphatidylinositols
Endocytosis
Breeding
Canidae
Molecular Biology
Myocardium

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Stern, J. A., White, S. N., Lehmkuhl, L. B., Reina-Doreste, 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. https://doi.org/10.1007/s00439-014-1454-0

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.

In: Human Genetics, Vol. 133, No. 9, 2014, p. 1139-1148.

Research output: Contribution to journalArticle

Stern, JA, White, SN, Lehmkuhl, LB, Reina-Doreste, Y, Ferguson, JL, Nascone-Yoder, NM & Meurs, KM 2014, 'A single codon insertion in PICALM is associated with development of familial subvalvular aortic stenosis in Newfoundland dogs', Human Genetics, vol. 133, no. 9, pp. 1139-1148. https://doi.org/10.1007/s00439-014-1454-0
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. In: Human Genetics. 2014 ; Vol. 133, No. 9. pp. 1139-1148.
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