Emergence of hereditary hyperplastic gingivitis in Newfoundland and Labrador, Canada: an exploration into the molecular aetiology at both the gene and genome levels

Clark, Jo-Anna B. J. (2016) Emergence of hereditary hyperplastic gingivitis in Newfoundland and Labrador, Canada: an exploration into the molecular aetiology at both the gene and genome levels. Doctoral (PhD) thesis, Memorial University of Newfoundland.

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Abstract

Hereditary hyperplastic gingivitis (HHG) is a benign fibrous enlargement of the gingival tissue to dental encapsulation in ranched silver foxes (Vulpes vulpes). It is an autosonal recessive condition displaying male sex-biased penetrance HHG demonstrates a pleiotropic association with superior fur quality. In 2004, after the introduction of a Finnish fox line, HHG emerged in Newfoundland and Labrador, Canada. While the underlying HHG aetiology is unknown, an analogous condition called hereditary gingival fibromatosis (HGF) occurs in humans, providing a platform for investigation into the molecular mechanisms of HHG. A mutation in the son of sevenless homolog 1 gene causes one form of HGF. Candidate gene sequencing of this and related genes including epidermal growth factor receptor (EGFR), growth factor receptor bound protein 2, and mitogen-activated protein kinase kinase 6 did not uncover any putative coding sequence or splice-site mutations. HHG was also examined at the genomic level, integrating knowledge of the chromosomal loci associated with the analogous human condition, HGF. This exploration was divided into the known genetic causes of isolated HGF and HGF-associated sundromes characterized by both gingival and hair overgrowth. Global gene expression differences between affected adn unaffected foxes pinpoint SOS2 and RASA1 as candidate gene for HHG; overall, the genomic expression patterns strongly indicate the involvement of the mitogen-activated protein kinase (MAPK) signalling pathway. Specifically, the error could occur prior to the Rat sarcoma protein in this pathway. Future exploration of the pathway could elucidate the genetic basis of HHG and more broadly the molecular aetiology of gingival overgrowth in humans and canines. Additional information regarding the HHG phenotype was revealed, including the potential involvement of androgens in disease severity. The steroid-5-alpha-reductase, alpha polypeptide 2 gene was found to be up-regulated in the HHG-affected foxes, and the link between androgens and gingival sensitivity in dogs might help explain the perceived sex biased penetrance originally noted in HHG. Overall the molecular mechanisms underpinning the HHG phenotype and future work revolve around the MAPK signalling pathway including influences that other gene products like androgens have on it.

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