An Deletion Is Highly Associated with a Juvenile-Onset Inherited Polyneuropathy in Leonberger and Saint Bernard Dogs


Leonberger dogs are a breed originally produced by crossing large-bodied dogs, including Saint Bernards and Newfoundlands. A peripheral neuropathy has been described in Leonbergers that is similar to a group of inherited polyneuropathies known as Charcot-Marie-Tooth disease in humans. We collected a cohort of well-characterized Leonberger polyneuropathy cases and controls, conducted a genome-wide association study, and ultimately identified a highly associated and likely causative mutation in the AHGEF10 gene. This sequence variant is a 10-bp deletion encompassing a splice site, which forces use of a downstream splice site to create a processed mRNA with a premature stop codon, and represents a loss-of-function mutation. The identical mutation was also found in several polyneuropathy-affected Saint Bernards. When homozygous, this deletion results in the onset of clinical signs before four years of age. ARHGEF10 has not previously been associated with severe CMT, but comes from a family of genes shown to be involved in neuron morphology. This first-documented severe polyneuropathy associated with an ARHGEF10 mutation in any species provides an opportunity to gain further insights into the pathobiology of diseases associated with this gene. The ARHGEF10 mutation does not, however, by itself account for all cases of polyneuropathy in Leonbergers or Saint Bernards.


Vyšlo v časopise: An Deletion Is Highly Associated with a Juvenile-Onset Inherited Polyneuropathy in Leonberger and Saint Bernard Dogs. PLoS Genet 10(10): e32767. doi:10.1371/journal.pgen.1004635
Kategorie: Research Article
prolekare.web.journal.doi_sk: 10.1371/journal.pgen.1004635

Souhrn

Leonberger dogs are a breed originally produced by crossing large-bodied dogs, including Saint Bernards and Newfoundlands. A peripheral neuropathy has been described in Leonbergers that is similar to a group of inherited polyneuropathies known as Charcot-Marie-Tooth disease in humans. We collected a cohort of well-characterized Leonberger polyneuropathy cases and controls, conducted a genome-wide association study, and ultimately identified a highly associated and likely causative mutation in the AHGEF10 gene. This sequence variant is a 10-bp deletion encompassing a splice site, which forces use of a downstream splice site to create a processed mRNA with a premature stop codon, and represents a loss-of-function mutation. The identical mutation was also found in several polyneuropathy-affected Saint Bernards. When homozygous, this deletion results in the onset of clinical signs before four years of age. ARHGEF10 has not previously been associated with severe CMT, but comes from a family of genes shown to be involved in neuron morphology. This first-documented severe polyneuropathy associated with an ARHGEF10 mutation in any species provides an opportunity to gain further insights into the pathobiology of diseases associated with this gene. The ARHGEF10 mutation does not, however, by itself account for all cases of polyneuropathy in Leonbergers or Saint Bernards.


Zdroje

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Genetika Reprodukčná medicína

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