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A SIX6 Nonsense Variant in Golden Retrievers with Congenital Eye Malformations

Causative genetic variants for more than 30 heritable eye disorders in dogs have been reported. For other clinically described eye disorders, the genetic cause is still unclear. We investigated four Golden Retriever litters segregating for highly variable congenital eye malformations. Several affect...

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Autores principales: Hug, Petra, Anderegg, Linda, Dürig, Nicole, Lepori, Vincent, Jagannathan, Vidhya, Spiess, Bernhard, Richter, Marianne, Leeb, Tosso
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6628151/
https://www.ncbi.nlm.nih.gov/pubmed/31207931
http://dx.doi.org/10.3390/genes10060454
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author Hug, Petra
Anderegg, Linda
Dürig, Nicole
Lepori, Vincent
Jagannathan, Vidhya
Spiess, Bernhard
Richter, Marianne
Leeb, Tosso
author_facet Hug, Petra
Anderegg, Linda
Dürig, Nicole
Lepori, Vincent
Jagannathan, Vidhya
Spiess, Bernhard
Richter, Marianne
Leeb, Tosso
author_sort Hug, Petra
collection PubMed
description Causative genetic variants for more than 30 heritable eye disorders in dogs have been reported. For other clinically described eye disorders, the genetic cause is still unclear. We investigated four Golden Retriever litters segregating for highly variable congenital eye malformations. Several affected puppies had unilateral or bilateral retina dysplasia and/or optic nerve hypoplasia. The four litters shared the same father or grandfather suggesting a heritable condition with an autosomal dominant mode of inheritance. The genome of one affected dog was sequenced and compared to 601 control genomes. A heterozygous private nonsense variant, c.487C>T, was found in the SIX6 gene. This variant is predicted to truncate about a third of the open reading frame, p.(Gln163*). We genotyped all available family members and 464 unrelated Golden Retrievers. All three available cases were heterozygous. Five additional close relatives including the common sire were also heterozygous, but did not show any obvious eye phenotypes. The variant was absent from the 464 unrelated Golden Retrievers and 17 non-affected siblings of the cases. The SIX6 protein is a homeobox transcription factor with a known role in eye development. In humans and other species, SIX6 loss of function variants were reported to cause congenital eye malformations. This strongly suggests that the c.487C>T variant detected contributed to the observed eye malformations. We hypothesize that the residual amount of functional SIX6 protein likely to be expressed in heterozygous dogs is sufficient to explain the observed incomplete penetrance and the varying severity of the eye defects in the affected dogs.
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spelling pubmed-66281512019-07-23 A SIX6 Nonsense Variant in Golden Retrievers with Congenital Eye Malformations Hug, Petra Anderegg, Linda Dürig, Nicole Lepori, Vincent Jagannathan, Vidhya Spiess, Bernhard Richter, Marianne Leeb, Tosso Genes (Basel) Article Causative genetic variants for more than 30 heritable eye disorders in dogs have been reported. For other clinically described eye disorders, the genetic cause is still unclear. We investigated four Golden Retriever litters segregating for highly variable congenital eye malformations. Several affected puppies had unilateral or bilateral retina dysplasia and/or optic nerve hypoplasia. The four litters shared the same father or grandfather suggesting a heritable condition with an autosomal dominant mode of inheritance. The genome of one affected dog was sequenced and compared to 601 control genomes. A heterozygous private nonsense variant, c.487C>T, was found in the SIX6 gene. This variant is predicted to truncate about a third of the open reading frame, p.(Gln163*). We genotyped all available family members and 464 unrelated Golden Retrievers. All three available cases were heterozygous. Five additional close relatives including the common sire were also heterozygous, but did not show any obvious eye phenotypes. The variant was absent from the 464 unrelated Golden Retrievers and 17 non-affected siblings of the cases. The SIX6 protein is a homeobox transcription factor with a known role in eye development. In humans and other species, SIX6 loss of function variants were reported to cause congenital eye malformations. This strongly suggests that the c.487C>T variant detected contributed to the observed eye malformations. We hypothesize that the residual amount of functional SIX6 protein likely to be expressed in heterozygous dogs is sufficient to explain the observed incomplete penetrance and the varying severity of the eye defects in the affected dogs. MDPI 2019-06-14 /pmc/articles/PMC6628151/ /pubmed/31207931 http://dx.doi.org/10.3390/genes10060454 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Hug, Petra
Anderegg, Linda
Dürig, Nicole
Lepori, Vincent
Jagannathan, Vidhya
Spiess, Bernhard
Richter, Marianne
Leeb, Tosso
A SIX6 Nonsense Variant in Golden Retrievers with Congenital Eye Malformations
title A SIX6 Nonsense Variant in Golden Retrievers with Congenital Eye Malformations
title_full A SIX6 Nonsense Variant in Golden Retrievers with Congenital Eye Malformations
title_fullStr A SIX6 Nonsense Variant in Golden Retrievers with Congenital Eye Malformations
title_full_unstemmed A SIX6 Nonsense Variant in Golden Retrievers with Congenital Eye Malformations
title_short A SIX6 Nonsense Variant in Golden Retrievers with Congenital Eye Malformations
title_sort six6 nonsense variant in golden retrievers with congenital eye malformations
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6628151/
https://www.ncbi.nlm.nih.gov/pubmed/31207931
http://dx.doi.org/10.3390/genes10060454
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