Identification of a Hypomorphic <i>FANCG</i> Variant in Bernese Mountain Dogs
Bernese mountain dogs (BMDs), have an overall cancer incidence of 50%, half of which is comprised of an otherwise rare tumor, histiocytic sarcoma (HS). While recent studies have identified driver mutations in the MAPK pathway, identification of key predisposing genes has been elusive. Studies have i...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-09-01
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| Series: | Genes |
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| Online Access: | https://www.mdpi.com/2073-4425/13/10/1693 |
| _version_ | 1797473110060957696 |
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| author | Katheryn Meek Ya-Ting Yang Marilia Takada Maciej Parys Marlee Richter Alexander I. Engleberg Tuddow Thaiwong Rachel L. Griffin Peter Z. Schall Alana J. Kramer Vilma Yuzbasiyan-Gurkan |
| author_facet | Katheryn Meek Ya-Ting Yang Marilia Takada Maciej Parys Marlee Richter Alexander I. Engleberg Tuddow Thaiwong Rachel L. Griffin Peter Z. Schall Alana J. Kramer Vilma Yuzbasiyan-Gurkan |
| author_sort | Katheryn Meek |
| collection | DOAJ |
| description | Bernese mountain dogs (BMDs), have an overall cancer incidence of 50%, half of which is comprised of an otherwise rare tumor, histiocytic sarcoma (HS). While recent studies have identified driver mutations in the MAPK pathway, identification of key predisposing genes has been elusive. Studies have identified several loci to be associated with predisposition to HS in BMDs, including near the <i>MTAP/CDKN2A</i> region, but no causative coding variant has been identified. Here we report the presence of a coding polymorphism in the gene encoding FANCG, near the <i>MTAP/CDKN2A</i> locus. This variant is in a conserved region of the protein and appears to be specific to BMDs. Canine fibroblasts derived from dogs homozygous for this variant are hypersensitive to cisplatin. We show this canine <i>FANCG</i> variant and a previously defined hypomorphic <i>FANCG</i> allele in humans impart similar defects in DNA repair. However, our data also indicate that this variant is neither necessary nor sufficient for the development of HS. Furthermore, BMDs homozygous for this <i>FANCG</i> allele display none of the characteristic phenotypes associated with Fanconi anemia (FA) such as anemia, short stature, infertility, or an earlier age of onset for HS. This is similar to findings in FA deficient mice, which do not develop overt FA without secondary genetic mutations that exacerbate the FA deficit. In sum, our data suggest that dogs with deficits in the FA pathway are, like mice, innately resistant to the development of FA. |
| first_indexed | 2024-03-09T20:11:17Z |
| format | Article |
| id | doaj.art-0bb0654aac1140199e74801c7b4ad017 |
| institution | Directory Open Access Journal |
| issn | 2073-4425 |
| language | English |
| last_indexed | 2024-03-09T20:11:17Z |
| publishDate | 2022-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Genes |
| spelling | doaj.art-0bb0654aac1140199e74801c7b4ad0172023-11-24T00:14:29ZengMDPI AGGenes2073-44252022-09-011310169310.3390/genes13101693Identification of a Hypomorphic <i>FANCG</i> Variant in Bernese Mountain DogsKatheryn Meek0Ya-Ting Yang1Marilia Takada2Maciej Parys3Marlee Richter4Alexander I. Engleberg5Tuddow Thaiwong6Rachel L. Griffin7Peter Z. Schall8Alana J. Kramer9Vilma Yuzbasiyan-Gurkan10Comparative Medicine and Integrative Biology Program, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824, USAComparative Medicine and Integrative Biology Program, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824, USAComparative Medicine and Integrative Biology Program, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824, USAComparative Medicine and Integrative Biology Program, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824, USADepartment of Small Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824, USADepartment of Small Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824, USAVeterinary Diagnostic Laboratory, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48190, USACollege of Veterinary Medicine, Michigan State University, East Lansing, MI 48824, USAComparative Medicine and Integrative Biology Program, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824, USACollege of Veterinary Medicine, Michigan State University, East Lansing, MI 48824, USAComparative Medicine and Integrative Biology Program, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824, USABernese mountain dogs (BMDs), have an overall cancer incidence of 50%, half of which is comprised of an otherwise rare tumor, histiocytic sarcoma (HS). While recent studies have identified driver mutations in the MAPK pathway, identification of key predisposing genes has been elusive. Studies have identified several loci to be associated with predisposition to HS in BMDs, including near the <i>MTAP/CDKN2A</i> region, but no causative coding variant has been identified. Here we report the presence of a coding polymorphism in the gene encoding FANCG, near the <i>MTAP/CDKN2A</i> locus. This variant is in a conserved region of the protein and appears to be specific to BMDs. Canine fibroblasts derived from dogs homozygous for this variant are hypersensitive to cisplatin. We show this canine <i>FANCG</i> variant and a previously defined hypomorphic <i>FANCG</i> allele in humans impart similar defects in DNA repair. However, our data also indicate that this variant is neither necessary nor sufficient for the development of HS. Furthermore, BMDs homozygous for this <i>FANCG</i> allele display none of the characteristic phenotypes associated with Fanconi anemia (FA) such as anemia, short stature, infertility, or an earlier age of onset for HS. This is similar to findings in FA deficient mice, which do not develop overt FA without secondary genetic mutations that exacerbate the FA deficit. In sum, our data suggest that dogs with deficits in the FA pathway are, like mice, innately resistant to the development of FA.https://www.mdpi.com/2073-4425/13/10/1693Bernese mountain doghistiocytic sarcomafanconi anemiacancercomparative genetics |
| spellingShingle | Katheryn Meek Ya-Ting Yang Marilia Takada Maciej Parys Marlee Richter Alexander I. Engleberg Tuddow Thaiwong Rachel L. Griffin Peter Z. Schall Alana J. Kramer Vilma Yuzbasiyan-Gurkan Identification of a Hypomorphic <i>FANCG</i> Variant in Bernese Mountain Dogs Genes Bernese mountain dog histiocytic sarcoma fanconi anemia cancer comparative genetics |
| title | Identification of a Hypomorphic <i>FANCG</i> Variant in Bernese Mountain Dogs |
| title_full | Identification of a Hypomorphic <i>FANCG</i> Variant in Bernese Mountain Dogs |
| title_fullStr | Identification of a Hypomorphic <i>FANCG</i> Variant in Bernese Mountain Dogs |
| title_full_unstemmed | Identification of a Hypomorphic <i>FANCG</i> Variant in Bernese Mountain Dogs |
| title_short | Identification of a Hypomorphic <i>FANCG</i> Variant in Bernese Mountain Dogs |
| title_sort | identification of a hypomorphic i fancg i variant in bernese mountain dogs |
| topic | Bernese mountain dog histiocytic sarcoma fanconi anemia cancer comparative genetics |
| url | https://www.mdpi.com/2073-4425/13/10/1693 |
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