An ARHGEF10 deletion is highly associated with a juvenile-onset inherited polyneuropathy in Leonberger and Saint Bernard dogs.
An inherited polyneuropathy (PN) observed in Leonberger dogs has clinical similarities to a genetically heterogeneous group of peripheral neuropathies termed Charcot-Marie-Tooth (CMT) disease in humans. The Leonberger disorder is a severe, juvenile-onset, chronic, progressive, and mixed PN, characte...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2014-10-01
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| Series: | PLoS Genetics |
| Online Access: | http://europepmc.org/articles/PMC4183422?pdf=render |
| _version_ | 1811326768790896640 |
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| author | Kari J Ekenstedt Doreen Becker Katie M Minor G Diane Shelton Edward E Patterson Tim Bley Anna Oevermann Thomas Bilzer Tosso Leeb Cord Drögemüller James R Mickelson |
| author_facet | Kari J Ekenstedt Doreen Becker Katie M Minor G Diane Shelton Edward E Patterson Tim Bley Anna Oevermann Thomas Bilzer Tosso Leeb Cord Drögemüller James R Mickelson |
| author_sort | Kari J Ekenstedt |
| collection | DOAJ |
| description | An inherited polyneuropathy (PN) observed in Leonberger dogs has clinical similarities to a genetically heterogeneous group of peripheral neuropathies termed Charcot-Marie-Tooth (CMT) disease in humans. The Leonberger disorder is a severe, juvenile-onset, chronic, progressive, and mixed PN, characterized by exercise intolerance, gait abnormalities and muscle atrophy of the pelvic limbs, as well as inspiratory stridor and dyspnea. We mapped a PN locus in Leonbergers to a 250 kb region on canine chromosome 16 (Praw = 1.16×10-10, Pgenome, corrected = 0.006) utilizing a high-density SNP array. Within this interval is the ARHGEF10 gene, a member of the rho family of GTPases known to be involved in neuronal growth and axonal migration, and implicated in human hypomyelination. ARHGEF10 sequencing identified a 10 bp deletion in affected dogs that removes four nucleotides from the 3'-end of exon 17 and six nucleotides from the 5'-end of intron 17 (c.1955_1958+6delCACGGTGAGC). This eliminates the 3'-splice junction of exon 17, creates an alternate splice site immediately downstream in which the processed mRNA contains a frame shift, and generates a premature stop codon predicted to truncate approximately 50% of the protein. Homozygosity for the deletion was highly associated with the severe juvenile-onset PN phenotype in both Leonberger and Saint Bernard dogs. The overall clinical picture of PN in these breeds, and the effects of sex and heterozygosity of the ARHGEF10 deletion, are less clear due to the likely presence of other forms of PN with variable ages of onset and severity of clinical signs. This is the first documented severe polyneuropathy associated with a mutation in ARHGEF10 in any species. |
| first_indexed | 2024-04-13T14:54:56Z |
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| id | doaj.art-023869903c2b403b8bb28c4159d5c2ff |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-04-13T14:54:56Z |
| publishDate | 2014-10-01 |
| publisher | Public Library of Science (PLoS) |
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| series | PLoS Genetics |
| spelling | doaj.art-023869903c2b403b8bb28c4159d5c2ff2022-12-22T02:42:28ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042014-10-011010e100463510.1371/journal.pgen.1004635An ARHGEF10 deletion is highly associated with a juvenile-onset inherited polyneuropathy in Leonberger and Saint Bernard dogs.Kari J EkenstedtDoreen BeckerKatie M MinorG Diane SheltonEdward E PattersonTim BleyAnna OevermannThomas BilzerTosso LeebCord DrögemüllerJames R MickelsonAn inherited polyneuropathy (PN) observed in Leonberger dogs has clinical similarities to a genetically heterogeneous group of peripheral neuropathies termed Charcot-Marie-Tooth (CMT) disease in humans. The Leonberger disorder is a severe, juvenile-onset, chronic, progressive, and mixed PN, characterized by exercise intolerance, gait abnormalities and muscle atrophy of the pelvic limbs, as well as inspiratory stridor and dyspnea. We mapped a PN locus in Leonbergers to a 250 kb region on canine chromosome 16 (Praw = 1.16×10-10, Pgenome, corrected = 0.006) utilizing a high-density SNP array. Within this interval is the ARHGEF10 gene, a member of the rho family of GTPases known to be involved in neuronal growth and axonal migration, and implicated in human hypomyelination. ARHGEF10 sequencing identified a 10 bp deletion in affected dogs that removes four nucleotides from the 3'-end of exon 17 and six nucleotides from the 5'-end of intron 17 (c.1955_1958+6delCACGGTGAGC). This eliminates the 3'-splice junction of exon 17, creates an alternate splice site immediately downstream in which the processed mRNA contains a frame shift, and generates a premature stop codon predicted to truncate approximately 50% of the protein. Homozygosity for the deletion was highly associated with the severe juvenile-onset PN phenotype in both Leonberger and Saint Bernard dogs. The overall clinical picture of PN in these breeds, and the effects of sex and heterozygosity of the ARHGEF10 deletion, are less clear due to the likely presence of other forms of PN with variable ages of onset and severity of clinical signs. This is the first documented severe polyneuropathy associated with a mutation in ARHGEF10 in any species.http://europepmc.org/articles/PMC4183422?pdf=render |
| spellingShingle | Kari J Ekenstedt Doreen Becker Katie M Minor G Diane Shelton Edward E Patterson Tim Bley Anna Oevermann Thomas Bilzer Tosso Leeb Cord Drögemüller James R Mickelson An ARHGEF10 deletion is highly associated with a juvenile-onset inherited polyneuropathy in Leonberger and Saint Bernard dogs. PLoS Genetics |
| title | An ARHGEF10 deletion is highly associated with a juvenile-onset inherited polyneuropathy in Leonberger and Saint Bernard dogs. |
| title_full | An ARHGEF10 deletion is highly associated with a juvenile-onset inherited polyneuropathy in Leonberger and Saint Bernard dogs. |
| title_fullStr | An ARHGEF10 deletion is highly associated with a juvenile-onset inherited polyneuropathy in Leonberger and Saint Bernard dogs. |
| title_full_unstemmed | An ARHGEF10 deletion is highly associated with a juvenile-onset inherited polyneuropathy in Leonberger and Saint Bernard dogs. |
| title_short | An ARHGEF10 deletion is highly associated with a juvenile-onset inherited polyneuropathy in Leonberger and Saint Bernard dogs. |
| title_sort | arhgef10 deletion is highly associated with a juvenile onset inherited polyneuropathy in leonberger and saint bernard dogs |
| url | http://europepmc.org/articles/PMC4183422?pdf=render |
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