OMIA:001917-9615 : Polyneuropathy, ARHGEF10-related in Canis lupus familiaris
Categories: Nervous system phene
Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 608236 (trait) , 608136 (gene)
Links to MONDO diseases: No links.
Mendelian trait/disorder: yes
Mode of inheritance: Probably autosomal recessive
Considered a defect: yes
Key variant known: yes
Year key variant first reported: 2014
Cross-species summary: An inherited polyneuropathy observed in Leonberger and Saint Bernard 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 polyneuropathy, characterized by exercise intolerance, gait abnormalities and muscle atrophy of the pelvic limbs, as well as inspiratory stridor and dyspnea.
Species-specific name: polyneuropathy
Species-specific symbol: LPN1; also known as ILPN (Jäderlund et al., 2011)
Species-specific description: An inherited polyneuropathy (PN) observed in Leonberger and Saint Bernard dogs has clinical similarities to a genetically heterogeneous group of peripheral neuropathies termed Charcot-Marie-Tooth (CMT) disease in humans. The 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.
History: Variants in other genes have been associated with other forms of polyneuropathy and/or laryngeal paralysis in various breeds: OMIA 002222-9615 (RAPGEF6), OMIA 002119-9615 (GJA9), OMIA 001970-9615 (RAB3GAP1), OMIA 002284-9615 (SBF2), OMIA 002301-9615 (CNTNAP1). References relating to polyneuropathies and laryngeal paralysis in dogs without known genetic associations are listed under OMIA 001292-9615 and OMIA 001206-9615, respectively.
Mapping: A GWAS on 52 affected and 41 control Leonbergers, each genotyped with the Illumina CanineHD BeadChip (yielding 101,284 informative SNPs) enabled Ekenstedt et al. (2014) to map this disorder to a region of chromosome CFA16, with the strongest association at 57,375,008 bp (CanFam2). Homozygosity mapping identified a 250kb region.
Molecular basis: Of the two genes in the candidate region (see mapping section), one (ARHGEF10) was a comparative candidate (see OMIM link above). Sequencing of this gene in affecteds and controls enabled Ekenstedt et al. 92014) to identify "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".
Clinical features: As summarised by Ekenstedt et al. (2014), this disorder in the Leonberger breed "is characterized by generalized weakness, hypotonia, and muscle atrophy secondary to denervation, particularly of the pelvic limbs . . . . Affected dogs frequently present with a high-stepping pelvic limb gait (pseudo-hypermetria of the hock) . . . , decreased or absent tendon reflexes, and changes associated with degeneration of the recurrent laryngeal nerve, including inspiratory stridor resulting from laryngeal paralysis. The age-of-onset of clinical signs can vary from <1 year up to 11 years of age; however, the juvenile-onset patients typically have a more severe and rapidly progressing course of disease. Peroneal nerve biopsies show decreased myelinated fiber density resulting from axonal degeneration and endoneurial fibrosis indicative of chronic nerve fiber loss. Cranial tibial muscle biopsies demonstrate neurogenic atrophy and fatty replacement of muscle fibers indicative of chronic denervation".
Breeds: Leonberger, Saint Bernard.
|Symbol||Description||Species||Chr||Location||OMIA gene details page||Other Links|
|ARHGEF10||Rho guanine nucleotide exchange factor (GEF) 10||Canis lupus familiaris||16||NC_051820.1 (61970321..61881132)||ARHGEF10||Homologene, Ensembl , NCBI gene|
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WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.
Since October 2021, OMIA includes a semiautomated lift-over pipeline to facilitate updates of genomic positions to a recent reference genome position. These changes to genomic positions are not always reflected in the ‘acknowledgements’ or ‘verbal description’ fields in this table.
|OMIA Variant ID||Breed(s)||Variant Phenotype||Gene||Allele||Type of Variant||Source of Genetic Variant||Reference Sequence||Chr.||g. or m.||c. or n.||p.||Verbal Description||EVA ID||Inferred EVA rsID||Year Published||PubMed ID(s)||Acknowledgements|
|960||Leonberger Saint Bernard||Polyneuropathy, ARHGEF10-related||ARHGEF10||deletion, small (<=20)||Naturally occurring variant||CanFam3.1||16||g.54349199_54349208del||c.1955_1958+6del||XM_005630036.3; XP_005630093.1; published as c.1955_1958+6delCACGGTGAGC - eliminating the 3'-splice junction of exon 17 and creating an alternate splice site leading to a truncated protein||2014||25275565||Genomic coordinates in CanFam3.1 provided by Robert Kuhn|
Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
|2014||Ekenstedt, K.J., Becker, D., Minor, K.M., Shelton, G.D., Patterson, E.E., Bley, T., Oevermann, A., Bilzer, T., Leeb, T., Drögemüller, C., Mickelson, J.R. :|
|An ARHGEF10 deletion is highly associated with a juvenile-onset inherited polyneuropathy in Leonberger and Saint Bernard dogs. PLoS Genet 10:e1004635, 2014. Pubmed reference: 25275565 . DOI: 10.1371/journal.pgen.1004635.|
|2011||Granger, N. :|
|Canine inherited motor and sensory neuropathies: an updated classification in 22 breeds and comparison to Charcot-Marie-Tooth disease. Vet J 188:274-85, 2011. Pubmed reference: 20638305 . DOI: 10.1016/j.tvjl.2010.06.003.|
|Hultin Jäderlund, K., Baranowska Körberg, I., Nødtvedt, A. :|
|Inherited polyneuropathy in Leonberger dogs. J Vet Intern Med 25:997-1002, 2011. Pubmed reference: 21985135 . DOI: 10.1111/j.1939-1676.2011.00785.x.|
|2003||Shelton, G.D., Podell, M., Poncelet, L., Schatzberg, S., Patterson, E., Powell, H.C., Mizisin, A.P. :|
|Inherited polyneuropathy in Leonberger dogs: a mixed or intermediate form of Charcot-Marie-Tooth disease? Muscle & Nerve 27:471-7, 2003. Pubmed reference: 12661049 . DOI: 10.1002/mus.10350.|
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