OMIA:001514-9615 : Acral mutilation syndrome in Canis lupus familiaris
Categories: Nervous system phene
Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 223900 (trait) , 201300 (trait) , 608654 (trait) , 613115 (trait) , 614213 (trait) , 600837 (gene)
Links to MONDO diseases: No links.
Mendelian trait/disorder: yes
Mode of inheritance: Autosomal recessive
Considered a defect: yes
Key variant known: yes
Year key variant first reported: 2016
Species-specific name: hereditary sensory neuropathy
Species-specific symbol: AMS
Inheritance: Correard et al. (2017): "a large pedigree of French spaniels was first drafted; careful analysis of this pedigree revealed a recessive autosomal mode of inheritance, as previously described (Paradis et al. 2005)"
Mapping: Plassais et al. (2016) "highlighted a common homozygous haplotype of 1.8 Mb (chr4:70,6–72,4Mb) shared by all affected dogs in the four sporting breeds", namely German Shorthaired Pointers, English Pointers, English Springer Spaniel and French Spaniel.
Molecular basis: "Targeted high-throughput sequencing of [the positional candidate segment] in 4 affected and 4 unaffected dogs" enabled Plassais et al. (2016) to identify 478 variants, only one of which "perfectly segregated with the expected recessive inheritance in 300 sporting dogs of known clinical status, while it was never present in 900 unaffected dogs from 130 other breeds. This variant, located 90 kb upstream of the GDNF gene, a highly relevant neurotrophic factor candidate gene, lies in [the last exon of] a long intergenic non-coding RNAs (lincRNA), GDNF-AS." The authors also reported that " Functional analyses (qRT-PCR, EMSA) confirmed that the mutation alters the binding of regulatory complex, leading to a significant decrease of both GDNF and GDNF-AS mRNA expression levels." Correard et al. (2017) provided additional information about this same variant: "The variant (chr4.g.70,875,561C>T) is located in an intergenic region, 90 kb upstream of GDNF, known to be involved in the regulation of sensory neuron . . . . Using an “in-house” improved annotation of the CanFam 3 genome assembly, the presence of a long non-coding RNA (lncRNA) was detected in the vicinity of GDNF . . . . Interestingly, the variant is located in the last exon of this lncRNA, potentially regulating GDNF."
Clinical features: As summarised by Plassais et al. (2016): " Clinical signs appear in young puppies and consist of acral analgesia, with or without sudden intense licking, biting and severe self-mutilation of the feet, whereas proprioception, motor abilities and spinal reflexes remain intact"
Prevalence: Correard et al. (2017): "This mutation [chr4.g.70,875,561C>T] is responsible for insensitivity to pain in four sporting dog breeds and it perfectly segregates with the disease in 250 sporting dogs of known clinical status. Moreover, it was not found in any of the 900 unaffected dogs from 130 different breeds."
Breeds: English Pointer, English Springer Spaniel, French Spaniel, German Shorthaired Pointer.
|Symbol||Description||Species||Chr||Location||OMIA gene details page||Other Links|
|GDNF||glial cell derived neurotrophic factor||Canis lupus familiaris||4||NC_006586.3 (70966694..70991860)||GDNF||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|
|444||English Pointer English Springer Spaniel French Spaniel German Shorthaired Pointer||Acral mutilation syndrome||GDNF||regulatory||Naturally occurring variant||CanFam3.1||4||g.70875561C>T||"This variant, located 90 kb upstream of the GDNF gene, a highly relevant neurotrophic factor candidate gene, lies in [the last exon of] a long intergenic non-coding RNAs (lincRNA), GDNF-AS."||2016||28033318|
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.
|2019||Correard, S., Plassais, J., Lagoutte, L., Botherel, N., Thibaud, J.L., Hédan, B., Richard, L., Lia, A.S., Delague, V., Mège, C., Mathis, S., Guaguère, E., Paradis, M., Vallat, J.M., Quignon, P., André, C. :|
|Canine neuropathies: powerful spontaneous models for human hereditary sensory neuropathies. Hum Genet 138:455-466, 2019. Pubmed reference: 30955094 . DOI: 10.1007/s00439-019-02003-x.|
|2017||Correard, S., Plassais, J., Lagoutte, L., Paradis, M., Guagère, E., Quignon, P., Derrien, T., André, C. :|
|A spontaneous dog model for a human sensory neuropathy: identification of a mutation in the upstream region of a neurotrophic factor. Bull Acad Vét Fr 169:190-194, 2017. DOI: 10.4267/2042/61953.|
|2016||Plassais , J., Lagoutte, L., Correard, S., Paradis, M., Guaguère, E., Hédan, B., Pommier, A., Botherel, N., Cadiergues, M.-C., Pilorge, P., Silversides, D., Bizot, M., Samuels, M., Arnan, C., Johnson, R., Hitte, C., Salbert, G., Méreau, A., Quignon, P., Derrien, T., André, C. :|
|A point mutation in a lincRNA upstream of GDNF is associated to a canine insensitivity to pain: A spontaneous model for human sensory neuropathies. PLoS Genetics 12:e1006482, 2016. Pubmed reference: 28033318 . DOI: 10.1371/journal.pgen.1006482.|
|2010||Bardagí, M., Montoliu, P., Ferrer, L., Fondevila, D., Pumarola, M. :|
|Acral mutilation syndrome in a miniature pinscher. J Comp Pathol 144:235-8, 2010. Pubmed reference: 20961556 . DOI: 10.1016/j.jcpa.2010.08.014.|
|2005||Paradis, M., de Jaham, C., Page, N., Sauve, F., Helie, P. :|
|Acral mutilation and analgesia in 13 French spaniels. Vet Dermatol 16:87-93, 2005. Pubmed reference: 15842538 . DOI: 10.1111/j.1365-3164.2005.00443.x.|
|1984||Cummings, J.F. , de Lahunta, A., Simpson, S.T., McDonald, J.M. :|
|Reduced substance P-like immunoreactivity in hereditary sensory neuropathy of pointer dogs. Acta Neuropathol. 63:33-40, 1984. Pubmed reference: 6203326 .|
|1983||Cummings, JF., de Lahunta, A., Braund, KG., Mitchell, WJ. :|
|Hereditary sensory neuropathy. Nociceptive loss and acral mutilation in pointer dogs: canine hereditary sensory neuropathy. Am J Pathol 112:136-8, 1983. Pubmed reference: 6574711 .|
|1981||Cummings, JF., de Lahunta, A., Winn, SS. :|
|Acral mutilation and nociceptive loss in English pointer dogs. A canine sensory neuropathy. Acta Neuropathol 53:119-27, 1981. Pubmed reference: 6259871 .|
|1973||Pivník, L. :|
|[Comparative problems of acrodystrophic neuropathies in man and dogs]. Schweiz Arch Neurol Neurochir Psychiatr. 112:365–371, 1973. Pubmed reference: 4725277 .|
|1964||Sanda, A., Pivník, L. :|
|Die Zehennekrose bei kurzhaarigen Vorstehhunden. Kleintierpraxis 9:76-83, 1964.|
- Created by Frank Nicholas on 28 Feb 2011
- Changed by Frank Nicholas on 31 Dec 2016
- Changed by Frank Nicholas on 09 Apr 2019
- Changed by Imke Tammen2 on 16 Aug 2021