OMIA 001514-9615 : Acral mutilation syndrome in Canis lupus familiaris

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 223900 , 201300 , 608654 , 613115 , 614213

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 Shorthair Pointer.

Associated gene:

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

Variants

By default, variants are sorted chronologically by year of publication, to provide a historical perspective. Readers can re-sort on any column by clicking on the column header. Click it again to sort in a descending order. To create a multiple-field sort, hold down Shift while clicking on the second, third etc relevant column headers.

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.

Breed(s) Variant Phenotype Gene Allele Type of Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Year Published PubMed ID(s) Acknowledgements
English Pointer English Springer Spaniel French Spaniel German Shorthair Pointer Acral mutilation syndrome GDNF regulatory "an “in-house” improved annotation of the CanFam 3 genome assembly" (Correard et al., 2017) 4 g.70,875,561C>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 The genomic coordinate was provided by Correard et al. (2017)

References


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 :, 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 zehernekrose bei kurghaarigen. Vorstehlunden Kleintierproxis 9:76 only, 1964.

Edit History


  • Created by Frank Nicholas on 28 Feb 2011
  • Changed by Frank Nicholas on 31 Dec 2016
  • Changed by Frank Nicholas on 09 Apr 2019