Categories: Nervous system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 223900 (trait) , 201300 (trait) , 608654 (trait) , 613115 (trait) , 614213 (trait) , 600837 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: 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 (Dog) (VBO_0200494), English Springer Spaniel (Dog) (VBO_0200497), French Spaniel (Dog) (VBO_0200548), German Shorthaired Pointer (Dog) (VBO_0200583), Miniature Pinscher (Dog) (VBO_0200893).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: