Categories: Nervous system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 613115 (trait) , 613114 (gene)

Links to relevant human diseases in MONDO:

• MONDO:0013142: neuropathy, hereditary sensory and autonomic, type 2B

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: Sensory neuropathy; hereditary sensory and autonomic neuropathy

Species-specific symbol: SN; HSAN

Molecular basis: Forman et al. (2016): "6.47 Mb inversion [omia.variant:752] was identified with breakpoints in intron 3 of FAM134B (chr4:86,910,352) and in an upstream intergenic region (chr4:80,439,639) . . . All three cases were homozygous for the inversion and all 170 controls homozygous for the reference allele." Amengual-Batle et al. (2018) reported the same variant in two affected mixed-breed dogs. 
Gutierrez-Quintana et al. (2021): "Whole genome sequencing identified a missense variant in the RETREG1 [also called Fam134B] (reticulophagy regulator 1) gene (c.656C > T, p.P219L) [omia.variant:1342]. All [three] affected [mixed breed] dogs were homozygous for the variant, which was not detected in 1193 dogs from different breeds." Letko et al. (2024) conducted whole genome sequencing on a purebred German Spitz with acral mutilation syndrome and identified the variant previously reported by Gutierrez-Quintana et al. (2021) (omia.variant:1342) as likely causal variant. "Haplotype analyses and targeted genotyping revealed a likely German Spitz ancestry of these mixed breed dogs" reported by Gutierrez-Quintana et al. (2021).

Clinical features: Forman et al. (2106): " Clinical signs start between two and seven months of age and include progressive proprioceptive ataxia with intermittent knuckling of the paws, hyperextension of the limbs, and self-mutilation wounds in the distal part of the limbs . . . . Usually, the pelvic limbs are more severely affected than the thoracic limbs. There is decreased or loss of proprioception and nociception in all limbs, and in some cases autonomic signs such as urinary incontinence and in the later stage regurgitation has also been reported (Vermeersch et al. 2005). Electrophysiological studies show decreased or absent sensory nerve compound action potentials, normal or reduced motor nerve conduction velocities and normal electromyography in the appendicular muscles." Gutierrez-Quintana et al. (2021): "Five related mixed breed puppies from 2 litters were presented over a 2-year period ... . All had a previous history of severe mutilation of the distal pelvic limbs and chronic progressive pelvic limb gait abnormalities. ... Electrodiagnostic testing was performed ... and abnormalities were limited to the absence of sensory nerve action potentials (SNAP) during sensory nerve stimulation."

Pathology: Gutierrez-Quintana et al. (2021): "No macroscopic changes were observed. Histopathological abnormalities were limited to the peripheral nerves, dorsal root ganglia, and autonomic ganglia. Nerve histology indicated moderate myelinated fiber loss and axonal features compatible with Wallerian degeneration with some dystrophic changes."

Breeds: Border Collie (Dog) (VBO_0200193), German Spitz (Dog) (VBO_0200585), Mixed Breed (Dog) (VBO_0200902).
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: