Categories: Nervous system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 614649 (gene) , 608984 (trait) , 619686 (trait)

Links to relevant human diseases in MONDO:

• MONDO:0030512: spastic paraplegia 85, autosomal recessive

Mendelian trait/disorder: yes

Mode of inheritance: Probably autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2024

Molecular basis: Cook et al. (2024) investigated neuroaxonal dystrophy in Miniature American Shepherd dogs and conducted "a genome-wide association study and autozygosity mapping approach, followed by whole-genome sequencing. ... The underlying genetic cause was identified as a 1-bp (base pair) deletion in RNF170 encoding ring finger protein 170, which perfectly segregates in an autosomal recessive pattern. This deletion is predicted to create a frameshift (XM_038559916.1:c.367delG) and early truncation of the RNF170 protein (XP_038415844.1:(p.Ala123Glnfs*11))."

Clinical features: Cook et al. (2024) reported that affected Miniature American Shepherd "dogs were typically young adults ... [displaying] varying degrees of hind limb weakness and ataxia, together with scuffing of the nails/dragging of digits. Kyphosis and a pacing/ambling gait were commonly reported. A cerebellar gait was also noted in several dogs. A few dogs had a reported change in behavior. Seizures were only reported in one dog ... . Overall, in the present cohort of MAS dogs from a wide international genetic pool, the onset of clinical signs was typically around the second year of life, although this varied somewhat between dogs; this variability, to an extent, depended on the astuteness of the owner's observations. Slowly progressive T3-L3 myelopathy signs were observed as the most common clinical presentation, with possible cervical, cerebellar, or forebrain signs also developing. Neither pain nor vestibular signs were reported in affected dogs. Gait abnormalities were always more obvious during the walk compared to faster gaits." The disease has a very slow progression and affected dogs may reach more than ten years of age. 

Pathology: Cook et al. (2024) reported histopathology from two affected Miniature American Shepherd dogs: "In both necropsied cases ... the evaluation of the brain and spinal cord showed widespread and bilateral neuroaxonal degeneration throughout the gray and white matter with the lateral cuneate nuclei in the brainstem being most severely affected ... . The neuroaxonal degeneration consisted of variable numbers of large, swollen, and hypereosinophilic axons (spheroids), dilated myelin sheaths, degenerated or dead neurons, and mixed gliosis. ... No other significant changes were seen in any of the organs evaluated."

Breed: Miniature American Shepherd (Dog) (VBO_0200880).
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: