Categories: Nervous system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 602329 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2012

Species-specific description: Ataxia is characterized by uncoordinated movements and represents a relatively non-specific clinical sign. This entry describes an ataxia form that is caused by a genetic variant in the SEL1L gene. Phenotypically related ataxias in dogs may also be caused by variants in the ATP1B2, CAPN1, GRM1, ITPR1, KCNJ10, RAB24, SNX14, and SPTBN2 genes. Thus locus heterogeneity for this phenotype must be considered.

History: This type of ataxia was first reported by Tonttila and Lindberg (1971).

Mapping: As reported by Kyöstilä et al. (2012), "A genome-wide association study [GWAS] in a cohort of 31 dogs mapped the ataxia gene to a 1.5 Mb locus on canine chromosome 8".

Molecular basis: Kyöstilä et al. (2012) reported the causative mutation as being a "missense mutation, c.1972T>C; p.Ser658Pro, in a highly conserved protein domain" of the SEL1L gene, whose peptide is a "component of the endoplasmic reticulum (ER)–associated protein degradation (ERAD) machinery". Since mutations in this gene have not previously been reported in any species, this discovery provides a new potential candidate gene for human progressive childhood ataxias.

Clinical features: "Neurological examinations on ten affected dogs revealed rapidly progressing generalized cerebellar ataxia, tremors, and failure to thrive. Clinical signs were present by the age of 3 months, and cerebellar shrinkage was detectable through MRI." (Kyöstilä et al. (2012)

Pathology: "Pathological and histological examinations indicated cerebellum-restricted neurodegeneration. Marked loss of Purkinje cells was detected in the cerebellar cortex with secondary changes in other cortical layers." (Kyöstilä et al. (2012)

Control: A simple blood test is now available for detecting carriers of the causative mutation.

Breed: Finnish Hound (Dog) (VBO_0200522).
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: