Categories: Nervous system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 602377 (gene) , 616346 (trait)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2008

Species-specific symbol: EIC

Species-specific description: Exercise-induced collapse (EIC) is an inherited neuromuscular disorder characterized by exercise intolerance in otherwise healthy young adult dogs. Clinical signs are precipitated by strenuous exercise. A causative mutation in dynamin 1 has been identified in retriever breeds listed below, but not yet in Border Collies. [Edited by Vicki N. Meyers-Wallen, VMD, PhD, Dipl. ACT in 2011; revised by FN 29 Oct 2020]

History: EIC was first identified in Labrador Retrievers (Taylor et al., 2008).

Inheritance: Exercise-induced callapse in Labrador retrievers is a Mendelian trait. Norton et al. (2021) concluded that the disease in border collies (BCC) is a moderately- to highly-heritable complex polygenetic disease.

Mapping: A genome-wide scan with 459 microsatellites in six families of Labrador Retrievers mapped the disorder to 60.4Mb on CFA9 (Patterson et al., 2008) Norton et al. (2021) aimed to "estimate the heritability (h2SNP) of BCC [Border Collie Collapse], define its underlying genetic architecture, and identify associated genomic loci using dense whole-genome single-nucleotide polymorphism (SNP) genotyping data. Genotype data were obtained for ~440,000 SNPs from 343 border collies (168 BCC cases and 175 controls). ... Genome-wide association analyses identified significantly associated loci on chromosomes 1, 6, 11, 20, and 28, which accounted for ~5% of the total BCC h2SNP."

Molecular basis: The causative mutation in Labrador retrievers, Chesapeake Bay retrievers and curly-coated retrievers is a G to T substitution in exon 6 that changes the amino acid codon from arginine to leucine (R256L) in a highly conserved region of DNM1 (Patterson et al., 2008).

Clinical features: Affected dogs have normal muscle mass, normal patellar reflexes before an episode of EIC, normal findings on muscle biopsy and are capable of moderate exertion without showing signs (Taylor et al., 2008, Patterson et al., 2008). Signs begin within 2 minutes after cessation of 5 to 15 minutes of strenuous exercise. Affected dogs develop a wobbly gait with hindlimb weakness and incoordination, wide based stance, and walking with crouched hind legs. Signs can progress to full body weakness, extensor rigidity, confusion, loss of consciousness, and rarely death. Episodes frequently last 5-10 minutes, often with complete recovery after 30 minutes. Loss of patellar reflexes persists after initial recovery.

Pathology: Dynamin 1 is a type of GTPase that facilitates continuous neurotransmission across synapses. At the presynaptic terminal membrane, it assists in release of membrane vesicles containing neurotransmitter, which is needed for continuous synaptic communication (Patterson et al 2008). During high intensity exercise, DNM1 activity is inadequate to maintain synaptic transmission, which causes reversible loss of motor function (Patterson et al., 2008).

Prevalence: In a population of 400 Labrador Retrievers from the Midwestern US, 37% were carriers and 3% were homozygous for the causative mutation. This suggests a high frequency of this mutation in Labrador Retrievers. Homozygous Labrador Retrievers have also been found in Europe, the Middle East, and Australia (Patterson et al., 2008).

Control: It is recommended that working dogs or those showing signs be tested, as well as relatives of affected dogs. Breeding of homozygous dogs should be avoided. Breeding of carriers to noncarriers will avoid production of affected dogs. [updated 29 Oct 2020, with thanks to Frank Coopman]

Genetic testing: A test is available to detect carriers and homozygotes (Patterson et al, 2008).

Breeds: Border Collie (Dog) (VBO_0200193), Boykin Spaniel (Dog) (VBO_0200214), Chesapeake Bay Retriever (Dog) (VBO_0200326), Curly Coated Retriever (Dog) (VBO_0200397), Labrador Retriever (Dog) (VBO_0200800), Pembroke Welsh Corgi (Dog) (VBO_0200995).
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: