Categories: Muscle phene

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 254090 (trait) , 120220 (gene)

Links to MONDO diseases: No links.

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2015

Cross-species summary: Severe muscle dystrophy, due to variants in the genes encoding subunits of collagen VI.

Species-specific name: Muscular Dystrophy

Species-specific symbol: UCMD

History: Steffen et al. (2015) described the clinics, pathology, and molecular genetics of Landseer dogs with a severe muscular dystrophy. An earlier report described a myopathic Labrador Retriever, in which antibody staining of sections from a muscle biospy showed reduced sarcolemmal collagen VI protein expression (Marioni-Henry et al. 2014). The molecular genetic defect in the Labrador Retriever was later identified to be caused by mutations in a different gene - see OMIA 002274-9615 : Muscular dystrophy, COL6A3-related in Canis lupus familiaris for more detail. This myopathic Labrador Retriever showed a milder clinical phenotype than the Landseer dogs with muscular dystrophy (Steffen et al. 2015).

Mapping: Steffen et al. (2015) used one complete Landseer family with 3 affected and 3 non-affected offspring and one additional distantly related affected Landseer to map the disease causing variant. Using a combination of linkage and homozygosity mapping they narrowed the most likely postions for the causative variant to two genome segments on chromosome 10 and 31 comprising a total of 4.8 Mb. The specific critical intervals were defined as Chr10:61,871,450 - 66,047,210 and Chr31:38,752,158 - 39,364,930 (CanFam 3 assembly).

Molecular basis: Steffen et al. (2015) sequenced the complete genome of an affected Landseer at 14.2x coverage. The dog had ~2.8 million homozygous variants compared to the Boxer reference genome. When concentrating on the critical intervals and comparing the data to 170 dog genomes from control dogs of other breeds, only one private non-synonymous variant remained in the affected Landseer, a nonsense variant in the COL6A1 gene on chromosome 31, c.289G>T or p.Glu97*. This variant perfectly co-segregated with the phenotype in cohort of 58 Landseer dogs including 5 affected dogs.

Collagen VI is made up of three different subunits encoded by the COL6A1, COL6A2, and COL6A3 genes. Variants abolishing the function of either these genes lead to a severe muscular dystrophy phenotype in humans, the so-called Ullrich congenital muscular dystrophy. Based on the knowledge from humans, the identified canine COL6A1 nonsense variant seemed a very likely candidate causative variant for the Landseer disease. Steffen et al. (2015) genotyped 404 Newfoundland dogs and 473 dogs from diverse other breeds and did not find the mutant allele in these breeds.

Clinical features: Generalized progressive muscle weakness is noticed very early in life. Due to the severity of the disease affected dogs are euthanized at 5-15 months of age (Steffen et al. 2015).

Brands et al. (2020) "present the long-term follow up characterization of the clinical and pathological phenotype of the Landseer dogs [homozgous for the p.Glu97* variant] and a comparative analysis between dogs and humans in order to provide the Landseer dog as a useful model for human UCMD".

Pathology: "All affected dogs showed pathological variation in muscle fiber size and most of the fibers were round to anisomorphic instead of having a (physiological) polygonal shape. Many small fibres were scattered throughout the biopsies, along with some hypercontracted fibres. Sporadically invading phagocytes grouped around degenerating fibers. Staining for acidic phosphatase showed an increase of activity, indicating degeneration to necrosis in a large number of fibres. Some biopsies correlated to an advanced stage of disease with distinct proliferation of the endomysial connective tissue and an increase of adipose tissue. These findings demonstrate different stages of muscular destruction with compensatory hypertrophy and replacement of lost fibers by connective tissue and fat cells. The histhopathological findings were typical for a muscular dystrophy. However, relatively normal immunohistochemistry findings with an anti-dystrophin antibody clearly showed that the muscular dystrophy in the Landseer dogs is different from the Duchenne/Becker type." (Steffen et al. 2015)

Breed: Landseer.

Associated gene: