LAMA2 Nonsense Variant in an Italian Greyhound with Congenital Muscular Dystrophy.
Matthias ChristenVictoria IndzhovaLing T GuoVidhya JagannathanTosso LeebG Diane SheltonJosep BrocalPublished in: Genes (2021)
A 4-month-old, male Italian Greyhound with clinical signs of a neuromuscular disease was investigated. The affected dog presented with an abnormal short-strided gait, generalized muscle atrophy, and poor growth since 2-months of age. Serum biochemistry revealed a marked elevation in creatine kinase activity. Electrodiagnostic testing supported a myopathy. Histopathology of muscle biopsies confirmed a dystrophic phenotype with excessive variability in myofiber size, degenerating fibers, and endomysial fibrosis. A heritable form of congenital muscular dystrophy (CMD) was suspected, and a genetic analysis initiated. We sequenced the genome of the affected dog and compared the data to that of 795 control genomes. This search revealed a private homozygous nonsense variant in LAMA2, XM_022419950.1:c.3285G>A, predicted to truncate 65% of the open reading frame of the wild type laminin α2 protein, XP_022275658.1:p.(Trp1095*). Immunofluorescent staining performed on muscle cryosections from the affected dog confirmed the complete absence of laminin α2 in skeletal muscle. LAMA2 loss of function variants were shown to cause severe laminin α2-related CMD in humans, mouse models, and in one previously described dog. Our data together with current knowledge on other species suggest the LAMA2 nonsense variant as cause for the CMD phenotype in the investigated dog.
Keyphrases
- muscular dystrophy
- skeletal muscle
- duchenne muscular dystrophy
- wild type
- healthcare
- mouse model
- electronic health record
- single cell
- atomic force microscopy
- minimally invasive
- type diabetes
- early onset
- weight gain
- copy number
- adipose tissue
- small molecule
- metabolic syndrome
- data analysis
- drug induced
- protein kinase
- physical activity
- artificial intelligence
- amino acid
- protein protein
- single molecule