LAMA2 Nonsense Variant in an Italian Greyhound with Congenital Muscular Dystrophy.

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...

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Bibliographic Details
Published in:Genes
Main Authors: Christen, Matthias, Indzhova, Victoria, Guo, Ling, Jagannathan, Vidhya, Leeb, Tosso, Shelton, G, Brocal, Josep
Format: Article in Journal/Newspaper
Language:unknown
Published: eScholarship, University of California 2021
Subjects:
Canis lupus familiaris
animal model
dog
laminin
merosin
muscle
neuromuscular disease
precision medicine
Animals
Codon
Nonsense
Dog Diseases
Dogs
Homozygote
Male
Skeletal
Muscular Dystrophy
Animal
Canis lupus
Online Access:https://escholarship.org/uc/item/52x6f92s
https://escholarship.org/content/qt52x6f92s/qt52x6f92s.pdf
https://doi.org/10.3390/genes12111823
Description
Summary: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.

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