Categories: Muscle phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 156225 (gene) , 607855 (trait) , 618138 (trait)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2021

Species-specific symbol: LAMA2-RD, CMD

Species-specific description: Muscular dystrophy due to causal variants in LAMA2 is one of several inherited forms of muscular dystrophy in dogs.

Molecular basis: Christen et al. (2021) "sequenced the genome of the affected [Italian Greyhound] 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." Shelton et al. (2022) "describe a disease variant in LAMA2 in an [2-year-old FS Staffordshire terrier] ... dog resulting in laminin α2-deficient CMD." Whole genome sequencing analysis identified "a 2245 bp deletion (chr1:67,734,331-67,736,575) encompassing LAMA2 exon 5 .... This deletion was observed as an absence of read alignments over this region in the case sequence data, while abundant reads were aligned from the control sequence data." The LAMA2 gene encodes laminin subunit α2, also referred to as merosin. Together with the laminin subunits β1 and γ1 (encoded by LAMB1 and LAMC1 respectively), laminin α2 forms the T-shaped heterotrimeric extracellular glycoprotein laminin-211. All 15 distinct known forms of laminins serve two main purposes: They form a scaffold that connects the extracellular matrix to the cell surface and they act as attachment site for other proteins of the cellular matrix. Laminin-211 serves this function in the basement membrane around the muscle fibers of skeletal muscles and in peripheral nerves. It links to sarcolemmal α-dystroglycan and α7β1 integrin, building the dystrophin-glycoprotein complex, an essential element for sarcolemmal stability and muscle function.

Clinical features: "The affected [Italian Greyhound] 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. ... Physical examination revealed a poor body condition score (1/9) with generalized skeletal muscle atrophy. The dog would stand with mild kyphosis and valgus deformities. When ambulating the dog would maintain this posture, show a stiff pelvic limb gait with limited flexion of both stifles and hocks, and would externally rotate both tarsi during the early swing phase while externally rotating the stifles during the postural stance phase. The patellar reflexes were decreased bilaterally and the withdrawal reflexes were mildly decreased in the thoracic limbs. ... At 8 months of age, the gait worsened with intermittent, bilateral pelvic limb lameness. A repeat orthopedic examination revealed grade 3 and grade 2 patellar luxation on the left and right pelvic limb, respectively. Body condition score remained poor at 2/9. The dog was still alive at the time of manuscript submission, at one year and six months of age. At that stage, he was occasionally stumbling in the thoracic limbs and was coping with two walks a day of approximately 1800 meters each. Occasionally, he was taken for approximately 4000 m walks on top of his regular walks, after which he seemed tired." (Christen et al. 2021). Shelton et al. (2022): "The [FS Staffordshire terrier] dog of this report presented for clinical evaluation at 2 years of age; however, clinical signs of weakness, stiff gait, and reduced jaw mobility had been present since the dog was adopted from a shelter at a few months of age. The history, neurological examination, increases in CK, electromyography abnormalities, and pathological changes on muscle biopsy were consistent with a chronic and progressive dystrophic myopathy. ... . Neither cranial nerve abnormalities nor behavioral changes were identified ..."

Pathology: Christen et al. (2021): "Biopsies [from the Italian Greyhound] were evaluated from the cranial tibial and gluteus muscles with similar changes in both muscles. A marked variability in myofiber size was observed with numerous atrophic fibers (diameters < 10 µm) and scattered hypertrophic fibers. Mild endomysial fibrosis, scattered myofibers containing internal nuclei, and occasional necrotic fibers undergoing phagocytosis were observed. The pattern of changes were consistent with a congenital myopathy with a dystrophic phenotype." Shelton et al. (2022): "A dystrophic phenotype was identified histologically in muscle biopsies [of the FS Staffordshire terrier], deficiency of laminin α2 protein was confirmed by immunofluorescent staining ..."

Breeds: Italian Greyhound (Dog) (VBO_0200713), Staffordshire Bull Terrier (Dog) (VBO_0201296).
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: