Laminin a2 Merosin deficiency

In humans, mutations in the lama2 gene, which encodes laminin a2, cause merosin-deficient congenital muscular dystrophy 1A (MDC1A), one subset of a broad category of disease known as congenital muscular dystrophy (CMD). MDC1A is inherited in an autosomal recessive fashion. Laminin a2 is present in the basal lamina of skeletal muscle, as well as other cell types and combines with ß and g subunits to form laminin 2. A lack of laminin a2 results in a severe disease that includes hypotonia at birth, delayed motor development, an inability to walk, elevated CK levels and some structural and functional defects of the central white matter (Tomé et al 1994; Philpot et al. 1995).

Multiple murine models of laminin a2 deficiency have been identified. Michelson originally described the Dy mouse in 1955 as dystrophia muscularis (Michelson et al. 1955). The Dy2J mouse has a less severe phenotype, surviving into adulthood. The mutation in the Dy2J model was determined to be a G to A substitution in a splice donor site (Xu et al. 1994). This mutation results in abnormal splicing products, one of which is translated into a protein that is missing 55 amino acids. While this deletion does not interfere with trimerization with b and g subunits of laminin, it may prevent assembly into basement membranes. Dy3K mice were created by knockout technology and represent a severe phenotype, with death occurring around 5 weeks of age (Miyagoe 1997). Recently, a new lama2 mutation was described, nmf417, in which a point mutation substitutes Arg for Cys at position 79, disrupting a universally conserved CxxC motif in the N-terminal domain. These mice have similar muscle and nervous system signs to the other lama2 mutant mice but do not show disruption of the basal lamina (Patton et al. 2008).

Laminin a2 deficiency has been identified in both dogs and cats. In cats, affected breeds have been identified as Domestic Shorthair mix, Persian mix, Siamese, and Maine Coon Cat indicating the likelihood of at least 3-4 different mutations. The presence of the disease in mixed breed cats suggests that lama2 mutations might be present in multiple other breeds of cat as well. Affected cats present with a range of severity, including elevated CK levels, muscle atrophy, weakness, rigidity, especially of the pelvic limbs, tail and spine, and muscle contractures. Muscles of the affected cats show dystrophic changes and nerves show demyelination (O'Brien et al. 2001; Poncelet et al. 2003; Awamura et al. 2008).

Laminin a2 deficiency has been reported in a Brittany-Springer Spaniel mixed breed dog. This dog had a similar clinical presentation to humans and cats with this disease, including elevated serum CK, dystrophic changes in muscle biopsies, abnormal gait and muscle weakness (Shelton et al. 2001). As with the mixed breed cats, the presence of this disease in a mixed breed dog indicates that mutations of the canine lama2 gene may be present in at least 2 different breeds, although the ancestry of the affected dog is not discussed and inbreeding is also a potential reason for homozygosity.

Diagnosis of laminin a2 deficiency in both the dog and cats described above has been on the basis of antibody staining. As yet, no mutations have been published for these models. In addition, there is no indication that breeding colonies of dogs or cats with this disease have been established.

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