Congenital muscular dystrophies

Merosin-deficient congenital muscular dystrophy (LAMA2-RD) is a neuromuscular disorder caused by mutations in the LAMA2 gene, coding for the alpha2 subunit of laminin-211 (merosin). LAMA2-RD patients carrying LAMA2 loss-of-function mutations lack merosin and their invariably severe clinical phenotype is characterised by the inability to acquire ambulation. A wider and often milder spectrum of disease severity results from missense mutations if they allow the production of a partially functional protein. To date, only one LAMA2-RD patient was reported with a very mild phenotype despite the total absence of merosin in muscle. This patient is still ambulant in the 4th decade of life with no respiratory insufficiency nor cardiomyopathy. Interestingly, this patient carries the same LAMA2 loss-of-function mutation as a severely affected sibling. We hypothesized that genetic modifier(s) in the atypical patient mitigate the consequences of the complete merosin deficiency via a novel mechanism. We performed RNA-sequencing on muscle samples obtained from the atypical patient, the affected sibling and unrelated LAMA2-RD patients with both total and partial merosin deficiency. Transcriptome analysis showed a similar LAMA2 gene expression in the atypical patient, the affected sibling and patients with absent merosin. A limited number of genes differentially expressed in the atypical patient affect pathways that could be relevant for the observed divergence of phenotype. We plan to study the role of possible candidate modifier(s)/pathway(s) in vivo in the candyfloss zebrafish model and shed more light on the mechanism responsible for the attenuated LAMA2-RD severity. New knowledge about the molecular aspects of the disease could lead to the development of new therapeutic approaches for LAMA2-RD.