The dominant form of LAMA5 syndrome is caused by c.9418G>A (p.Val3140Met) missense mutation located in the LG3 globular domain, at C-terminal region of the protein (Sampaolo S et al., J Med Genet 2017). The p.V3140M mutation perturbs the LAMA5 protein cleavage and also modifies the expression profile of extracellular matrix genes involved in tissue repair, wound healing and inflammation in mutated fibroblast cell cultures. These findings suggest the critical role of LAMA5 as regulative and signalling molecule involved in the organization of the histoarchitecture (cellular density and orientation) of body tissues, in homeostasis maintenance and in the cellular turnover and regeneration processes by interacting with other ECM molecules, circulating hormones and vitamins, inflammatory cytokines and neuroimmunomodulator factors.
Targeted sequencing genes for congenital connective tissue diseases including also LAMA5 gene is advised.
The recessive form of LAMA5 syndrome is associated to c.8046C > T (p.Arg2659Trp) homozygous missense mutation (Maselli et al. Am J Med Genet A 2017; Maselli et al. Ann N Y Acad Sci 2018), located in the domain II of the protein involved in the coil-coiled structure. This mutation caused decreased binding of laminin α5 to Synaptic vesicle glycoprotein 2A (SV2A) and impaired laminin-521 cell adhesion and cell projection support in primary neuronal cultures. These results confirm the key role of LAMA5 in signalling, cell adhesion, in the organization of tissue architecture, in the neurite outgrowth.
Targeted sequencing genes for congenital myasthenia, including LAMA5 gene mutation screening, is necessary.