Splicing mutation in LAMP2 gene leading to exon skipping and cardiomyopathy development

Mutations in LAMP2 (Xq24) encoding a lysosomal-associated membrane protein 2 crucial to the maintenance and adhesion of the lysosome cause a Danon disease. It is an X-linked glycogen storage disease that includes cardiomyopathy (hypertrophic or dilated), skeletal myopathy and mental retardation. Here, we report a woman, carrying the mutation c.864 + 1G > A (IVS6 + 1G > A, rs727503119) in heterozygosity and affected with late-onset dilated cardiomyopathy. We demonstrated the effects of the mutation on the splicing LAMP2 in cardiac muscle. The variant c.864 + 1G > A is located in the canonical splice donor site in intron 6. Functional analysis reveals that mutation c.864 + 1G > A leads to the skipping of exon 6 in cardiac muscle. The protein loses 41 amino acids in the second luminal domain of LAMP2 without frameshift and premature termination of protein synthesis. Using qRT-PCR we revealed a significantly low level of wild-type LAMP2 mRNA in patient that can be explained by X-inactivation.