Danon disease: a novel LAMP2 mutation affecting the pre-mRNA splicing and causing aberrant transcripts and partial protein expression.

LAMP2, the causative gene of Danon disease, located on chromosome Xq24, encodes the lysosome-associated membrane protein-2 (LAMP-2). We describe clinical features and molecular data in an Italian patient with Danon disease. The patient had hyperCKemia, hypertrophic cardiomyopathy, no muscle weakness and slight mental impairment. Muscle biopsy revealed autophagic vacuoles with sarcolemmal features and glycogen storage. Immunohistochemistry and immunoblot revealed traces of LAMP-2 protein in skeletal muscle. Molecular analysis of the LAMP2 gene revealed a novel hemizygous mutation affecting the invariant +1 position of the splice site of intron 8, resulting in aberrant transcripts with skipping of exon 8 in all three LAMP-2 isoforms, skipping of exons 7 and 8 in LAMP-2A and 2C, and a 15 bp deletion in exon 8 of LAMP-2B. Low levels of normal LAMP-2B transcript were also present. Danon disease is an under-recognized and frequently fatal condition, treatable by heart transplantation. Investigation of the primary molecular defect is important for cardiac surveillance and genetic counseling.