Primary LAMP-2 deficiency causes X-linked vacuolar cardiomyopathy and myopathy (Danon disease).
"Lysosomal glycogen storage disease with normal acid maltase" which was originally described by Danon et al., is characterized clinically by cardiomyopathy, myopathy and variable mental retardation. The pathological hallmark of the disease is intracytoplasmic vacuoles containing autophagic material and glycogen in skeletal and cardiac muscle cells. Sarcolemmal proteins and basal lamina are associated with the vacuolar membranes. Here we report ten unrelated patients, including one of the patients from the original case report, who have primary deficiencies of LAMP-2, a principal lysosomal membrane protein. From these results and the finding that LAMP-2-deficient mice manifest a similar vacuolar cardioskeletal myopathy, we conclude that primary LAMP-2 deficiency is the cause of Danon disease. To our knowledge this is the first example of human cardiopathy-myopathy that is caused by mutations in a lysosomal structural protein rather than an enzymatic protein.
Nishino
I
I
Department of Neurology, Columbia University, New York, New York 10032, USA. nishino@ncnp.go.jp
Fu
J
J
Tanji
K
K
Yamada
T
T
Shimojo
S
S
Koori
T
T
Mora
M
M
Riggs
J E
JE
Oh
S J
SJ
Koga
Y
Y
Sue
C M
CM
Yamamoto
A
A
Murakami
N
N
Shanske
S
S
Byrne
E
E
Bonilla
E
E
Nonaka
I
I
DiMauro
S
S
Hirano
M
M
D015703:Antigens, CD / Q000235:genetics / Q000502:physiology; D015153:Blotting, Western; D009202:Cardiomyopathies / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D004252:DNA Mutational Analysis; D005260:Female; D008040:Genetic Linkage; D006801:Humans; D007150:Immunohistochemistry; D016464:Lysosomal Storage Diseases / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D051907:Lysosomal Membrane Proteins; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009135:Muscular Diseases / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D017422:Sequence Analysis, DNA; D014617:Vacuoles / Q000473:pathology; D014960:X Chromosome
D015703:Antigens, CD; D051907:Lysosomal Membrane Proteins; D008562:Membrane Glycoproteins