Disease relevance of LAMP2

• Here, we report that neisseria infection also reduces the levels of three other lysosomal markers: LAMP2, lysosomal acid phosphatase (LAP), and CD63 [1].
• CONCLUSIONS: LAMP2 mutations may account for a significant proportion of cases of HCM in children, especially when skeletal myopathy and/or WPW is present, suggesting that Danon disease is an underrecognized entity in the pediatric cardiology community [2].
• The teenage sister of the proband is a carrier of the same LAMP2 mutation and has HCM without skeletal myopathy or WPW [2].
• CONCLUSIONS: LAMP2 mutations typically cause multisystem glycogen-storage disease (Danon's disease) but can also present as a primary cardiomyopathy [3].
• Clinical features associated with defects in LAMP2 included male sex, severe hypertrophy, early onset (at 8 to 17 years of age), ventricular preexcitation, and asymptomatic elevations of two serum proteins [3].

Psychiatry related information on LAMP2

• Danon disease, an X-linked dominant disorder, results from mutations in the lysosome-associated membrane protein-2 (LAMP2) gene and presents with hypertrophic cardiomyopathy, skeletal myopathy, and mental retardation [4].

High impact information on LAMP2

• 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 [5].
• Primary LAMP-2 deficiency causes X-linked vacuolar cardiomyopathy and myopathy (Danon disease) [5].
• Overexpression of Lamp-2 isoform A (Lamp-2a), an established component of chaperone-mediated autophagy, enhanced cytoplasmic autoantigen presentation [6].
• Furthermore, there is evidence that LAMP-2 functions in chaperone-mediated autophagy [7].
• Knockout of LAMP-2 in mice has revealed roles for LAMP-2 in lysosomal enzyme targeting, autophagy and lysosomal biogenesis [7].

Chemical compound and disease context of LAMP2

• Lamp-1 and Lamp-2 immunoreactivity was present at the luminal side of the ductal carcinoma cells whereas Mac-2-BP immunoreactivity was diffusely spread over the whole cytoplasm and the nucleolus of ductal carcinoma cells [8].

Biological context of LAMP2

• Serum and amino acid-starved LAMP2-negative cells exhibited an accumulation of autophagic vacuoles and then succumbed to cell death with hallmarks of apoptosis such as loss of the mitochondrial transmembrane potential, caspase activation and chromatin condensation [9].
• Here, we show that inactivation of LAMP2 by RNA interference or by homologous recombination leads to autophagic vacuolization in nutrient-depleted cells [9].
• BACKGROUND: Mutations in sarcomere protein, PRKAG2, LAMP2, alpha-galactosidase A (GLA), and several mitochondrial genes can cause rare familial cardiomyopathies, but their contribution to increased left ventricular wall thickness (LVWT) in the community is unknown [10].
• Lysosome-associated membrane proteins h-LAMP1 (CD107a) and h-LAMP2 (CD107b) are activation-dependent cell surface glycoproteins in human peripheral blood mononuclear cells which mediate cell adhesion to vascular endothelium [11].
• These results clearly indicate that human lamp-1 and lamp-2 are coded by separate genes on different chromosomes [12].

Anatomical context of LAMP2

• Cells that lack LAMP2 expression showed an enhanced accumulation of vacuoles carrying the marker LC3, yet a decreased colocalization of LC3 and lysosomes, suggesting that the fusion between autophagic vacuoles and lysosomes was inhibited [9].
• While a fraction of mitochondria from starved LAMP2-expressing cells colocalized with lysosomal markers, within autophagolysosomes, no such colocalization was found on removal of LAMP2 from the experimental system [9].
• METHODS AND RESULTS: LAMP2 was amplified from genomic DNA isolated from peripheral lymphocytes of 50 patients diagnosed with HCM and analyzed by direct DNA sequencing [2].
• Six sarcomere gene mutations were found in 7 samples; no samples contained mutations in GLA, PRKAG2, or LAMP2 [13].
• Functional analysis utilizing a fluorescence-based adhesion assay revealed that cell surface lamp2 mediates adhesion of PBMCs to vascular endothelium, possibly by interacting with endothelial selectins [11].

Associations of LAMP2 with chemical compounds

• This analysis has confirmed the presence of a CpG island and has identified the first exon of the human LAMP2 gene, encoding a glycoprotein of the lysosomal membrane [14].
• Newly synthesized lysosomal membrane glycoproteins lamp-1 and lamp-2 are primarily sorted at the trans-Golgi network (TGN) by recognition of a tyrosine-based signal sequence in their cytoplasmic tails [15].
• Sorting of lysosomal membrane glycoproteins lamp-1 and lamp-2 into vesicles distinct from mannose 6-phosphate receptor/gamma-adaptin vesicles at the trans-Golgi network [15].
• The deduced amino acid sequences indicate that h-lamp-1 and h-lamp-2 consist of 416 and 408 amino acid residues, respectively, and suggest that 27 and 28 NH2-terminal residues are cleavable signal peptides [16].
• HL-60 cells were induced to differentiate into granulocytic cells by dimethyl sulfoxide, and structures of Asn-linked oligosaccharides attached to lysosomal membrane glycoproteins (lamp-1 and lamp-2) were elucidated before and after differentiation [17].

Physical interactions of LAMP2

• The bacteria bound readily to Lamp-1 while there was almost no binding to Lamp-2 [18].

Co-localisations of LAMP2

• In fact immunocytochemical studies in transduced oligodendrocytes revealed that the GALC colocalizes in vesicles lysosomal-associated membrane protein-2 (LAMP2) (+) [19].

Regulatory relationships of LAMP2

• Immunological techniques were used to examine the localization of LAMP-2 in control platelets and those from an individual with Hermansky-Pudlak syndrome (HPS), a condition characterised by platelet dense granule deficiency [20].

Other interactions of LAMP2

• Kinetic analysis revealed that the majority of the increase in both lamp1 and lamp2 occurred within the first 2 hr of incubation and that a subset of PBMCs maintained expression for at least 96 hr [11].
• Genetic analyses of 20 subjects with massive hypertrophy (left ventricular wall thickness, > or =30 mm) but without electrophysiological abnormalities revealed mutations in neither LAMP2 nor PRKAG2 [3].
• The findings are consistent with the results obtained by endo-beta-N-acetylglucosaminidase F treatment of h-lamp-1 and h-lamp-2 precursors, described in the preceding paper (Carlsson, S. R., Roth, J., Piller, F., and Fukuda, M. (1988) J. Biol. Chem. 263, 18911-18919) [16].
• In contrast, the BACE-LL/AA mutant, in which Leu(499) and Leu(500) in the COOH-terminal sequence (DDISLLK) were replaced by alanines, only partially co-localized with LAMP2-positive compartments following inhibition of lysosomal hydrolases [21].
• Furthermore, the selective degradation of LAMP-1 and LAMP-2, as well as LIMP-2, was also observed by treatment of the lysosomal membrane fraction isolated from wild-type macrophages with purified cathepsin E at pH 5 [22].

Analytical, diagnostic and therapeutic context of LAMP2

• This was accompanied by a reduced expression of the lysosome-associated proteins 1 and 2 (LAMP1 and LAMP2) as determined by both microscopy and Western blot analysis [23].
• RESULTS: On flow cytometry, all mast cells expressed LAMP-3 at their cell membranes, whereas LAMP-1 and LAMP-2 were barely detectable (HMC-1 cells) or expressed at low levels (<10% of skin mast cells) [24].
• I-cells analyzed by immunofluorescence microscopy with monoclonal antibodies against hLAMP-1 and hLAMP-2 showed intense staining of the inclusion bodies covering most of the cytoplasm of the cells [25].
• Immunofluorescence confocal microscopy of ABCA1-wt showed both plasma membrane localization and substantial co-localization with LAMP2 in late endosomes [26].
• The combination of myopathy and cardiomyopathy, the biochemical and electron microscopy findings in a muscle biopsy, and the pedigree suggested Danon disease (MIM 300257), an X-linked lysosomal storage disorder caused by deficiency of lysosome-associated membrane protein-2 (LAMP2) [27].

References