RBCC Red Blood Cell Collection

LAMP2 [Confidence: high (a blood group or CD marker)]
Lysosome-associated membrane glycoprotein 2; LAMP-2; Lysosome-associated membrane protein 2 (CD107 antigen-like family member B; CD107b; Flags: Precursor)

UniProt P13473
ID LAMP2_HUMAN Reviewed; 410 AA.
AC P13473; A8K4X5; D3DTF0; Q16641; Q6Q3G8; Q96J30; Q99534; Q9UD93;
read moreDT 01-JAN-1990, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-1996, sequence version 2.
DT 22-JAN-2014, entry version 156.
DE RecName: Full=Lysosome-associated membrane glycoprotein 2;
DE Short=LAMP-2;
DE Short=Lysosome-associated membrane protein 2;
DE AltName: Full=CD107 antigen-like family member B;
DE AltName: CD_antigen=CD107b;
DE Flags: Precursor;
GN Name=LAMP2;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM LAMP-2A), AND PROTEIN SEQUENCE OF
RP 29-64; 216-223 AND 238-256.
RX PubMed=3198605;
RA Fukuda M., Viitala J., Matteson J., Carlsson S.R.;
RT "Cloning of cDNAs encoding human lysosomal membrane glycoproteins, h-
RT lamp-1 and h-lamp-2. Comparison of their deduced amino acid
RT sequences.";
RL J. Biol. Chem. 263:18920-18928(1988).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM LAMP-2A).
RC TISSUE=Placenta;
RX PubMed=8517882;
RA Sawada R., Jardine K.A., Fukuda M.;
RT "The genes of major lysosomal membrane glycoproteins, lamp-1 and lamp-
RT 2. 5'-flanking sequence of lamp-2 gene and comparison of exon
RT organization in two genes.";
RL J. Biol. Chem. 268:9014-9022(1993).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM LAMP-2B), AND FUNCTION.
RC TISSUE=Fibroblast;
RX PubMed=8407947;
RA Fritz G., Dosch J., Thielmann H.W., Kaina B.;
RT "Molecular and cellular characterization of Mex-/methylation-resistant
RT phenotype. Gene and cDNA cloning, serum dependence, and tumor
RT suppression of transfectant strains.";
RL J. Biol. Chem. 268:21102-21112(1993).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM LAMP-2A).
RC TISSUE=Liver;
RX PubMed=7999007; DOI=10.1006/bbrc.1994.2620;
RA Konecki D.S., Foetisch K., Schlotter M., Lichter-Konecki U.;
RT "Complete cDNA sequence of human lysosome-associated membrane protein-
RT 2.";
RL Biochem. Biophys. Res. Commun. 205:1-5(1994).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM LAMP-2B).
RX PubMed=7488019; DOI=10.1006/bbrc.1995.2528;
RA Konecki D.S., Foetisch K., Zimmer K.P., Schlotter M.,
RA Lichter-Konecki U.;
RT "An alternatively spliced form of the human lysosome-associated
RT membrane protein-2 gene is expressed in a tissue-specific manner.";
RL Biochem. Biophys. Res. Commun. 215:757-767(1995).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM LAMP-2C).
RA Zhou D., Blum J.S.;
RT "Lamp-2 isoforms play different roles in lysosomal biogenesis.";
RL Submitted (FEB-2004) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM LAMP-2A).
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15772651; DOI=10.1038/nature03440;
RA Ross M.T., Grafham D.V., Coffey A.J., Scherer S., McLay K., Muzny D.,
RA Platzer M., Howell G.R., Burrows C., Bird C.P., Frankish A.,
RA Lovell F.L., Howe K.L., Ashurst J.L., Fulton R.S., Sudbrak R., Wen G.,
RA Jones M.C., Hurles M.E., Andrews T.D., Scott C.E., Searle S.,
RA Ramser J., Whittaker A., Deadman R., Carter N.P., Hunt S.E., Chen R.,
RA Cree A., Gunaratne P., Havlak P., Hodgson A., Metzker M.L.,
RA Richards S., Scott G., Steffen D., Sodergren E., Wheeler D.A.,
RA Worley K.C., Ainscough R., Ambrose K.D., Ansari-Lari M.A., Aradhya S.,
RA Ashwell R.I., Babbage A.K., Bagguley C.L., Ballabio A., Banerjee R.,
RA Barker G.E., Barlow K.F., Barrett I.P., Bates K.N., Beare D.M.,
RA Beasley H., Beasley O., Beck A., Bethel G., Blechschmidt K., Brady N.,
RA Bray-Allen S., Bridgeman A.M., Brown A.J., Brown M.J., Bonnin D.,
RA Bruford E.A., Buhay C., Burch P., Burford D., Burgess J., Burrill W.,
RA Burton J., Bye J.M., Carder C., Carrel L., Chako J., Chapman J.C.,
RA Chavez D., Chen E., Chen G., Chen Y., Chen Z., Chinault C.,
RA Ciccodicola A., Clark S.Y., Clarke G., Clee C.M., Clegg S.,
RA Clerc-Blankenburg K., Clifford K., Cobley V., Cole C.G., Conquer J.S.,
RA Corby N., Connor R.E., David R., Davies J., Davis C., Davis J.,
RA Delgado O., Deshazo D., Dhami P., Ding Y., Dinh H., Dodsworth S.,
RA Draper H., Dugan-Rocha S., Dunham A., Dunn M., Durbin K.J., Dutta I.,
RA Eades T., Ellwood M., Emery-Cohen A., Errington H., Evans K.L.,
RA Faulkner L., Francis F., Frankland J., Fraser A.E., Galgoczy P.,
RA Gilbert J., Gill R., Gloeckner G., Gregory S.G., Gribble S.,
RA Griffiths C., Grocock R., Gu Y., Gwilliam R., Hamilton C., Hart E.A.,
RA Hawes A., Heath P.D., Heitmann K., Hennig S., Hernandez J.,
RA Hinzmann B., Ho S., Hoffs M., Howden P.J., Huckle E.J., Hume J.,
RA Hunt P.J., Hunt A.R., Isherwood J., Jacob L., Johnson D., Jones S.,
RA de Jong P.J., Joseph S.S., Keenan S., Kelly S., Kershaw J.K., Khan Z.,
RA Kioschis P., Klages S., Knights A.J., Kosiura A., Kovar-Smith C.,
RA Laird G.K., Langford C., Lawlor S., Leversha M., Lewis L., Liu W.,
RA Lloyd C., Lloyd D.M., Loulseged H., Loveland J.E., Lovell J.D.,
RA Lozado R., Lu J., Lyne R., Ma J., Maheshwari M., Matthews L.H.,
RA McDowall J., McLaren S., McMurray A., Meidl P., Meitinger T.,
RA Milne S., Miner G., Mistry S.L., Morgan M., Morris S., Mueller I.,
RA Mullikin J.C., Nguyen N., Nordsiek G., Nyakatura G., O'dell C.N.,
RA Okwuonu G., Palmer S., Pandian R., Parker D., Parrish J.,
RA Pasternak S., Patel D., Pearce A.V., Pearson D.M., Pelan S.E.,
RA Perez L., Porter K.M., Ramsey Y., Reichwald K., Rhodes S.,
RA Ridler K.A., Schlessinger D., Schueler M.G., Sehra H.K.,
RA Shaw-Smith C., Shen H., Sheridan E.M., Shownkeen R., Skuce C.D.,
RA Smith M.L., Sotheran E.C., Steingruber H.E., Steward C.A., Storey R.,
RA Swann R.M., Swarbreck D., Tabor P.E., Taudien S., Taylor T.,
RA Teague B., Thomas K., Thorpe A., Timms K., Tracey A., Trevanion S.,
RA Tromans A.C., d'Urso M., Verduzco D., Villasana D., Waldron L.,
RA Wall M., Wang Q., Warren J., Warry G.L., Wei X., West A.,
RA Whitehead S.L., Whiteley M.N., Wilkinson J.E., Willey D.L.,
RA Williams G., Williams L., Williamson A., Williamson H., Wilming L.,
RA Woodmansey R.L., Wray P.W., Yen J., Zhang J., Zhou J., Zoghbi H.,
RA Zorilla S., Buck D., Reinhardt R., Poustka A., Rosenthal A.,
RA Lehrach H., Meindl A., Minx P.J., Hillier L.W., Willard H.F.,
RA Wilson R.K., Waterston R.H., Rice C.M., Vaudin M., Coulson A.,
RA Nelson D.L., Weinstock G., Sulston J.E., Durbin R.M., Hubbard T.,
RA Gibbs R.A., Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence of the human X chromosome.";
RL Nature 434:325-337(2005).
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM LAMP-2B).
RC TISSUE=Lymph;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [11]
RP PROTEIN SEQUENCE OF 29-66.
RX PubMed=2912382; DOI=10.1016/0003-9861(89)90597-3;
RA Mane S.M., Marzella L., Bainton D.F., Holt V.K., Cha Y.,
RA Hildreth J.E.K., August J.T.;
RT "Purification and characterization of human lysosomal membrane
RT glycoproteins.";
RL Arch. Biochem. Biophys. 268:360-378(1989).
RN [12]
RP PROTEIN SEQUENCE OF 29-43.
RX PubMed=15340161; DOI=10.1110/ps.04682504;
RA Zhang Z., Henzel W.J.;
RT "Signal peptide prediction based on analysis of experimentally
RT verified cleavage sites.";
RL Protein Sci. 13:2819-2824(2004).
RN [13]
RP POLYLACTOSAMINOGLYCANS.
RX PubMed=2243102;
RA Carlsson S.R., Fukuda M.;
RT "The polylactosaminoglycans of human lysosomal membrane glycoproteins
RT lamp-1 and lamp-2. Localization on the peptide backbones.";
RL J. Biol. Chem. 265:20488-20495(1990).
RN [14]
RP GLYCOSYLATION OF HINGE REGION, AND PROTEIN SEQUENCE OF 187-215.
RX PubMed=8323299; DOI=10.1006/abbi.1993.1322;
RA Carlsson S.R., Lycksell P.-O., Fukuda M.;
RT "Assignment of O-glycan attachment sites to the hinge-like regions of
RT human lysosomal membrane glycoproteins lamp-1 and lamp-2.";
RL Arch. Biochem. Biophys. 304:65-73(1993).
RN [15]
RP GLYCOSYLATION AT ASN-49 AND ASN-101.
RX PubMed=12754519; DOI=10.1038/nbt827;
RA Zhang H., Li X.-J., Martin D.B., Aebersold R.;
RT "Identification and quantification of N-linked glycoproteins using
RT hydrazide chemistry, stable isotope labeling and mass spectrometry.";
RL Nat. Biotechnol. 21:660-666(2003).
RN [16]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-32; ASN-38; ASN-49;
RP ASN-101; ASN-123 AND ASN-257, AND MASS SPECTROMETRY.
RC TISSUE=Plasma;
RX PubMed=16335952; DOI=10.1021/pr0502065;
RA Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E.,
RA Moore R.J., Smith R.D.;
RT "Human plasma N-glycoproteome analysis by immunoaffinity subtraction,
RT hydrazide chemistry, and mass spectrometry.";
RL J. Proteome Res. 4:2070-2080(2005).
RN [17]
RP NOMENCLATURE.
RX PubMed=16190986; DOI=10.1111/j.1600-0854.2005.00337.x;
RA Eskelinen E.L., Cuervo A.M., Taylor M.R., Nishino I., Blum J.S.,
RA Dice J.F., Sandoval I.V., Lippincott-Schwartz J., August J.T.,
RA Saftig P.;
RT "Unifying nomenclature for the isoforms of the lysosomal membrane
RT protein LAMP-2.";
RL Traffic 6:1058-1061(2005).
RN [18]
RP SUBCELLULAR LOCATION [LARGE SCALE ANALYSIS], AND MASS SPECTROMETRY.
RC TISSUE=Placenta;
RX PubMed=17897319; DOI=10.1111/j.1600-0854.2007.00643.x;
RA Schroeder B., Wrocklage C., Pan C., Jaeger R., Koesters B.,
RA Schaefer H., Elsaesser H.-P., Mann M., Hasilik A.;
RT "Integral and associated lysosomal membrane proteins.";
RL Traffic 8:1676-1686(2007).
RN [19]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-101; ASN-123; ASN-257 AND
RP ASN-356, AND MASS SPECTROMETRY.
RC TISSUE=Liver;
RX PubMed=19159218; DOI=10.1021/pr8008012;
RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.;
RT "Glycoproteomics analysis of human liver tissue by combination of
RT multiple enzyme digestion and hydrazide chemistry.";
RL J. Proteome Res. 8:651-661(2009).
RN [20]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [21]
RP VARIANT DAND ARG-321.
RX PubMed=15673802; DOI=10.1056/NEJMoa033349;
RA Arad M., Maron B.J., Gorham J.M., Johnson W.H. Jr., Saul J.P.,
RA Perez-Atayde A.R., Spirito P., Wright G.B., Kanter R.J., Seidman C.E.,
RA Seidman J.G.;
RT "Glycogen storage diseases presenting as hypertrophic
RT cardiomyopathy.";
RL N. Engl. J. Med. 352:362-372(2005).
RN [22]
RP VARIANT DAND ARG-321.
RX PubMed=15907287; DOI=10.1016/j.nmd.2005.02.008;
RA Musumeci O., Rodolico C., Nishino I., Di Guardo G., Migliorato A.,
RA Aguennouz M., Mazzeo A., Messina C., Vita G., Toscano A.;
RT "Asymptomatic hyperCKemia in a case of Danon disease due to a missense
RT mutation in Lamp-2 gene.";
RL Neuromuscul. Disord. 15:409-411(2005).
CC -!- FUNCTION: Implicated in tumor cell metastasis. May function in
CC protection of the lysosomal membrane from autodigestion,
CC maintenance of the acidic environment of the lysosome, adhesion
CC when expressed on the cell surface (plasma membrane), and inter-
CC and intracellular signal transduction. Protects cells from the
CC toxic effects of methylating mutagens.
CC -!- SUBCELLULAR LOCATION: Cell membrane; Single-pass type I membrane
CC protein. Endosome membrane; Single-pass type I membrane protein.
CC Lysosome membrane; Single-pass type I membrane protein. Note=This
CC protein shuttles between lysosomes, endosomes, and the plasma
CC membrane.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=LAMP-2A;
CC IsoId=P13473-1; Sequence=Displayed;
CC Name=LAMP-2B;
CC IsoId=P13473-2; Sequence=VSP_003044;
CC Name=LAMP-2C;
CC IsoId=P13473-3; Sequence=VSP_042519;
CC -!- TISSUE SPECIFICITY: Isoform LAMP-2A is highly expressed in
CC placenta, lung and liver, less in kidney and pancreas, low in
CC brain and skeletal muscle. Isoform LAMP-2B is highly expressed in
CC skeletal muscle, less in brain, placenta, lung, kidney and
CC pancreas, very low in liver.
CC -!- PTM: O- and N-glycosylated; some of the 16 N-linked glycans are
CC polylactosaminoglycans.
CC -!- DISEASE: Danon disease (DAND) [MIM:300257]: DAND is a lysosomal
CC glycogen storage disease characterized by the clinical triad of
CC cardiomyopathy, vacuolar myopathy and mental retardation. It is
CC often associated with an accumulation of glycogen in muscle and
CC lysosomes. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- SIMILARITY: Belongs to the LAMP family.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/LAMP2";
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DR EMBL; J04183; AAA60383.1; -; mRNA.
DR EMBL; L09717; AAB41647.1; -; Genomic_DNA.
DR EMBL; L09709; AAB41647.1; JOINED; Genomic_DNA.
DR EMBL; L09710; AAB41647.1; JOINED; Genomic_DNA.
DR EMBL; L09711; AAB41647.1; JOINED; Genomic_DNA.
DR EMBL; L09712; AAB41647.1; JOINED; Genomic_DNA.
DR EMBL; L09713; AAB41647.1; JOINED; Genomic_DNA.
DR EMBL; L09714; AAB41647.1; JOINED; Genomic_DNA.
DR EMBL; L09715; AAB41647.1; JOINED; Genomic_DNA.
DR EMBL; L09716; AAB41647.1; JOINED; Genomic_DNA.
DR EMBL; X77196; CAA54416.1; -; mRNA.
DR EMBL; S79873; AAB35426.1; -; mRNA.
DR EMBL; U36336; AAA91149.1; -; mRNA.
DR EMBL; AY561849; AAS67876.1; -; mRNA.
DR EMBL; AK291090; BAF83779.1; -; mRNA.
DR EMBL; AC002476; AAB67313.1; -; Genomic_DNA.
DR EMBL; AC002476; AAB67314.1; -; Genomic_DNA.
DR EMBL; CH471107; EAX11881.1; -; Genomic_DNA.
DR EMBL; CH471107; EAX11882.1; -; Genomic_DNA.
DR EMBL; CH471107; EAX11883.1; -; Genomic_DNA.
DR EMBL; CH471107; EAX11884.1; -; Genomic_DNA.
DR EMBL; BC002965; AAH02965.1; -; mRNA.
DR PIR; JC2414; B31959.
DR PIR; JC4317; JC4317.
DR RefSeq; NP_001116078.1; NM_001122606.1.
DR RefSeq; NP_002285.1; NM_002294.2.
DR RefSeq; NP_054701.1; NM_013995.2.
DR UniGene; Hs.496684; -.
DR ProteinModelPortal; P13473; -.
DR SMR; P13473; 219-370.
DR IntAct; P13473; 12.
DR MINT; MINT-5003281; -.
DR STRING; 9606.ENSP00000408411; -.
DR TCDB; 9.A.16.1.2; the lysosomal protein import (lpi) family.
DR PhosphoSite; P13473; -.
DR UniCarbKB; P13473; -.
DR DMDM; 1708854; -.
DR PaxDb; P13473; -.
DR PRIDE; P13473; -.
DR DNASU; 3920; -.
DR Ensembl; ENST00000200639; ENSP00000200639; ENSG00000005893.
DR Ensembl; ENST00000371335; ENSP00000360386; ENSG00000005893.
DR Ensembl; ENST00000434600; ENSP00000408411; ENSG00000005893.
DR GeneID; 3920; -.
DR KEGG; hsa:3920; -.
DR UCSC; uc004est.4; human.
DR CTD; 3920; -.
DR GeneCards; GC0XM119560; -.
DR HGNC; HGNC:6501; LAMP2.
DR HPA; CAB005272; -.
DR HPA; HPA029100; -.
DR MIM; 300257; phenotype.
DR MIM; 309060; gene.
DR neXtProt; NX_P13473; -.
DR Orphanet; 34587; Glycogen storage disease due to LAMP-2 deficiency.
DR PharmGKB; PA30285; -.
DR eggNOG; NOG301998; -.
DR HOGENOM; HOG000230942; -.
DR HOVERGEN; HBG052303; -.
DR KO; K06528; -.
DR OMA; AEECFAD; -.
DR OrthoDB; EOG7ZD1VH; -.
DR PhylomeDB; P13473; -.
DR Reactome; REACT_604; Hemostasis.
DR ChiTaRS; LAMP2; human.
DR GeneWiki; LAMP2; -.
DR GenomeRNAi; 3920; -.
DR NextBio; 15399; -.
DR PMAP-CutDB; P13473; -.
DR PRO; PR:P13473; -.
DR ArrayExpress; P13473; -.
DR Bgee; P13473; -.
DR CleanEx; HS_LAMP2; -.
DR Genevestigator; P13473; -.
DR GO; GO:0016021; C:integral to membrane; IEA:UniProtKB-KW.
DR GO; GO:0031902; C:late endosome membrane; IDA:MGI.
DR GO; GO:0005765; C:lysosomal membrane; IDA:UniProtKB.
DR GO; GO:0030670; C:phagocytic vesicle membrane; IEA:Ensembl.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0031088; C:platelet dense granule membrane; IDA:MGI.
DR GO; GO:0030168; P:platelet activation; TAS:Reactome.
DR GO; GO:0002576; P:platelet degranulation; TAS:Reactome.
DR InterPro; IPR018134; LAMP_CS.
DR InterPro; IPR002000; Lysosome-assoc_membr_glycop.
DR PANTHER; PTHR11506; PTHR11506; 1.
DR Pfam; PF01299; Lamp; 1.
DR PRINTS; PR00336; LYSASSOCTDMP.
DR PROSITE; PS00310; LAMP_1; 1.
DR PROSITE; PS00311; LAMP_2; 1.
DR PROSITE; PS51407; LAMP_3; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Cell membrane; Complete proteome;
KW Direct protein sequencing; Disease mutation; Disulfide bond; Endosome;
KW Glycogen storage disease; Glycoprotein; Lysosome; Membrane;
KW Polymorphism; Reference proteome; Signal; Transmembrane;
KW Transmembrane helix.
FT SIGNAL 1 28
FT CHAIN 29 410 Lysosome-associated membrane glycoprotein
FT 2.
FT /FTId=PRO_0000017110.
FT TOPO_DOM 29 375 Lumenal (Potential).
FT TRANSMEM 376 399 Helical; (Potential).
FT TOPO_DOM 400 410 Cytoplasmic (Potential).
FT REGION 29 192 First lumenal domain.
FT REGION 193 228 Hinge.
FT REGION 229 375 Second lumenal domain.
FT CARBOHYD 32 32 N-linked (GlcNAc...)
FT (polylactosaminoglycan).
FT CARBOHYD 38 38 N-linked (GlcNAc...)
FT (polylactosaminoglycan).
FT CARBOHYD 49 49 N-linked (GlcNAc...).
FT CARBOHYD 58 58 N-linked (GlcNAc...).
FT CARBOHYD 75 75 N-linked (GlcNAc...).
FT CARBOHYD 101 101 N-linked (GlcNAc...).
FT CARBOHYD 123 123 N-linked (GlcNAc...).
FT CARBOHYD 179 179 N-linked (GlcNAc...).
FT CARBOHYD 195 195 O-linked (GalNAc...).
FT CARBOHYD 196 196 O-linked (GalNAc...).
FT CARBOHYD 200 200 O-linked (GalNAc...).
FT CARBOHYD 203 203 O-linked (GalNAc...).
FT CARBOHYD 204 204 O-linked (GalNAc...).
FT CARBOHYD 207 207 O-linked (GalNAc...); partial.
FT CARBOHYD 209 209 O-linked (GalNAc...); partial.
FT CARBOHYD 210 210 O-linked (GalNAc...).
FT CARBOHYD 211 211 O-linked (GalNAc...).
FT CARBOHYD 213 213 O-linked (GalNAc...); partial.
FT CARBOHYD 229 229 N-linked (GlcNAc...).
FT CARBOHYD 242 242 N-linked (GlcNAc...).
FT CARBOHYD 257 257 N-linked (GlcNAc...).
FT CARBOHYD 275 275 N-linked (GlcNAc...).
FT CARBOHYD 300 300 N-linked (GlcNAc...).
FT CARBOHYD 307 307 N-linked (GlcNAc...)
FT (polylactosaminoglycan).
FT CARBOHYD 317 317 N-linked (GlcNAc...).
FT CARBOHYD 356 356 N-linked (GlcNAc...).
FT DISULFID 41 79 By similarity.
FT DISULFID 153 189 By similarity.
FT DISULFID 232 265 By similarity.
FT DISULFID 331 368 By similarity.
FT VAR_SEQ 366 410 QDCSADDDNFLVPIAVGAALAGVLILVLLAYFIGLKHHHAG
FT YEQF -> EECSADSDLNFLIPVAVGVALGFLIIVVFISYM
FT IGRRKSRTGYQSV (in isoform LAMP-2C).
FT /FTId=VSP_042519.
FT VAR_SEQ 367 410 DCSADDDNFLVPIAVGAALAGVLILVLLAYFIGLKHHHAGY
FT EQF -> ECSLDDDTILIPIIVGAGLSGLIIVIVIAYVIGR
FT RKSYAGYQTL (in isoform LAMP-2B).
FT /FTId=VSP_003044.
FT VARIANT 256 256 P -> H (in dbSNP:rs1043878).
FT /FTId=VAR_011992.
FT VARIANT 321 321 W -> R (in DAND).
FT /FTId=VAR_026230.
FT CONFLICT 8 13 PVPGSG -> RFRSGLR (in Ref. 3).
FT CONFLICT 53 53 R -> G (in Ref. 3).
FT CONFLICT 68 68 D -> V (in Ref. 2; AAB41647).
FT CONFLICT 111 111 I -> N (in Ref. 2; AAB41647).
FT CONFLICT 143 143 I -> Y (in Ref. 2; AAB41647).
FT CONFLICT 220 220 A -> P (in Ref. 2; AAB41647).
FT CONFLICT 234 234 L -> R (in Ref. 2; AAB41647).
FT CONFLICT 263 269 GSCRSHT -> AAAVSH (in Ref. 3).
FT CONFLICT 322 326 DAPLG -> MPP (in Ref. 1; AAA60383).
SQ SEQUENCE 410 AA; 44961 MW; 9E08E3B62D58F454 CRC64;
MVCFRLFPVP GSGLVLVCLV LGAVRSYALE LNLTDSENAT CLYAKWQMNF TVRYETTNKT
YKTVTISDHG TVTYNGSICG DDQNGPKIAV QFGPGFSWIA NFTKAASTYS IDSVSFSYNT
GDNTTFPDAE DKGILTVDEL LAIRIPLNDL FRCNSLSTLE KNDVVQHYWD VLVQAFVQNG
TVSTNEFLCD KDKTSTVAPT IHTTVPSPTT TPTPKEKPEA GTYSVNNGND TCLLATMGLQ
LNITQDKVAS VININPNTTH STGSCRSHTA LLRLNSSTIK YLDFVFAVKN ENRFYLKEVN
ISMYLVNGSV FSIANNNLSY WDAPLGSSYM CNKEQTVSVS GAFQINTFDL RVQPFNVTQG
KYSTAQDCSA DDDNFLVPIA VGAALAGVLI LVLLAYFIGL KHHHAGYEQF
//

MIM 300257
*RECORD*
*FIELD* NO
300257
*FIELD* TI
#300257 DANON DISEASE
;;VACUOLAR CARDIOMYOPATHY AND MYOPATHY, X-LINKED;;
PSEUDOGLYCOGENOSIS II;;
read moreANTOPOL DISEASE;;
LYSOSOMAL GLYCOGEN STORAGE DISEASE WITHOUT ACID MALTASE DEFICIENCY,
FORMERLY;;
GLYCOGEN STORAGE DISEASE IIb; GSD2B, FORMERLY;;
GSD IIb, FORMERLY
*FIELD* TX
A number sign (#) is used with this entry because of evidence that Danon
disease, also known as X-linked vacuolar cardiomyopathy and myopathy, is
caused by mutation in the gene encoding lysosome-associated membrane
protein-2 (LAMP2; 309060).

DESCRIPTION

Danon disease is an X-linked dominant disorder predominantly affecting
cardiac muscle. Skeletal muscle involvement and mental retardation are
variable features. The accumulation of glycogen in muscle and lysosomes
originally led to the classification of Danon disease as a variant of
glycogen storage disease II (Pompe disease; 232300) with 'normal acid
maltase' or alpha-glucosidase (GAA; 606800) (Danon et al., 1981).
However, Nishino et al. (2000) stated that Danon disease is not a
glycogen storage disease because glycogen is not always increased.

Sugie et al. (2005) classified Danon disease as a form of autophagic
vacuolar myopathy, characterized by intracytoplasmic autophagic vacuoles
with sarcolemmal features. The characteristic vacuole is believed to be
an autolysosome surrounded by secondarily-generated membranes containing
sarcolemmal proteins, basal lamina, and acetylcholinesterase activity.

X-linked myopathy with excessive autophagy (XMEA; 310440) is a distinct
disorder with similar pathologic features.

CLINICAL FEATURES

Antopol et al. (1940) described 2 brothers who died in the second decade
of life with heart failure. Autopsy of 1 patient showed glycogen storage
disease limited to the myocardium. Mehrizi and Oppenheimer (1960)
reported 2 related patients with heart failure associated with unusual
deposition of glycogen in the myocardium.

Danon et al. (1981) reported 2 unrelated males with mental retardation,
hypertrophic cardiomyopathy, and proximal muscle weakness. One patient
had hepatomegaly. Examination of skeletal muscle biopsies showed
features suggestive of a lysosomal glycogen storage disease. However,
acid alpha-glucosidase activity was normal, excluding a diagnosis of
Pompe disease, or glycogen storage disease type II (GSD II). Both
patients died at the age of 17 years. Riggs et al. (1983) described
lysosomal storage disease with normal acid maltase activity in 2
brothers. One of the brothers showed muscle weakness at age 3 years.
Both patients had Wolff-Parkinson-White electrocardiographic findings.

Bergia et al. (1986) reported a kindred in which 2 sisters gave birth to
a total of 3 sons with mental retardation, scapuloperoneal muscular
weakness, and hypertrophic cardiomyopathy. Intellectual deterioration
began at about age 5 years. Hypertrophic cardiomyopathy manifesting
itself in the teens led to death at ages 17 and 21 years in 2 of the
patients. On evaluation in their teens, the affected males showed
wasting of distal muscle groups, positive Gowers maneuver, and
predominant humeroperoneal distribution of muscle weakness. Creatine
kinase was elevated as was also lactate dehydrogenase, aspartate
aminotransferase, and alanine aminotransferase. A marked myopia was also
present. The mother of 2 of the patients, a presumed carrier of the
mutant gene, had evidence of cardiomyopathy without elevated serum
muscle enzymes.

Tripathy et al. (1988) described an 18-year-old black male who developed
manifestations of complete atrioventricular nodal block; endomyocardial
biopsy showed membrane-bound glycogen resembling the findings of GSD II.
The glycogenosis appeared to be limited to the myocardium because the
rest of the physical examination, the histology, and enzyme studies of
muscle and skin fibroblasts were normal.

Dworzak et al. (1994) described a Sicilian family in which 3 males and 2
females over 3 generations were affected with lysosomal glycogen storage
myopathy with normal acid maltase. Cardiac disease had led to the death
of a woman in the first generation and of one of her sons. The proband,
his sister, and her son, were alive and had been studied in detail. The
index case underwent heart transplant. His 32-year-old sister had atrial
fibrillation and mild left ventricular enlargement with systolic
dysfunction on echocardiogram. She also had mild intellectual
impairment, limb weakness, and mild muscle involvement on muscle biopsy.
Dworzak et al. (1994) stated that this was the first case of a female
with multisystem involvement.

In skeletal muscle biopsies from 3 patients with Danon disease, Murakami
et al. (1995) found intracytoplasmic vacuoles with occasional folds or
indentations in the sarcolemma that were connected to the membrane
enclosing the vacuoles. Immunohistochemical studies showed that the
vacuolar membranes contained acetylcholinesterase and proteins of the
sarcolemma and basal lamina.

Sugie et al. (2002) described the clinicopathologic features of 20
affected men and 18 affected women from 13 families with Danon disease
confirmed by genetic analysis. All patients had cardiomyopathy. Men were
affected before the age of 20 years, whereas most affected women
developed cardiomyopathy in adulthood. Eighteen of 20 male patients
(90%) and 6 of 18 female patients (33%) had skeletal myopathy; 14 of 20
male patients (70%) and 1 of 18 female patients (6%) had mental
retardation. Muscle histology revealed basophilic vacuoles that
contained acid phosphatase-positive material within membranes that
lacked LAMP2. Heart transplantation was the most effective treatment for
the otherwise lethal cardiomyopathy.

Laforet et al. (2004) reported a patient with Danon disease who had
features of axonal Charcot-Marie-Tooth disease (see, e.g., CMT2A1;
118210), including pes cavus, distal muscular atrophy of the lower limb,
and distal sensory loss. He also developed progressive visual loss due
to retinopathy as a young adult.

Lobrinus et al. (2005) reported a Swiss family with Danon disease
confirmed by genetic analysis. There were 4 affected males and 2
affected females. The proband developed severe left ventricular
cardiomyopathy with ventricular arrhythmia in adolescence. He had
diffuse muscular atrophy with mild proximal and axial weakness and
markedly increased serum creatine kinase. IQ was 76. Two first cousins
had mild muscle involvement, normal intelligence, and cardiac
involvement with cardiac symptom onset in adolescence. The mother of the
2 cousins died suddenly at age 40 years from cardiomyopathy. Cardiac
muscle biopsy from the proband and 1 cousin showed hypertrophic
cardiomyocytes with enlarged and irregular nuclei and vacuolated
cytoplasm, as well as absence of LAMP2 protein. Electron microscopy
showed that the vacuoles contained degenerating mitochondria, glycogen,
small vesicles, and granular debris. Although skeletal muscle biopsies
from all 3 patients showed normal morphology and normal glycogen
content, all had complete absence of the LAMP2 protein. Cytoplasmic
vacuoles could be seen in about 10% of skeletal muscle fibers in the
proband and in approximately 1% of fibers in 1 cousin. No vacuoles were
observed in the skeletal muscle of the other cousin. There was
immunoreactivity to complement components C5b-9 of the membrane attack
complex in some of the vacuoles, but not on the fiber surface.

Balmer et al. (2005) reported a mother and son with Danon disease
confirmed by genetic analysis. The boy presented at age 2.5 years with
mild left ventricular hypertrophy and mild myopathy. His heart disease
progressed, resulting in death at age 16 years shortly before planned
heart transplantation. His affected mother developed severe dilated
cardiomyopathy and died at age 46 years. Postmortem analysis showed
fibrosis and necrosis of the myocardium. Balmer et al. (2005) emphasized
that cardiac transplantation is the only effective therapeutic option in
Danon disease.

Prall et al. (2006) reported the ophthalmic manifestations of
genetically proven Danon disease in 4 females and 2 males. The females
demonstrated a peripheral pigmentary retinopathy, lens changes, myopia,
abnormal electroretinogram, and abnormal visual fields. The males
demonstrated a nearly complete loss of pigment in the retinal pigment
epithelium. Prall et al. (2006) suggested that retinopathy could
potentially be used to identify asymptomatic carriers.

Schorderet et al. (2007) identified diffuse retinal dysfunction,
affecting the cones more than the rods, in 2 brothers and their maternal
aunt with Danon disease caused by a mutation in LAMP2. Expression of the
disease was milder in the aunt, who was an obligate carrier, than in the
hemizygous boys, possibly due to lyonization.

Taylor et al. (2007) identified genetically confirmed Danon disease
(309060.0012) in and reported long-term follow-up on the family that
presented with dilated cardiomyopathy and was linked to the DMD gene
(300337) by Towbin et al. (1993). The original female proband and her 3
sons had dilated cardiomyopathy; subsequently, 3 other male relatives
developed severe concentric cardiac hypertrophy associated with
Wolff-Parkinson-White syndrome. Other features in this family included
skeletal myopathy with high serum creatine kinase, mild cognitive
impairment in males, and a pigmentary retinopathy in females. Cardiac
biopsy specimens showed extensive vacuolar changes in an affected adult
male, but the skeletal muscle biopsy in a 13-month-old mutation-carrying
male showed no vacuolization by standard histology. Taylor et al. (2007)
concluded that X-linked dilated cardiomyopathy may be the presenting
sign of Danon syndrome and that the absence of vacuolar myopathy in
biopsies from young patients may not exclude Danon disease.

Maron et al. (2009) reported the clinical course and outcome of 7 young
patients (6 boys and 1 girl) in whom LAMP2 mutations were previously
identified by Arad et al. (2005). Over a mean follow-up period of 8.6
years and by ages 14 to 24 years, the patients developed left
ventricular systolic dysfunction and cavity enlargement, with adverse
clinical consequences including death from progressive refractory heart
failure in 4 patients, sudden death in 1, aborted cardiac arrest in 1,
and cardiac transplantation in 1. Left ventricular hypertrophy was
particularly marked, with massive ventricular septal thickness in 2
patients of 60 mm and 65 mm at age 23 and 14 years, respectively. In 6
patients, a ventricular preexcitation pattern at study entry was
associated with markedly increased R-wave or S-wave voltages and deeply
inverted T-waves. Autopsy findings included a combination of
histopathologic features that were consistent with lysosomal storage
disease, such as clusters of vacuolated myocytes, but also typical of
CMH due to sarcomere protein mutations (see, e.g., 192600), such as
myocyte disarray, small vessel disease, and myocardial scarring. Maron
et al. (2009) noted that 7 female LAMP2 obligate carriers in 2 of the
families, aged 19 to 51 years, had remained asymptomatic, underscoring
the striking differences in clinical phenotypes and outcomes between
female carriers and affected male patients.

Boucek et al. (2011) presented data on 82 patients with Danon disease
from 36 families. Men were severely affected with cognitive disabilities
(100%), hypertrophic cardiomyopathy (88%), and muscle weakness (80%).
Men had a high morbidity and were unlikely to reach the age of 25 years
without a cardiac transplantation. Women were less severely affected but
reported higher than expected levels of cognitive (47%) and skeletal
muscle complaints (50%) and manifesting an equal prevalence of dilated
cardiomyopathy and hypertrophic cardiomyopathy. Combining their data
with that of 63 other Danon disease case reports in the literature,
Boucek et al. (2011) determined that the average ages of first symptom,
cardiac transplantation, and death were 12.1, 17.9, and 19.0 years in
men and 27.9, 33.7, and 34.6 years in women, respectively. Boucek et al.
(2011) concluded that women with Danon disease present with clinical
symptoms and events approximately 15 years after men and report a higher
proportion of cognitive and skeletal muscle problems than had been
recognized.

INHERITANCE

Byrne et al. (1986) described a family in which 7 members of 3
generations had cardioskeletal myopathy with accumulation of glycogen in
lysosomes but normal acid maltase levels. Cardiomyopathy dominated the
clinical picture with death between ages 18 and 40 years. There was no
male-to-male transmission, but 3 affected females were as severely
affected as the 4 males.

Dworzak et al. (1994) found reports of 12 young boys with mild myopathy,
varying degrees of mental retardation, and severe cardiomyopathy, whose
skeletal muscle examination showed lysosomal glycogen storage not due to
acid maltase deficiency. Only 2 cases were sporadic. All of the 10 other
cases had a brother or male relative in the maternal line who was either
equally affected or had died from heart disease in the second decade. In
most cases females were also affected, but cardiomyopathy was the only
reported phenotypic expression. The females generally died in the fourth
decade. The pattern suggested X-linked dominant inheritance.

MOLECULAR GENETICS

In 10 unrelated patients with Danon disease, Nishino et al. (2000)
identified 10 different mutations in the LAMP2 gene (see, e.g.,
309060.0001-309060.0006). All of the mutations resulted in premature
termination of the LAMP2 protein. Several patients had previously been
reported by Danon et al. (1981), Dworzak et al. (1994), Riggs et al.
(1983), and Byrne et al. (1986). Western blot analysis of skeletal
muscle biopsies from the patients showed marked deficiency or complete
absence of the LAMP2 protein. From these results, and the finding that
Lamp2-deficient mice manifest a singular vacuolar cardioskeletal
myopathy, Nishino et al. (2000) concluded that primary LAMP2 deficiency
is the cause of Danon disease. The authors stated that this was the
first example of human cardiomyopathy caused by mutations in a lysosomal
structural protein rather than an enzymatic protein.

Charron et al. (2004) analyzed the LAMP2 gene in 50 patients with
hypertrophic cardiomyopathy (CMH; see 192600) who were negative for
mutations in 9 sarcomeric genes and did not have autosomal dominant
inheritance. The authors identified 2 different mutations in the LAMP2
gene (309060.0008 and 309060.0009) in 2 patients, both with skeletal
muscle weakness on examination and PAS-positive sarcoplasmic vacuoles on
skeletal muscle biopsy by light microscopy, who died at ages 22 and 25
years, respectively. The prevalence of Danon disease was therefore 1% of
patients with CMH (2 of 197 patients initially screened with CMH in this
study) or 4% of enrolled index cases (2 of 50 index patients who were
screened for LAMP2 mutations). Danon disease was responsible for 50% of
the cases of CMH with clinical skeletal myopathy (2 of 4 patients); none
of the 41 patients with isolated CMH had Danon disease.

In genetic analyses of 24 subjects with increased left ventricular wall
thickness and electrocardiogram suggesting ventricular preexcitation,
Arad et al. (2005) found 4 LAMP2 mutations (see, e.g., 309060.0010).
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 2 serum proteins.
Mutations in heterozygous state appeared to be responsible for unusual
heart disease in some females.

In the family ('XLCM-2') that presented with dilated cardiomyopathy and
was linked to the DMD gene by Towbin et al. (1993), Taylor et al. (2007)
identified a 1-bp deletion in the LAMP2 gene (309060.0012).

GENOTYPE/PHENOTYPE CORRELATIONS

In a male patient with hypertrophic cardiomyopathy, exercise
intolerance, and hyperCKemia consistent with a mild form of Danon
disease, Musumeci et al. (2005) identified a missense mutation in the
LAMP2 gene (309060.0011). The patient did not have muscle weakness or
mental retardation. Musumeci et al. (2005) noted that all previous
mutations in the LAMP2 gene causing Danon disease resulted in premature
termination of the protein, and stated that this was the first missense
mutation reported in the LAMP2 gene.

NOMENCLATURE

Although this disorder was originally described as a type of glycogen
storage disease, Danon et al. (1981) recognized that acid
alpha-glucosidase and other enzymes of glycogen metabolism were normal
in affected patients. The subsequent identification of the structural
lysosome-associated membrane protein-2 gene as responsible for the
disorder enabled the proper identification of Danon disease as resulting
from a defect of the lysosomal membrane (Nishino et al., 2000). Former
designations for this disorder are retained here for historical
purposes.

*FIELD* RF
1. Antopol, W.; Boas, E. P.; Levison, W.; Tuchman, L. R.: Cardiac
hypertrophy caused by glycogen storage disease in a 15-year-old boy. Am.
Heart J. 20: 546-556, 1940.

2. Arad, M.; Maron, B. J.; Gorham, J. M.; Johnson, W. H., Jr.; Saul,
J. P.; Perez-Atayde, A. R.; Spirito, P.; Wright, G. B.; Kanter, R.
J.; Seidman, C. E.; Seidman, J. G.: Glycogen storage diseases presenting
as hypertrophic cardiomyopathy. New Eng. J. Med. 352: 362-372, 2005.

3. Balmer, C.; Ballhausen, D.; Bosshard, N. U.; Steinmann, B.; Boltshauser,
E.; Bauersfield, U.; Superti-Furga, A.: Familial X-linked cardiomyopathy
(Danon disease): diagnostic confirmation by mutation analysis of the
LAMP2 gene. Europ. J. Pediat. 164: 509-514, 2005.

4. Bergia, B.; Sybers, H. D.; Butler, I. J.: Familial lethal cardiomyopathy
with mental retardation and scapuloperoneal muscular dystrophy. J.
Neurol. Neurosurg. Psychiat. 49: 1423-1426, 1986.

5. Boucek, D.; Jirikowic, J.; Taylor, M.: Natural history of Danon
disease. Genet. Med. 13: 563-568, 2011.

6. Byrne, E.; Dennett, X.; Crotty, B.; Trounce, I.; Sands, J. M.;
Hawkins, R.; Hammond, J.; Anderson, S.; Haan, E. A.; Pollard, A.:
Dominantly inherited cardioskeletal myopathy with lysosomal glycogen
storage and normal acid maltase levels. Brain 109: 523-536, 1986.

7. Charron, P.; Villard, E.; Sebillon, P.; Laforet, P.; Maisonobe,
T.; Duboscq-Bidot, L.; Romero, N.; Drouin-Garraud, V.; Frebourg, T.;
Richard, P.; Eymard, B.; Komajda, M.: Danon's disease as a cause
of hypertrophic cardiomyopathy: a systematic survey. Heart 90: 842-846,
2004.

8. Danon, M. J.; Oh, S. J.; DiMauro, S.; Manaligod, J. R.; Eastwood,
A.; Naidu, S.; Schliselfeld, L. H.: Lysosomal glycogen storage disease
with normal acid maltase. Neurology 31: 51-57, 1981.

9. Dworzak, F.; Casazza, F.; Mora, C. M.; De Maria, R.; Gronda, E.;
Baroldi, G.; Rimoldi, M.; Morandi, L.; Cornelio, F.: Lysosomal glycogen
storage with normal acid maltase: a familial study with successful
heart transplant. Neuromusc. Disord. 4: 243-247, 1994.

10. Laforet, P.; Charron, P.; Maisonobe, T.; Romero, N. B.; Villard,
E.; Sebillon, P.; Drouin-Garraud, V.; Dubourg, O.; Fardeau, M.; Komajda,
M.; Eymard, B.: Charcot-Marie-Tooth features and maculopathy in a
patient with Danon disease. Neurology 63: 1535 only, 2004.

11. Lobrinus, J. A.; Schorderet, D. F.; Payot, M.; Jeanrenaud, X.;
Bottani, A.; Superti-Furga, A.; Schlaepfer, J.; Fromer, M.; Jeannet,
P.-Y.: Morphological, clinical and genetic aspects in a family with
a novel LAMP-2 gene mutation (Danon disease). Neuromusc. Disord. 15:
293-298, 2005.

12. Maron, B. J.; Roberts, W. C.; Arad, M.; Haas, T. S.; Spirito,
P.; Wright, G. B.; Almquist, A. K.; Baffa, J. M.; Saul, J. P.; Ho,
C. Y.; Seidman, J.; Seidman, C. E.: Clinical outcome and phenotypic
expression in LAMP2 cardiomyopathy. JAMA 301: 1253-1259, 2009.

13. Mehrizi, A.; Oppenheimer, E. H.: Heart failure associated with
unusual deposition of glycogen in the myocardium. Bull. Johns Hopkins
Hosp. 107: 329-336, 1960.

14. Murakami, N.; Goto, Y.; Itoh, M.; Katsumi, Y.; Wada, T.; Ozawa,
E.; Nonaka, I.: Sarcolemmal indentation in cardiomyopathy with mental
retardation and vacuolar myopathy. Neuromusc. Disord. 5: 149-155,
1995.

15. Musumeci, O.; Rodolico, C.; Nishino, I.; Di Guardo, G.; Migliorato,
A.; Aguennouz, M.; Mazzeo, A.; Messina, C.; Vita, G.; Toscano, A.
: Asymptomatic hyperCKemia in a case of Danon disease due to a missense
mutation in the Lamp-2 gene. Neuromusc. Disord. 15: 409-411, 2005.

16. Nishino, I.; Fu, J.; Tanji, K.; Yamada, T.; Shimojo, S.; Koori,
T.; Mora, M.; Riggs, J. E.; Oh, S. J.; Koga, Y.; Sue, C. M.; Yamamoto,
A.; Murakami, N.; Shanske, S.; Byrne, E.; Bonilla, E.; Nonaka, I.;
DiMauro, S.; Hirano, M.: Primary LAMP-2 deficiency causes X-linked
vacuolar cardiomyopathy and myopathy (Danon disease). Nature 406:
906-910, 2000.

17. Prall, F. R.; Drack, A.; Taylor, M.; Ku, L.; Olson, J. L.; Gregory,
D.; Mestroni, L.; Mandava, N.: Ophthalmic manifestations of Danon
disease. Ophthalmology 113: 1010-1013, 2006.

18. Riggs, J. E.; Schochet, S. S., Jr.; Gutmann, L.; Shanske, S.;
Neal, W. A.; DiMauro, S.: Lysosomal glycogen storage disease without
acid maltase deficiency. Neurology 33: 873-877, 1983.

19. Schorderet, D. F.; Cottet, S.; Lobrinus, J. A.; Borruat, F.-X.;
Balmer, A.; Munier, F. L.: Retinopathy in Danon disease. Arch. Ophthal. 125:
231-236, 2007.

20. Sugie, K.; Noguchi, S.; Kozuka, Y.; Arikawa-Hirasawa, E.; Tanaka,
M.; Yan, C.; Saftig, P.; von Figura, K.; Hirano, M.; Ueno, S.; Nonaka,
I.; Nishino, I.: Autophagic vacuoles with sarcolemmal features delineate
Danon disease and related myopathies. J. Neuropath. Exp. Neurol. 64:
513-522, 2005.

21. Sugie, K.; Yamamoto, A.; Murayama, K.; Oh, S. J.; Takahashi, M.;
Mora, M.; Riggs, J. E.; Colomer, J.; Iturriaga, C.; Meloni, A.; Lamperti,
C.; Saitoh, S.; Byrne, E.; DiMauro, S.; Nonaka, I.; Hirano, M.; Nishino,
I.: Clinicopathological features of genetically confirmed Danon disease. Neurology 58:
1773-1778, 2002.

22. Taylor, M. R. G.; Ku, L.; Slavov, D.; Cavanaugh, J.; Boucek, M.;
Zhu, X.; Graw, S.; Carniel, E.; Barnes, C.; Quan, D.; Prall, R.; Lovell,
M. A.; Mierau, G.; Ruegg, P.; Mandava, N.; Bristow, M. R.; Towbin,
J. A.; Mestroni, L.: Danon disease presenting with dilated cardiomyopathy
and a complex phenotype. J. Hum. Genet. 52: 830-835, 2007.

23. Towbin, J. A.; Hejtmancik, J. F.; Brink, P.; Gelb, B.; Zhu, X.
M.; Chamberlain, J. S.; McCabe, E. R. B.; Swift, M.: X-linked dilated
cardiomyopathy: molecular genetic evidence of linkage to the Duchenne
muscular dystrophy (dystrophin) gene at the Xp21 locus. Circulation 87:
1854-1865, 1993.

24. Tripathy, D.; Coleman, R. A.; Vidaillet, H. J., Jr.; Steenbergen,
C.; Hirschhorn, K.; Packer, D. L.: Complete heart block with myocardial
membrane-bound glycogen and normal peripheral alpha-glucosidase activity. Ann.
Intern. Med. 109: 985-987, 1988.

*FIELD* CS
INHERITANCE:
X-linked dominant

HEAD AND NECK:
[Eyes];
Moderate central loss of visual acuity in males (20/60);
Normal to near-normal visual acuity in carrier females (20/30-20/20);
Fine lamellar white opacities on slit lamp exam in carrier females;
Near complete loss of peripheral retinal pigment in males;
Peppered pigmentary mottling of peripheral retinal pigment in carrier
females;
Nonspecific changes on electroretinogram in carrier females

CARDIOVASCULAR:
[Heart];
Hypertrophic cardiomyopathy;
Dilated cardiomyopathy;
Cardiomegaly;
Arrhythmias;
Wolff-Parkinson-White syndrome;
Hypokinesia;
Decreased contractility;
Biopsy shows hypertrophic cardiomyocytes;
Cardiomyocytes have irregular nuclei;
Cardiomyocytes show glycogen accumulation in myofibrils and lysosomes;
Cardiomyocytes contain vacuolated cytoplasm with degenerated mitochondria,
glycogen, and granular debris;
Myocardial fibrosis;
Myocardial necrosis;
Severely decreased or absent LAMP2 protein

SKELETAL:
[Feet];
Pes cavus (uncommon)

MUSCLE, SOFT TISSUE:
Proximal muscle weakness (85% of patients);
Diffuse muscle atrophy;
Exercise intolerance;
Muscle cramps with exercise;
EMG shows myopathic changes;
Muscle biopsy shows sarcoplasmic PAS-positive vacuoles;
Muscle biopsy shows glycogen accumulation in myofibrils and lysosomes;
Indentations or folds of the sarcolemma are connected to the membranes
enclosing the vacuoles;
Vacuoles are autophagocytic;
Vacuolar membranes immunostain with sarcolemmal proteins;
Severely decreased or absent LAMP2 protein;
Positive staining for complement C5b-9 membrane attack complex proteins
within vacuoles, but not on muscle fiber membrane;
Normal alpha-glucosidase or acid maltase activity (GAA, 606800)

NEUROLOGIC:
[Central nervous system];
Mental retardation (70%);
Cognitive impairment, mild;
Delayed development

LABORATORY ABNORMALITIES:
Increased serum creatine kinase

MISCELLANEOUS:
Phenotypic variability;
Not all patients have skeletal muscle symptoms or mental retardation;
Sudden death in affected males occurs in teens;
Sudden death in affected females occurs in the forties;
Females often show milder phenotype with later onset of cardiac symptoms

MOLECULAR BASIS:
Caused by mutation in the lysosome associated membrane protein-2 gene
(LAMP2, 309060.0001)

*FIELD* CN
Jane Kelly - updated: 3/23/2007

*FIELD* CD
Cassandra L. Kniffin: 7/25/2005

*FIELD* ED
joanna: 09/11/2007
joanna: 3/23/2007
joanna: 12/7/2005
ckniffin: 7/27/2005

*FIELD* CN
Ada Hamosh - updated: 10/1/2012
Marla J. F. O'Neill - updated: 5/10/2010
Marla J. F. O'Neill - updated: 3/20/2008
Jane Kelly - updated: 12/5/2007
Marla J. F. O'Neill - updated: 9/6/2007
Jane Kelly - updated: 3/23/2007
Cassandra L. Kniffin - reorganized: 8/8/2005
Cassandra L. Kniffin - updated: 7/27/2005
Victor A. McKusick - updated: 2/17/2005
Victor A. McKusick - updated: 9/18/2002
Victor A. McKusick - updated: 11/2/2001
Ada Hamosh - updated: 8/31/2000
Victor A. McKusick - updated: 7/19/1999
Victor A. McKusick - updated: 10/20/1997

*FIELD* CD
Victor A. McKusick: 6/3/1986

*FIELD* ED
carol: 09/11/2013
tpirozzi: 6/28/2013
alopez: 6/27/2013
alopez: 10/3/2012
terry: 10/1/2012
wwang: 5/12/2010
terry: 5/10/2010
wwang: 3/27/2008
terry: 3/20/2008
carol: 12/5/2007
carol: 11/13/2007
ckniffin: 11/13/2007
carol: 9/6/2007
carol: 5/30/2007
carol: 3/23/2007
carol: 12/8/2005
ckniffin: 8/8/2005
carol: 8/8/2005
ckniffin: 7/27/2005
tkritzer: 5/12/2005
tkritzer: 2/23/2005
terry: 2/17/2005
carol: 10/21/2004
ckniffin: 7/29/2004
carol: 9/23/2002
tkritzer: 9/23/2002
tkritzer: 9/18/2002
carol: 11/8/2001
mcapotos: 11/2/2001
mgross: 9/1/2000
mgross: 8/31/2000

MIM 309060
*RECORD*
*FIELD* NO
309060
*FIELD* TI
*309060 LYSOSOME-ASSOCIATED MEMBRANE PROTEIN 2; LAMP2
;;LYSOSOME-ASSOCIATED MEMBRANE PROTEIN B; LAMPB;;
read moreLYSOSOMAL MEMBRANE GLYCOPROTEIN, 110-KD; LGP110;;
CD107B
*FIELD* TX

DESCRIPTION

The lysosomal membrane plays a vital role in the function of lysosomes
by sequestering numerous acid hydrolases that are responsible for the
degradation of foreign materials and for specialized autolytic
functions. LAMP1 (153330) and LAMP2 are glycoproteins that constitute a
significant fraction of the total lysosomal membrane glycoproteins. Both
consist of polypeptides of about 40 kD, with 16 to 20 N-linked
saccharides attached to the core polypeptides (Fukuda et al., 1988).

CLONING

Fukuda et al. (1988) isolated human cDNAs encoding LAMP1 and LAMP2.

Using mouse Lgp110 to screen a human liver cDNA library, Konecki et al.
(1994) cloned LAMP2. Sequencing analysis indicated that there are 4
polyadenylation signals in the 3-prime UTR, with the second being the
most frequently used. The deduced 410-amino acid protein contains a
leader sequence; a luminal domain consisting of 2 homologous domains
with 4 identically spaced cysteines linked by 2 disulfide bonds; a
20-amino acid transmembrane region; and a short cytoplasmic tail
containing the lysosomal membrane targeting signal. The protein is
heavily N-glycosylated.

By screening human liver and pheochromocytoma cDNA libraries, Konecki et
al. (1995) identified a LAMP2 variant, which they called LAMP2B, that
results from alternative splicing of exon 9. They designated the variant
reported by Konecki et al. (1994) as LAMP2A. The deduced LAMP2B protein
contains 410 amino acids, like the LAMP2A protein, but its C-terminal
sequence differs in the last 11 amino acids of the luminal domain, the
transmembrane domain, and the cytoplasmic tail. LAMP2B retains the
lysosomal targeting signal, gly-tyr-x-x, and has the same number of
potential glycosylation sites as LAMB2A. The LAMP2B variant has 3
polyadenylation signals in the 3-prime UTR. Using a common 5-prime LAMP2
sequence as probe for Northern blot analysis, Konecki et al. (1995)
identified 6 major LAMP2 transcripts in liver and 4 major transcripts in
pheochromocytoma mRNA. By Northern blot analysis using LAMP2B-specific
probes, they detected highest expression of LAMP2B in skeletal muscle,
with very low expression in liver. LAMP2B was also expressed in
fibroblasts and fetal liver. Northern blot analysis using
LAMP2A-specific probes detected highest LAMP2A expression in placenta,
lung, and liver, with much lower expression in skeletal muscle.
Immunoelectron microscopy localized LAMP2 primarily on the luminal side
of endocytic organelles. No labeling of the plasma membrane was
observed.

GENE FUNCTION

LAMP2 is thought to protect the lysosomal membrane from proteolytic
enzymes within lysosomes and to act as a receptor for proteins to be
imported into lysosomes (Fukuda, 1994).

Kain et al. (2008) found that virtually all individuals with
pauci-immune focal necrotizing glomerulonephritis (FNGN) had
autoantibodies against LAMP2 and that autoantibodies against LAMP2
caused this disease when injected into rats. A monoclonal antibody to
human LAMP2 induced apoptosis of human microvascular endothelium in
vitro. The autoantibodies in individuals with pauci-immune FNGN commonly
recognize a human LAMP2 epitope with 100% homology to the bacterial
adhesin FimH, with which they crossreact. Rats immunized with FimH
developed pauci-immune FNGN and also developed antibodies to rat and
human LAMP2. Finally, Kain et al. (2008) showed that infections with
fimbriated pathogens are common before the onset of FNGN. Thus, Kain et
al. (2008) concluded that FimH-triggered autoimmunity to LAMP2 provides
a previously undescribed clinically relevant molecular mechanism for the
development of pauci-immune FNGN.

GENE STRUCTURE

Konecki et al. (1995) determined that the LAMP2 gene contains 9 coding
exons, with 2 alternate last exons, 9a and 9b.

MAPPING

By in situ hybridization, Mattei et al. (1990) mapped the LAMP2 gene to
Xq24-q25. This was taken to support the view that LAMP1 and LAMP2
diverged relatively early in evolution and that they have distinct
functions which emerged as soon as eukaryotic cells acquired lysosomes
as subcellular compartments.

Isolation and identification of human genes can be helped by isolation
of cDNA clones, identification of DNA fragments conserved in distant
species, and direct sequence analysis. Identification of CpG islands is
an additional tool. CpG islands, unmethylated tracts of DNA that are 0.5
to 2 kb long and very rich in G+C and in the dinucleotide CpG, are
located in the 5-prime region of all sequenced housekeeping genes and of
many tissue-specific genes (Bird, 1987). The lack of methylation of CpG
islands makes them a preferential site of cleavage for
methylation-sensitive restriction enzymes with one or more CpGs in their
recognition site, such as HpaII, EagI, SacII, BssHII, and NotI. Lindsay
and Bird (1987) demonstrated the usefulness of CpG islands as landmarks
for identifying genes. In an EagI-EcoRI library of the distal long arm
of the human X chromosome, Manoni et al. (1991) found a clone that
mapped to Xq24 (by hybridization with a panel of human-hamster cell
hybrids carrying deletions of different portions of the human X
chromosome between Xq24 and Xqter). Using Southern hybridization and
hamster/human hybrid cell panels, Schleutker et al. (1991) confirmed the
localization of the LAMP2 gene on the X chromosome. In the course of
high-resolution comparative mapping of the proximal region of the mouse
X chromosome, Blair et al. (1995) demonstrated the location of the Lamp2
gene in relation to others.

MOLECULAR GENETICS

Nishino et al. (2000) identified mutations in the LAMP2 gene in 10
patients with Danon disease (300257).

Charron et al. (2004) analyzed the LAMP2 gene in 50 patients diagnosed
with hypertrophic cardiomyopathy (CMH; see 192600) who were negative for
mutations in 9 sarcomeric genes and did not have autosomal dominant
inheritance. The authors identified 2 different mutations in the LAMP2
gene (309060.0008 and 309060.0009)in 2 patients, both of whom had
skeletal muscle weakness on examination and PAS-positive sarcoplasmic
vacuoles on skeletal muscle biopsy by light microscopy.

LAMP2 mutations typically cause multisystem Danon disease, which can
also present as a primary cardiomyopathy. In genetic analyses of 24
subjects with increased left ventricular wall thickness and
electrocardiogram suggesting ventricular preexcitation, Arad et al.
(2005) found 4 LAMP2 mutations (see, e.g., 309060.0010) and 7 PRKAG2
(602743) mutations. 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 2 serum
proteins. Mutations in heterozygous state appeared to be responsible for
unusual heart disease in some females.

In a family ('XLCM-2') that presented with dilated cardiomyopathy and
was linked to the dystrophin gene (300377) by Towbin et al. (1993),
Taylor et al. (2007) identified a mutation in the LAMP2 gene
(309060.0012), confirming a diagnosis of Danon disease.

ANIMAL MODEL

Tanaka et al. (2000) generated mice deficient in Lamp2 by targeted
disruption. Lamp2 knockout mice showed elevated mortality and reduced
weight compared with their wildtype littermates. About 50% of
Lamp2-deficient animals died between postnatal days 20 and 40,
independent of sex and genetic background (C57B6/Jx129SV and 129SV). In
addition, Lamp2-deficient mice were smaller than wildtype mice.
Surviving mice were fertile and had an almost normal life span.
Ultrastructurally, there was extensive accumulation of autophagic
vacuoles in many tissues, including liver, pancreas, spleen, kidney, and
skeletal and heart muscle. In hepatocytes, the autophagic degradation of
long-lived proteins was severely impaired. Cardiac myocytes were
ultrastructurally abnormal and heart contractility was severely reduced.
These findings indicated that LAMP2 is critical for autophagy. This
theory was further substantiated by the finding that human LAMP2
deficiency, which causes Danon disease, is associated with the
accumulation of autophagic material in striated myocytes.

*FIELD* AV
.0001
DANON DISEASE
LAMP2, 2-BP DEL, 1097AA

In a male Japanese patient with Danon disease (300257) diagnosed after
muscle biopsy, Nishino et al. (2000) identified a 2-bp deletion
(1097delAA) in exon 9b of the LAMP2 gene, resulting in a frameshift.

.0002
DANON DISEASE
LAMP2, LEU113TER

In a male Japanese patient with Danon disease (300257), Nishino et al.
(2000) identified a 440T-A transition in the LAMP2 gene, resulting in a
leu113-to-ter (L113X) substitution.

.0003
DANON DISEASE
LAMP2, IVS6, G-C, +5

In a Japanese patient with Danon disease (300257), Nishino et al. (2000)
identified a G-to-C transversion at the +5 position of intron 6 of the
LAMP2 gene. This mutation resulted in the skipping of exon 6.

.0004
DANON DISEASE
LAMP2, 1-BP INS, 974A

In an Italian patient with Danon disease (300257), Nishino et al. (2000)
identified a 1-bp insertion (974insA) in exon 8 of the LAMP2 gene. This
patient was initially described by Dworzak et al. (1994).

.0005
DANON DISEASE
LAMP2, IVS5, G-A, +1

In affected members of 3 different families with Danon disease (300257),
Nishino et al. (2000) identified a 6-bp insertion at the junctions of
exons 5 and 6 of the LAMP2 gene. The inserted nucleotides had the same
sequence as the 5-prime end of intron 5. Conceivably, nucleotides 7 and
8 (GT) immediately after the inserted sequence in intron 5 were
recognized as an alternative splice donor site. The inserted sequence
encoded an in-frame stop codon, which predicted premature termination of
the nascent polypeptide. This mutation was found in a Japanese family,
an African American family, and an Anglo-Saxon family. The African
American family was originally reported by Danon et al. (1981), and the
Anglo-Saxon family had been reported by Riggs et al. (1983).

.0006
DANON DISEASE
LAMP2, 1-BP DEL, 14G

In affected members of a large Greek family with Danon disease (300257)
initially reported by Byrne et al. (1986), Nishino et al. (2000)
identified a 1-bp deletion (14delG) in exon 1 of the LAMP2 gene,
resulting in a frameshift.

.0007
DANON DISEASE
LAMP2, 1-BP INS, 883T

Takahashi et al. (2002) described a brother and sister with a 1-bp
insertion (883insT) in the LAMP2 gene resulting in Danon disease
(300257). The mutation was not detected in their mother's peripheral
blood or buccal cells, thus indicating germline mosaicism. The proband
was a 7-year-old boy with normal early motor and cognitive development,
found to have an abnormal EKG and elevated blood creatinine kinase. EKG
indicated left ventricular hypertrophy, confirmed by echocardiogram.
Neurologic examination showed normal mentation and mild weakness of the
neck muscles. He attended regular school. The 6-year-old sister had
developed normally and had an unremarkable clinical examination, but on
EKG showed left ventricular hypertrophy and by echocardiogram
hypertrophic cardiomyopathy.

.0008
DANON DISEASE
LAMP2, 7-BP DEL

In a 24-year-old male with Danon disease (300257), Charron et al. (2004)
identified a 7-bp deletion (173del7) in the LAMP2 gene, resulting in a
frameshift and a premature stop at codon 17. The patient's mother also
carried the mutation; 3 of her brothers and her mother had premature
cardiac deaths at ages ranging from 7 to 34 years. The patient had
markedly decreased left ventricular function with an ejection fraction
of 20%, mild distal muscle weakness, mild amyotrophy of the lower limbs
with pes cavus, and no mental retardation; he also had severe decreased
visual acuity bilaterally, due to choriocapillary atrophy. He died of
heart failure at 25 years of age while awaiting transplantation.

.0009
DANON DISEASE
LAMP2, GLN174TER

In a patient with Danon disease (300257), Charron et al. (2004)
identified a de novo 657C-T transition in exon 4 of the LAMP2 gene,
resulting in a gln174-to-ter (Q174X) substitution. The patient was
diagnosed at age 14 years because of syncope, at which time ECG revealed
normal sinus rhythm with high QRS voltage and Wolff-Parkinson-White
syndrome and echocardiography showed increased left ventricular wall
thickness with no outflow tract gradient and a normal ejection fraction.
He had mild skeletal weakness but no mental retardation or ophthalmic
abnormality. At 22 years of age, he underwent cardiac transplantation
due to severe heart failure and died in the postoperative period.

.0010
DANON DISEASE
LAMP2, VAL310ILE

In a male proband with glycogen storage disease (300257) presenting as
hypertrophic cardiomyopathy, Arad et al. (2005) found a 928G-A
transition in the LAMP2 gene that resulted in a val310-to-ile (V310I)
amino acid substitution. The mutation affected RNA processing and hence
produced a frameshift (K289FS). Genetic studies demonstrated mosaicism:
both mutant and wildtype LAMP2 sequences were identified despite a
normal XY karyotype.

.0011
DANON DISEASE
LAMP2, TRP321ARG

In a male patient with hypertrophic cardiomyopathy, exercise
intolerance, and hyperCKemia consistent with a mild form of Danon
disease (300257), Musumeci et al. (2005) identified a 961T-C transition
in exon 8 of the LAMP2 gene, resulting in a trp321-to-arg (W321R)
substitution in a highly conserved region of the protein. Muscle biopsy
showed LAMP2 deficiency, PAS-positive sarcoplasmic vacuoles, and intense
staining for complement C5b-9 membrane attack complex proteins within
the vacuoles. The patient did not have muscle weakness or mental
retardation. Musumeci et al. (2005) stated that this was the first
missense mutation reported in the LAMP2 gene.

.0012
DANON DISEASE
LAMP2, 1-BP DEL, 1219A

In a family with dilated and hypertrophic cardiomyopathy, cardiac
preexcitation, and skeletal myopathy with elevated CK levels (Danon
disease, 300257), originally studied by Towbin et al. (1993), Taylor et
al. (2007) identified a 1-bp deletion (1219delA) in exon 8 of the LAMP2
gene, resulting in a frameshift at codon 361 predicted to obliterate the
carboxy sequences for both the lysosomal transmembrane and lysosomal
targeting domains. The mutation was present in all affected individuals
and obligate carriers tested, and was not found in over 300 control
chromosomes.

*FIELD* RF
1. Arad, M.; Maron, B. J.; Gorham, J. M.; Johnson, W. H., Jr.; Saul,
J. P.; Perez-Atayde, A. R.; Spirito, P.; Wright, G. B.; Kanter, R.
J.; Seidman, C. E.; Seidman, J. G.: Glycogen storage diseases presenting
as hypertrophic cardiomyopathy. New Eng. J. Med. 352: 362-372, 2005.

2. Bird, A. P.: HTF islands as gene markers in the vertebrate nucleus. Trends
Genet. 3: 342-347, 1987.

3. Blair, H. J.; Ho, M.; Monaco, A. P.; Fisher, S.; Craig, I. W.;
Boyd, Y.: High-resolution comparative mapping of the proximal region
of the mouse X chromosome. Genomics 28: 305-310, 1995.

4. Byrne, E.; Dennett, X.; Crotty, B.; Trounce, I.; Sands, J. M.;
Hawkins, R.; Hammond, J.; Anderson, S.; Haan, E. A.; Pollard, A.:
Dominantly inherited cardioskeletal myopathy with lysosomal glycogen
storage and normal acid maltase levels. Brain 109: 523-536, 1986.

5. Charron, P.; Villard, E.; Sebillon, P.; Laforet, P.; Maisonobe,
T.; Duboscq-Bidot, L.; Romero, N.; Drouin-Garraud, V.; Frebourg, T.;
Richard, P.; Eymard, B.; Komajda, M.: Danon's disease as a cause
of hypertrophic cardiomyopathy: a systematic survey. Heart 90: 842-846,
2004.

6. Danon, M. J.; Oh, S. J.; DiMauro, S.; Manaligod, J. R.; Eastwood,
A.; Naidu, S.; Schliselfeld, L. H.: Lysosomal glycogen storage disease
with normal acid maltase. Neurology 31: 51-57, 1981.

7. Dworzak, F.; Casazza, F.; Mora, C. M.; De Maria, R.; Gronda, E.;
Baroldi, G.; Rimoldi, M.; Morandi, L.; Cornelio, F.: Lysosomal glycogen
storage with normal acid maltase: a familial study with successful
heart transplant. Neuromusc. Disord. 4: 243-247, 1994.

8. Fukuda, M.: Biogenesis of the lysosomal membrane. Subcell. Biochem. 22:
199-230, 1994.

9. Fukuda, M.; Viitala, J.; Matteson, J.; Carlsson, S. R.: Cloning
of the cDNAs encoding human lysosomal membrane glycoproteins, h-lamp-1
and h-lamp-2: comparison of their deduced amino acid sequences. J.
Biol. Chem. 263: 18920-18928, 1988.

10. Kain, R.; Exner, M.; Brandes, R.; Ziebermayr, R.; Cunningham,
D.; Alderson, C. A.; Davidovits, A.; Raab, I.; Jahn, R.; Ashour, O.;
Spitzauer, S.; Sunder-Plassmann, G.; Fukuda, M.; Klemm, P.; Rees,
A. J.; Kerjaschki, D.: Molecular mimicry in pauci-immune focal necrotizing
glomerulonephritis. Nature Med. 14: 1088-1096, 2008.

11. Konecki, D. S.; Foetisch, K.; Schlotter, M.; Lichter-Konecki,
U.: Complete cDNA sequence of human lysosome-associated membrane
protein-2. Biochem. Biophys. Res. Commun. 205: 1-5, 1994.

12. Konecki, D. S.; Foetisch, K.; Zimmer, K.-P.; Schlotter, M.; Lichter-Konecki,
U.: An alternatively spliced form of the human lysosome-associated
membrane protein-2 gene is expressed in a tissue-specific manner. Biochem.
Biophys. Res. Commun. 215: 757-767, 1995.

13. Lindsay, S.; Bird, A. P.: Use of restriction enzymes to detect
potential gene sequences in mammalian DNA. Nature 327: 336-338,
1987.

14. Manoni, M.; Tribioli, C.; Lazzari, B.; DeBellis, G.; Patrosso,
C.; Pergolizzi, R.; Pellegrini, M.; Maestrini, E.; Rivella, S.; Vezzoni,
P.; Toniolo, D.: The nucleotide sequence of a CpG island demonstrates
the presence of the first exon of the gene encoding the human lysosomal
membrane protein LAMP2 and assigns the gene to Xq24. Genomics 9:
551-554, 1991.

15. Mattei, M.-G.; Matterson, J.; Chen, J. W.; Williams, M. A.; Fukuda,
M.: Two human lysosomal membrane glycoproteins, h-lamp-1 and h-lamp-2,
are encoded by genes localized to chromosome 13q34 and chromosome
Xq24-25, respectively. J. Biol. Chem. 265: 7548-7551, 1990.

16. Musumeci, O.; Rodolico, C.; Nishino, I.; Di Guardo, G.; Migliorato,
A.; Aguennouz, M.; Mazzeo, A.; Messina, C.; Vita, G.; Toscano, A.
: Asymptomatic hyperCKemia in a case of Danon disease due to a missense
mutation in the Lamp-2 gene. Neuromusc. Disord. 15: 409-411, 2005.

17. Nishino, I.; Fu, J.; Tanji, K.; Yamada, T.; Shimojo, S.; Koori,
T.; Mora, M.; Riggs, J. E.; Oh, S. J.; Koga, Y.; Sue, C. M.; Yamamoto,
A.; Murakami, N.; Shanske, S.; Byrne, E.; Bonilla, E.; Nonaka, I.;
DiMauro, S.; Hirano, M.: Primary LAMP-2 deficiency causes X-linked
vacuolar cardiomyopathy and myopathy (Danon disease). Nature 406:
906-910, 2000.

18. Riggs, J. E.; Schochet, S. S., Jr.; Gutmann, L.; Shanske, S.;
Neal, W. A.; DiMauro, S.: Lysosomal glycogen storage disease without
acid maltase deficiency. Neurology 33: 873-877, 1983.

19. Schleutker, J.; Haataja, L.; Renlund, M.; Puhakka, L.; Viitala,
J.; Peltonen, L.; Aula, P.: Confirmation of the chromosomal localization
of human lamp genes and their exclusion as candidate genes for Salla
disease. Hum. Genet. 88: 95-97, 1991.

20. Takahashi, M.; Yamamoto, A.; Takano, K.; Sudo, A.; Wada, T.; Goto,
Y. I.; Nishino, I.; Saitoh, S.: Germline mosaicism of a novel mutation
in lysosome-associated membrane protein-2 deficiency (Danon disease). Ann.
Neurol. 52: 122-125, 2002.

21. Tanaka, Y.; Guhe, G.; Suter, A.; Eskelinen, E.-L.; Hartmann, D.;
Lullmann-Rauch, R.; Janssen, P. M. L.; Blanz, J.; von Figura, K.;
Saftig, P.: Accumulation of autophagic vacuoles and cardiomyopathy
in LAMP-2-deficient mice. Nature 406: 902-906, 2000.

22. Taylor, M. R. G.; Ku, L.; Slavov, D.; Cavanaugh, J.; Boucek, M.;
Zhu, X.; Graw, S.; Carniel, E.; Barnes, C.; Quan, D.; Prall, R.; Lovell,
M. A.; Mierau, G.; Ruegg, P.; Mandava, N.; Bristow, M. R.; Towbin,
J. A.; Mestroni, L.: Danon disease presenting with dilated cardiomyopathy
and a complex phenotype. J. Hum. Genet. 52: 830-835, 2007.

23. Towbin, J. A.; Hejtmancik, J. F.; Brink, P.; Gelb, B.; Zhu, X.
M.; Chamberlain, J. S.; McCabe, E. R. B.; Swift, M.: X-linked dilated
cardiomyopathy: molecular genetic evidence of linkage to the Duchenne
muscular dystrophy (dystrophin) gene at the Xp21 locus. Circulation 87:
1854-1865, 1993.

*FIELD* CN
Ada Hamosh - updated: 11/12/2008
Marla J. F. O'Neill - updated: 3/20/2008
Marla J. F. O'Neill - updated: 9/6/2007
Cassandra L. Kniffin - updated: 7/27/2005
Victor A. McKusick - updated: 3/3/2005
Victor A. McKusick - updated: 2/17/2005
Patricia A. Hartz - updated: 11/11/2004
Victor A. McKusick - updated: 9/18/2002
Ada Hamosh - updated: 8/31/2000

*FIELD* CD
Victor A. McKusick: 10/25/1990

*FIELD* ED
mgross: 01/19/2012
alopez: 11/18/2008
terry: 11/12/2008
wwang: 3/27/2008
terry: 3/20/2008
carol: 9/6/2007
terry: 11/16/2006
terry: 10/12/2005
carol: 8/8/2005
ckniffin: 7/27/2005
alopez: 3/21/2005
alopez: 3/18/2005
terry: 3/3/2005
tkritzer: 2/23/2005
terry: 2/17/2005
mgross: 11/11/2004
tkritzer: 10/6/2004
carol: 9/23/2002
tkritzer: 9/23/2002
tkritzer: 9/20/2002
tkritzer: 9/18/2002
mgross: 8/31/2000
terry: 8/31/2000
carol: 8/19/1998
mark: 8/25/1995
carol: 2/27/1995
mimadm: 2/27/1994
supermim: 3/17/1992
carol: 2/29/1992
carol: 1/3/1992