Full text data of CTSD
CTSD
(CPSD)
[Confidence: low (only semi-automatic identification from reviews)]
Cathepsin D; 3.4.23.5; Cathepsin D light chain; Cathepsin D heavy chain; Flags: Precursor
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Cathepsin D; 3.4.23.5; Cathepsin D light chain; Cathepsin D heavy chain; Flags: Precursor
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
P07339
ID CATD_HUMAN Reviewed; 412 AA.
AC P07339; Q6IB57;
DT 01-APR-1988, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-APR-1988, sequence version 1.
DT 22-JAN-2014, entry version 167.
DE RecName: Full=Cathepsin D;
DE EC=3.4.23.5;
DE Contains:
DE RecName: Full=Cathepsin D light chain;
DE Contains:
DE RecName: Full=Cathepsin D heavy chain;
DE Flags: Precursor;
GN Name=CTSD; Synonyms=CPSD;
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].
RX PubMed=3927292; DOI=10.1073/pnas.82.15.4910;
RA Faust P.L., Kornfeld S., Chirgwin J.M.;
RT "Cloning and sequence analysis of cDNA for human cathepsin D.";
RL Proc. Natl. Acad. Sci. U.S.A. 82:4910-4914(1985).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=3588310; DOI=10.1093/nar/15.9.3773;
RA Westley B.R., May F.E.B.;
RT "Oestrogen regulates cathepsin D mRNA levels in oestrogen responsive
RT human breast cancer cells.";
RL Nucleic Acids Res. 15:3773-3786(1987).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=2069717; DOI=10.1089/dna.1991.10.423;
RA Redecker B., Heckendorf B., Grosch H.W., Mersmann G., Hasilik A.;
RT "Molecular organization of the human cathepsin D gene.";
RL DNA Cell Biol. 10:423-431(1991).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Kidney;
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 [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-22.
RX PubMed=8262386; DOI=10.1016/0378-1119(93)90107-E;
RA May F.E., Smith D.J., Westley B.R.;
RT "The human cathepsin D-encoding gene is transcribed from an estrogen-
RT regulated and a constitutive start point.";
RL Gene 134:277-282(1993).
RN [8]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-22.
RX PubMed=7935485; DOI=10.1210/me.8.6.693;
RA Augereau P., Miralles F., Cavailles V., Gaudelet C., Parker M.,
RA Rochefort H.;
RT "Characterization of the proximal estrogen-responsive element of human
RT cathepsin D gene.";
RL Mol. Endocrinol. 8:693-703(1994).
RN [9]
RP PROTEIN SEQUENCE OF 170-180.
RC TISSUE=Liver;
RA Hochstrasser D.F., Frutiger S., Paquet N., Bairoch A., Ravier F.,
RA Pasquali C., Sanchez J.-C., Tissot J.-D., Bjellqvist B., Vargas R.,
RA Appel R.D., Hughes G.J.;
RL Submitted (JUN-1992) to UniProtKB.
RN [10]
RP SUBCELLULAR LOCATION [LARGE SCALE ANALYSIS], AND MASS SPECTROMETRY.
RC TISSUE=Melanoma;
RX PubMed=12643545; DOI=10.1021/pr025562r;
RA Basrur V., Yang F., Kushimoto T., Higashimoto Y., Yasumoto K.,
RA Valencia J., Muller J., Vieira W.D., Watabe H., Shabanowitz J.,
RA Hearing V.J., Hunt D.F., Appella E.;
RT "Proteomic analysis of early melanosomes: identification of novel
RT melanosomal proteins.";
RL J. Proteome Res. 2:69-79(2003).
RN [11]
RP GLYCOSYLATION AT ASN-263.
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 [12]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-263, AND MASS
RP 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 [13]
RP INVOLVEMENT IN CLN10, AND VARIANT ARG-282.
RX PubMed=16670177; DOI=10.1093/brain/awl107;
RA Siintola E., Partanen S., Stromme P., Haapanen A., Haltia M.,
RA Maehlen J., Lehesjoki A.E., Tyynela J.;
RT "Cathepsin D deficiency underlies congenital human neuronal ceroid-
RT lipofuscinosis.";
RL Brain 129:1438-1445(2006).
RN [14]
RP SUBCELLULAR LOCATION [LARGE SCALE ANALYSIS], AND MASS SPECTROMETRY.
RC TISSUE=Melanoma;
RX PubMed=17081065; DOI=10.1021/pr060363j;
RA Chi A., Valencia J.C., Hu Z.-Z., Watabe H., Yamaguchi H.,
RA Mangini N.J., Huang H., Canfield V.A., Cheng K.C., Yang F., Abe R.,
RA Yamagishi S., Shabanowitz J., Hearing V.J., Wu C., Appella E.,
RA Hunt D.F.;
RT "Proteomic and bioinformatic characterization of the biogenesis and
RT function of melanosomes.";
RL J. Proteome Res. 5:3135-3144(2006).
RN [15]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-263, AND MASS
RP SPECTROMETRY.
RC TISSUE=Platelet;
RX PubMed=16263699; DOI=10.1074/mcp.M500324-MCP200;
RA Lewandrowski U., Moebius J., Walter U., Sickmann A.;
RT "Elucidation of N-glycosylation sites on human platelet proteins: a
RT glycoproteomic approach.";
RL Mol. Cell. Proteomics 5:226-233(2006).
RN [16]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-134 AND ASN-263, AND MASS
RP 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 [17]
RP TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION.
RX PubMed=20551380; DOI=10.1074/mcp.M110.001693;
RA Didangelos A., Yin X., Mandal K., Baumert M., Jahangiri M., Mayr M.;
RT "Proteomics characterization of extracellular space components in the
RT human aorta.";
RL Mol. Cell. Proteomics 9:2048-2062(2010).
RN [18]
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 [19]
RP GLYCOSYLATION AT THR-63, AND MASS SPECTROMETRY.
RX PubMed=23234360; DOI=10.1021/pr300963h;
RA Halim A., Ruetschi U., Larson G., Nilsson J.;
RT "LC-MS/MS characterization of O-glycosylation sites and glycan
RT structures of human cerebrospinal fluid glycoproteins.";
RL J. Proteome Res. 12:573-584(2013).
RN [20]
RP X-RAY CRYSTALLOGRAPHY (3 ANGSTROMS).
RC TISSUE=Spleen;
RX PubMed=8467789;
RA Metcalf P., Fusek M.;
RT "Two crystal structures for cathepsin D: the lysosomal targeting
RT signal and active site.";
RL EMBO J. 12:1293-1302(1993).
RN [21]
RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS).
RC TISSUE=Liver;
RX PubMed=8393577; DOI=10.1073/pnas.90.14.6796;
RA Baldwin E.T., Bhat T.N., Gulnik S., Hosur M.V., Sowder R.C. II,
RA Cachau R.E., Collins J., Silva A.M., Erickson J.W.;
RT "Crystal structures of native and inhibited forms of human cathepsin
RT D: implications for lysosomal targeting and drug design.";
RL Proc. Natl. Acad. Sci. U.S.A. 90:6796-6800(1993).
RN [22]
RP VARIANT VAL-58.
RX PubMed=10716266;
RX DOI=10.1002/1531-8249(200003)47:3<399::AID-ANA22>3.3.CO;2-X;
RA Papassotiropoulos A., Bagli M., Kurz A., Kornhuber J., Forstl H.,
RA Maier W., Pauls J., Lautenschlager N., Heun R.;
RT "A genetic variation of cathepsin D is a major risk factor for
RT Alzheimer's disease.";
RL Ann. Neurol. 47:399-403(2000).
RN [23]
RP VARIANTS CLN10 ILE-229 AND CYS-383.
RX PubMed=16685649; DOI=10.1086/504159;
RA Steinfeld R., Reinhardt K., Schreiber K., Hillebrand M., Kraetzner R.,
RA Bruck W., Saftig P., Gartner J.;
RT "Cathepsin D deficiency is associated with a human neurodegenerative
RT disorder.";
RL Am. J. Hum. Genet. 78:988-998(2006).
RN [24]
RP VARIANT CLN10 ILE-229.
RX PubMed=21990111; DOI=10.1002/humu.21624;
RA Kousi M., Lehesjoki A.E., Mole S.E.;
RT "Update of the mutation spectrum and clinical correlations of over 360
RT mutations in eight genes that underlie the neuronal ceroid
RT lipofuscinoses.";
RL Hum. Mutat. 33:42-63(2012).
CC -!- FUNCTION: Acid protease active in intracellular protein breakdown.
CC Involved in the pathogenesis of several diseases such as breast
CC cancer and possibly Alzheimer disease.
CC -!- CATALYTIC ACTIVITY: Specificity similar to, but narrower than,
CC that of pepsin A. Does not cleave the 4-Gln-|-His-5 bond in B
CC chain of insulin.
CC -!- SUBUNIT: Consists of a light chain and a heavy chain.
CC -!- INTERACTION:
CC P05067:APP; NbExp=2; IntAct=EBI-2115097, EBI-77613;
CC -!- SUBCELLULAR LOCATION: Lysosome. Melanosome. Secreted,
CC extracellular space. Note=Identified by mass spectrometry in
CC melanosome fractions from stage I to stage IV. In aortic samples,
CC detected as an extracellular protein loosely bound to the matrix
CC (PubMed:20551380).
CC -!- TISSUE SPECIFICITY: Expressed in the aorta extrcellular space (at
CC protein level).
CC -!- PTM: N- and O-glycosylated.
CC -!- POLYMORPHISM: The Val-58 allele is significantly overrepresented
CC in demented patients (11.8%) compared with non-demented controls
CC (4.9%). Carriers of the Val-58 allele have a 3.1-fold increased
CC risk for developing AD than non-carriers.
CC -!- DISEASE: Ceroid lipofuscinosis, neuronal, 10 (CLN10) [MIM:610127]:
CC A form of neuronal ceroid lipofuscinosis with onset at birth or
CC early childhood. Neuronal ceroid lipofuscinoses are progressive
CC neurodegenerative, lysosomal storage diseases characterized by
CC intracellular accumulation of autofluorescent liposomal material,
CC and clinically by seizures, dementia, visual loss, and/or cerebral
CC atrophy. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- SIMILARITY: Belongs to the peptidase A1 family.
CC -!- WEB RESOURCE: Name=NCL CTSD; Note=Neural Ceroid Lipofuscinoses
CC mutation db;
CC URL="http://www.ucl.ac.uk/ncl/catD.shtml";
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DR EMBL; M11233; AAB59529.1; -; mRNA.
DR EMBL; X05344; CAA28955.1; -; mRNA.
DR EMBL; M63138; AAA51922.1; -; Genomic_DNA.
DR EMBL; M63134; AAA51922.1; JOINED; Genomic_DNA.
DR EMBL; M63135; AAA51922.1; JOINED; Genomic_DNA.
DR EMBL; M63136; AAA51922.1; JOINED; Genomic_DNA.
DR EMBL; M63137; AAA51922.1; JOINED; Genomic_DNA.
DR EMBL; CR456947; CAG33228.1; -; mRNA.
DR EMBL; BT006910; AAP35556.1; -; mRNA.
DR EMBL; BT020155; AAV38957.1; -; mRNA.
DR EMBL; BC016320; AAH16320.1; -; mRNA.
DR EMBL; L12980; AAA16314.1; -; Genomic_DNA.
DR EMBL; S74689; AAD14156.1; -; Genomic_DNA.
DR EMBL; S52557; AAD13868.1; -; Genomic_DNA.
DR PIR; A25771; KHHUD.
DR RefSeq; NP_001900.1; NM_001909.4.
DR UniGene; Hs.654447; -.
DR PDB; 1LYA; X-ray; 2.50 A; A/C=65-161, B/D=170-410.
DR PDB; 1LYB; X-ray; 2.50 A; A/C=65-161, B/D=170-410.
DR PDB; 1LYW; X-ray; 2.50 A; A/C/E/G=65-161, B/D/F/H=170-410.
DR PDBsum; 1LYA; -.
DR PDBsum; 1LYB; -.
DR PDBsum; 1LYW; -.
DR ProteinModelPortal; P07339; -.
DR SMR; P07339; 23-410.
DR IntAct; P07339; 15.
DR MINT; MINT-3005628; -.
DR STRING; 9606.ENSP00000236671; -.
DR BindingDB; P07339; -.
DR ChEMBL; CHEMBL2581; -.
DR DrugBank; DB00047; Insulin Glargine recombinant.
DR DrugBank; DB00046; Insulin Lyspro recombinant.
DR DrugBank; DB00030; Insulin recombinant.
DR DrugBank; DB00071; Insulin, porcine.
DR GuidetoPHARMACOLOGY; 2345; -.
DR MEROPS; A01.009; -.
DR PhosphoSite; P07339; -.
DR DMDM; 115717; -.
DR DOSAC-COBS-2DPAGE; P07339; -.
DR REPRODUCTION-2DPAGE; IPI00011229; -.
DR SWISS-2DPAGE; P07339; -.
DR UCD-2DPAGE; P07339; -.
DR PaxDb; P07339; -.
DR PeptideAtlas; P07339; -.
DR PRIDE; P07339; -.
DR DNASU; 1509; -.
DR Ensembl; ENST00000236671; ENSP00000236671; ENSG00000117984.
DR GeneID; 1509; -.
DR KEGG; hsa:1509; -.
DR UCSC; uc001luc.2; human.
DR CTD; 1509; -.
DR GeneCards; GC11M001773; -.
DR H-InvDB; HIX0009359; -.
DR HGNC; HGNC:2529; CTSD.
DR HPA; CAB000109; -.
DR HPA; HPA003001; -.
DR MIM; 116840; gene.
DR MIM; 610127; phenotype.
DR neXtProt; NX_P07339; -.
DR Orphanet; 228337; CLN10 disease.
DR PharmGKB; PA27029; -.
DR eggNOG; NOG248684; -.
DR HOGENOM; HOG000197681; -.
DR HOVERGEN; HBG000482; -.
DR InParanoid; P07339; -.
DR KO; K01379; -.
DR OMA; GEYMISC; -.
DR PhylomeDB; P07339; -.
DR BioCyc; MetaCyc:HS04183-MONOMER; -.
DR Reactome; REACT_118779; Extracellular matrix organization.
DR Reactome; REACT_17015; Metabolism of proteins.
DR Reactome; REACT_6900; Immune System.
DR EvolutionaryTrace; P07339; -.
DR GeneWiki; Cathepsin_D; -.
DR GenomeRNAi; 1509; -.
DR NextBio; 6247; -.
DR PMAP-CutDB; P07339; -.
DR PRO; PR:P07339; -.
DR ArrayExpress; P07339; -.
DR Bgee; P07339; -.
DR CleanEx; HS_CTSD; -.
DR Genevestigator; P07339; -.
DR GO; GO:0005615; C:extracellular space; IDA:BHF-UCL.
DR GO; GO:0043202; C:lysosomal lumen; TAS:Reactome.
DR GO; GO:0042470; C:melanosome; IEA:UniProtKB-SubCell.
DR GO; GO:0005739; C:mitochondrion; IEA:Ensembl.
DR GO; GO:0004190; F:aspartic-type endopeptidase activity; TAS:ProtInc.
DR GO; GO:0019886; P:antigen processing and presentation of exogenous peptide antigen via MHC class II; TAS:Reactome.
DR GO; GO:0000045; P:autophagic vacuole assembly; IEA:Ensembl.
DR GO; GO:0008219; P:cell death; IEA:UniProtKB-KW.
DR GO; GO:0030574; P:collagen catabolic process; TAS:Reactome.
DR GO; GO:0022617; P:extracellular matrix disassembly; TAS:Reactome.
DR GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW.
DR Gene3D; 2.40.70.10; -; 2.
DR InterPro; IPR001461; Aspartic_peptidase.
DR InterPro; IPR001969; Aspartic_peptidase_AS.
DR InterPro; IPR012848; Aspartic_peptidase_N.
DR InterPro; IPR021109; Peptidase_aspartic_dom.
DR PANTHER; PTHR13683; PTHR13683; 1.
DR Pfam; PF07966; A1_Propeptide; 1.
DR Pfam; PF00026; Asp; 1.
DR PRINTS; PR00792; PEPSIN.
DR SUPFAM; SSF50630; SSF50630; 1.
DR PROSITE; PS00141; ASP_PROTEASE; 2.
PE 1: Evidence at protein level;
KW 3D-structure; Alzheimer disease; Aspartyl protease; Complete proteome;
KW Direct protein sequencing; Disease mutation; Disulfide bond;
KW Glycoprotein; Hydrolase; Lysosome; Neurodegeneration;
KW Neuronal ceroid lipofuscinosis; Polymorphism; Protease;
KW Reference proteome; Secreted; Signal; Zymogen.
FT SIGNAL 1 18
FT PROPEP 19 64 Activation peptide.
FT /FTId=PRO_0000025949.
FT CHAIN 65 412 Cathepsin D.
FT /FTId=PRO_0000025950.
FT CHAIN 65 161 Cathepsin D light chain (Probable).
FT /FTId=PRO_0000025951.
FT CHAIN 169 412 Cathepsin D heavy chain (Probable).
FT /FTId=PRO_0000025952.
FT ACT_SITE 97 97
FT ACT_SITE 295 295
FT CARBOHYD 63 63 O-linked (GalNAc...).
FT CARBOHYD 134 134 N-linked (GlcNAc...).
FT CARBOHYD 263 263 N-linked (GlcNAc...).
FT DISULFID 91 160
FT DISULFID 110 117
FT DISULFID 286 290
FT DISULFID 329 366
FT VARIANT 58 58 A -> V (associated with increased risk
FT for AD; possibly influences secretion and
FT intracellular maturation; dbSNP:rs17571).
FT /FTId=VAR_011621.
FT VARIANT 229 229 F -> I (in CLN10).
FT /FTId=VAR_029362.
FT VARIANT 282 282 G -> R (in dbSNP:rs147278302).
FT /FTId=VAR_058490.
FT VARIANT 383 383 W -> C (in CLN10).
FT /FTId=VAR_029363.
FT STRAND 67 74
FT TURN 75 77
FT STRAND 78 85
FT TURN 86 89
FT STRAND 90 97
FT STRAND 103 107
FT HELIX 115 118
FT HELIX 125 127
FT STRAND 132 141
FT STRAND 146 159
FT STRAND 172 184
FT TURN 189 191
FT STRAND 194 200
FT HELIX 204 206
FT HELIX 208 210
FT HELIX 214 220
FT STRAND 224 233
FT STRAND 236 238
FT STRAND 243 247
FT HELIX 252 254
FT STRAND 255 263
FT TURN 267 270
FT STRAND 271 279
FT TURN 280 282
FT STRAND 284 286
FT STRAND 290 294
FT STRAND 299 303
FT HELIX 305 315
FT STRAND 318 321
FT STRAND 324 328
FT HELIX 329 334
FT STRAND 338 342
FT STRAND 345 349
FT TURN 351 353
FT STRAND 354 358
FT TURN 359 362
FT STRAND 363 372
FT TURN 377 379
FT STRAND 383 385
FT HELIX 387 390
FT STRAND 393 398
FT TURN 399 402
FT STRAND 403 409
SQ SEQUENCE 412 AA; 44552 MW; 903FB8412E0CF0B0 CRC64;
MQPSSLLPLA LCLLAAPASA LVRIPLHKFT SIRRTMSEVG GSVEDLIAKG PVSKYSQAVP
AVTEGPIPEV LKNYMDAQYY GEIGIGTPPQ CFTVVFDTGS SNLWVPSIHC KLLDIACWIH
HKYNSDKSST YVKNGTSFDI HYGSGSLSGY LSQDTVSVPC QSASSASALG GVKVERQVFG
EATKQPGITF IAAKFDGILG MAYPRISVNN VLPVFDNLMQ QKLVDQNIFS FYLSRDPDAQ
PGGELMLGGT DSKYYKGSLS YLNVTRKAYW QVHLDQVEVA SGLTLCKEGC EAIVDTGTSL
MVGPVDEVRE LQKAIGAVPL IQGEYMIPCE KVSTLPAITL KLGGKGYKLS PEDYTLKVSQ
AGKTLCLSGF MGMDIPPPSG PLWILGDVFI GRYYTVFDRD NNRVGFAEAA RL
//
ID CATD_HUMAN Reviewed; 412 AA.
AC P07339; Q6IB57;
DT 01-APR-1988, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-APR-1988, sequence version 1.
DT 22-JAN-2014, entry version 167.
DE RecName: Full=Cathepsin D;
DE EC=3.4.23.5;
DE Contains:
DE RecName: Full=Cathepsin D light chain;
DE Contains:
DE RecName: Full=Cathepsin D heavy chain;
DE Flags: Precursor;
GN Name=CTSD; Synonyms=CPSD;
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].
RX PubMed=3927292; DOI=10.1073/pnas.82.15.4910;
RA Faust P.L., Kornfeld S., Chirgwin J.M.;
RT "Cloning and sequence analysis of cDNA for human cathepsin D.";
RL Proc. Natl. Acad. Sci. U.S.A. 82:4910-4914(1985).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=3588310; DOI=10.1093/nar/15.9.3773;
RA Westley B.R., May F.E.B.;
RT "Oestrogen regulates cathepsin D mRNA levels in oestrogen responsive
RT human breast cancer cells.";
RL Nucleic Acids Res. 15:3773-3786(1987).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=2069717; DOI=10.1089/dna.1991.10.423;
RA Redecker B., Heckendorf B., Grosch H.W., Mersmann G., Hasilik A.;
RT "Molecular organization of the human cathepsin D gene.";
RL DNA Cell Biol. 10:423-431(1991).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Kidney;
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 [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-22.
RX PubMed=8262386; DOI=10.1016/0378-1119(93)90107-E;
RA May F.E., Smith D.J., Westley B.R.;
RT "The human cathepsin D-encoding gene is transcribed from an estrogen-
RT regulated and a constitutive start point.";
RL Gene 134:277-282(1993).
RN [8]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-22.
RX PubMed=7935485; DOI=10.1210/me.8.6.693;
RA Augereau P., Miralles F., Cavailles V., Gaudelet C., Parker M.,
RA Rochefort H.;
RT "Characterization of the proximal estrogen-responsive element of human
RT cathepsin D gene.";
RL Mol. Endocrinol. 8:693-703(1994).
RN [9]
RP PROTEIN SEQUENCE OF 170-180.
RC TISSUE=Liver;
RA Hochstrasser D.F., Frutiger S., Paquet N., Bairoch A., Ravier F.,
RA Pasquali C., Sanchez J.-C., Tissot J.-D., Bjellqvist B., Vargas R.,
RA Appel R.D., Hughes G.J.;
RL Submitted (JUN-1992) to UniProtKB.
RN [10]
RP SUBCELLULAR LOCATION [LARGE SCALE ANALYSIS], AND MASS SPECTROMETRY.
RC TISSUE=Melanoma;
RX PubMed=12643545; DOI=10.1021/pr025562r;
RA Basrur V., Yang F., Kushimoto T., Higashimoto Y., Yasumoto K.,
RA Valencia J., Muller J., Vieira W.D., Watabe H., Shabanowitz J.,
RA Hearing V.J., Hunt D.F., Appella E.;
RT "Proteomic analysis of early melanosomes: identification of novel
RT melanosomal proteins.";
RL J. Proteome Res. 2:69-79(2003).
RN [11]
RP GLYCOSYLATION AT ASN-263.
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 [12]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-263, AND MASS
RP 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 [13]
RP INVOLVEMENT IN CLN10, AND VARIANT ARG-282.
RX PubMed=16670177; DOI=10.1093/brain/awl107;
RA Siintola E., Partanen S., Stromme P., Haapanen A., Haltia M.,
RA Maehlen J., Lehesjoki A.E., Tyynela J.;
RT "Cathepsin D deficiency underlies congenital human neuronal ceroid-
RT lipofuscinosis.";
RL Brain 129:1438-1445(2006).
RN [14]
RP SUBCELLULAR LOCATION [LARGE SCALE ANALYSIS], AND MASS SPECTROMETRY.
RC TISSUE=Melanoma;
RX PubMed=17081065; DOI=10.1021/pr060363j;
RA Chi A., Valencia J.C., Hu Z.-Z., Watabe H., Yamaguchi H.,
RA Mangini N.J., Huang H., Canfield V.A., Cheng K.C., Yang F., Abe R.,
RA Yamagishi S., Shabanowitz J., Hearing V.J., Wu C., Appella E.,
RA Hunt D.F.;
RT "Proteomic and bioinformatic characterization of the biogenesis and
RT function of melanosomes.";
RL J. Proteome Res. 5:3135-3144(2006).
RN [15]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-263, AND MASS
RP SPECTROMETRY.
RC TISSUE=Platelet;
RX PubMed=16263699; DOI=10.1074/mcp.M500324-MCP200;
RA Lewandrowski U., Moebius J., Walter U., Sickmann A.;
RT "Elucidation of N-glycosylation sites on human platelet proteins: a
RT glycoproteomic approach.";
RL Mol. Cell. Proteomics 5:226-233(2006).
RN [16]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-134 AND ASN-263, AND MASS
RP 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 [17]
RP TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION.
RX PubMed=20551380; DOI=10.1074/mcp.M110.001693;
RA Didangelos A., Yin X., Mandal K., Baumert M., Jahangiri M., Mayr M.;
RT "Proteomics characterization of extracellular space components in the
RT human aorta.";
RL Mol. Cell. Proteomics 9:2048-2062(2010).
RN [18]
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 [19]
RP GLYCOSYLATION AT THR-63, AND MASS SPECTROMETRY.
RX PubMed=23234360; DOI=10.1021/pr300963h;
RA Halim A., Ruetschi U., Larson G., Nilsson J.;
RT "LC-MS/MS characterization of O-glycosylation sites and glycan
RT structures of human cerebrospinal fluid glycoproteins.";
RL J. Proteome Res. 12:573-584(2013).
RN [20]
RP X-RAY CRYSTALLOGRAPHY (3 ANGSTROMS).
RC TISSUE=Spleen;
RX PubMed=8467789;
RA Metcalf P., Fusek M.;
RT "Two crystal structures for cathepsin D: the lysosomal targeting
RT signal and active site.";
RL EMBO J. 12:1293-1302(1993).
RN [21]
RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS).
RC TISSUE=Liver;
RX PubMed=8393577; DOI=10.1073/pnas.90.14.6796;
RA Baldwin E.T., Bhat T.N., Gulnik S., Hosur M.V., Sowder R.C. II,
RA Cachau R.E., Collins J., Silva A.M., Erickson J.W.;
RT "Crystal structures of native and inhibited forms of human cathepsin
RT D: implications for lysosomal targeting and drug design.";
RL Proc. Natl. Acad. Sci. U.S.A. 90:6796-6800(1993).
RN [22]
RP VARIANT VAL-58.
RX PubMed=10716266;
RX DOI=10.1002/1531-8249(200003)47:3<399::AID-ANA22>3.3.CO;2-X;
RA Papassotiropoulos A., Bagli M., Kurz A., Kornhuber J., Forstl H.,
RA Maier W., Pauls J., Lautenschlager N., Heun R.;
RT "A genetic variation of cathepsin D is a major risk factor for
RT Alzheimer's disease.";
RL Ann. Neurol. 47:399-403(2000).
RN [23]
RP VARIANTS CLN10 ILE-229 AND CYS-383.
RX PubMed=16685649; DOI=10.1086/504159;
RA Steinfeld R., Reinhardt K., Schreiber K., Hillebrand M., Kraetzner R.,
RA Bruck W., Saftig P., Gartner J.;
RT "Cathepsin D deficiency is associated with a human neurodegenerative
RT disorder.";
RL Am. J. Hum. Genet. 78:988-998(2006).
RN [24]
RP VARIANT CLN10 ILE-229.
RX PubMed=21990111; DOI=10.1002/humu.21624;
RA Kousi M., Lehesjoki A.E., Mole S.E.;
RT "Update of the mutation spectrum and clinical correlations of over 360
RT mutations in eight genes that underlie the neuronal ceroid
RT lipofuscinoses.";
RL Hum. Mutat. 33:42-63(2012).
CC -!- FUNCTION: Acid protease active in intracellular protein breakdown.
CC Involved in the pathogenesis of several diseases such as breast
CC cancer and possibly Alzheimer disease.
CC -!- CATALYTIC ACTIVITY: Specificity similar to, but narrower than,
CC that of pepsin A. Does not cleave the 4-Gln-|-His-5 bond in B
CC chain of insulin.
CC -!- SUBUNIT: Consists of a light chain and a heavy chain.
CC -!- INTERACTION:
CC P05067:APP; NbExp=2; IntAct=EBI-2115097, EBI-77613;
CC -!- SUBCELLULAR LOCATION: Lysosome. Melanosome. Secreted,
CC extracellular space. Note=Identified by mass spectrometry in
CC melanosome fractions from stage I to stage IV. In aortic samples,
CC detected as an extracellular protein loosely bound to the matrix
CC (PubMed:20551380).
CC -!- TISSUE SPECIFICITY: Expressed in the aorta extrcellular space (at
CC protein level).
CC -!- PTM: N- and O-glycosylated.
CC -!- POLYMORPHISM: The Val-58 allele is significantly overrepresented
CC in demented patients (11.8%) compared with non-demented controls
CC (4.9%). Carriers of the Val-58 allele have a 3.1-fold increased
CC risk for developing AD than non-carriers.
CC -!- DISEASE: Ceroid lipofuscinosis, neuronal, 10 (CLN10) [MIM:610127]:
CC A form of neuronal ceroid lipofuscinosis with onset at birth or
CC early childhood. Neuronal ceroid lipofuscinoses are progressive
CC neurodegenerative, lysosomal storage diseases characterized by
CC intracellular accumulation of autofluorescent liposomal material,
CC and clinically by seizures, dementia, visual loss, and/or cerebral
CC atrophy. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- SIMILARITY: Belongs to the peptidase A1 family.
CC -!- WEB RESOURCE: Name=NCL CTSD; Note=Neural Ceroid Lipofuscinoses
CC mutation db;
CC URL="http://www.ucl.ac.uk/ncl/catD.shtml";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
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DR EMBL; M11233; AAB59529.1; -; mRNA.
DR EMBL; X05344; CAA28955.1; -; mRNA.
DR EMBL; M63138; AAA51922.1; -; Genomic_DNA.
DR EMBL; M63134; AAA51922.1; JOINED; Genomic_DNA.
DR EMBL; M63135; AAA51922.1; JOINED; Genomic_DNA.
DR EMBL; M63136; AAA51922.1; JOINED; Genomic_DNA.
DR EMBL; M63137; AAA51922.1; JOINED; Genomic_DNA.
DR EMBL; CR456947; CAG33228.1; -; mRNA.
DR EMBL; BT006910; AAP35556.1; -; mRNA.
DR EMBL; BT020155; AAV38957.1; -; mRNA.
DR EMBL; BC016320; AAH16320.1; -; mRNA.
DR EMBL; L12980; AAA16314.1; -; Genomic_DNA.
DR EMBL; S74689; AAD14156.1; -; Genomic_DNA.
DR EMBL; S52557; AAD13868.1; -; Genomic_DNA.
DR PIR; A25771; KHHUD.
DR RefSeq; NP_001900.1; NM_001909.4.
DR UniGene; Hs.654447; -.
DR PDB; 1LYA; X-ray; 2.50 A; A/C=65-161, B/D=170-410.
DR PDB; 1LYB; X-ray; 2.50 A; A/C=65-161, B/D=170-410.
DR PDB; 1LYW; X-ray; 2.50 A; A/C/E/G=65-161, B/D/F/H=170-410.
DR PDBsum; 1LYA; -.
DR PDBsum; 1LYB; -.
DR PDBsum; 1LYW; -.
DR ProteinModelPortal; P07339; -.
DR SMR; P07339; 23-410.
DR IntAct; P07339; 15.
DR MINT; MINT-3005628; -.
DR STRING; 9606.ENSP00000236671; -.
DR BindingDB; P07339; -.
DR ChEMBL; CHEMBL2581; -.
DR DrugBank; DB00047; Insulin Glargine recombinant.
DR DrugBank; DB00046; Insulin Lyspro recombinant.
DR DrugBank; DB00030; Insulin recombinant.
DR DrugBank; DB00071; Insulin, porcine.
DR GuidetoPHARMACOLOGY; 2345; -.
DR MEROPS; A01.009; -.
DR PhosphoSite; P07339; -.
DR DMDM; 115717; -.
DR DOSAC-COBS-2DPAGE; P07339; -.
DR REPRODUCTION-2DPAGE; IPI00011229; -.
DR SWISS-2DPAGE; P07339; -.
DR UCD-2DPAGE; P07339; -.
DR PaxDb; P07339; -.
DR PeptideAtlas; P07339; -.
DR PRIDE; P07339; -.
DR DNASU; 1509; -.
DR Ensembl; ENST00000236671; ENSP00000236671; ENSG00000117984.
DR GeneID; 1509; -.
DR KEGG; hsa:1509; -.
DR UCSC; uc001luc.2; human.
DR CTD; 1509; -.
DR GeneCards; GC11M001773; -.
DR H-InvDB; HIX0009359; -.
DR HGNC; HGNC:2529; CTSD.
DR HPA; CAB000109; -.
DR HPA; HPA003001; -.
DR MIM; 116840; gene.
DR MIM; 610127; phenotype.
DR neXtProt; NX_P07339; -.
DR Orphanet; 228337; CLN10 disease.
DR PharmGKB; PA27029; -.
DR eggNOG; NOG248684; -.
DR HOGENOM; HOG000197681; -.
DR HOVERGEN; HBG000482; -.
DR InParanoid; P07339; -.
DR KO; K01379; -.
DR OMA; GEYMISC; -.
DR PhylomeDB; P07339; -.
DR BioCyc; MetaCyc:HS04183-MONOMER; -.
DR Reactome; REACT_118779; Extracellular matrix organization.
DR Reactome; REACT_17015; Metabolism of proteins.
DR Reactome; REACT_6900; Immune System.
DR EvolutionaryTrace; P07339; -.
DR GeneWiki; Cathepsin_D; -.
DR GenomeRNAi; 1509; -.
DR NextBio; 6247; -.
DR PMAP-CutDB; P07339; -.
DR PRO; PR:P07339; -.
DR ArrayExpress; P07339; -.
DR Bgee; P07339; -.
DR CleanEx; HS_CTSD; -.
DR Genevestigator; P07339; -.
DR GO; GO:0005615; C:extracellular space; IDA:BHF-UCL.
DR GO; GO:0043202; C:lysosomal lumen; TAS:Reactome.
DR GO; GO:0042470; C:melanosome; IEA:UniProtKB-SubCell.
DR GO; GO:0005739; C:mitochondrion; IEA:Ensembl.
DR GO; GO:0004190; F:aspartic-type endopeptidase activity; TAS:ProtInc.
DR GO; GO:0019886; P:antigen processing and presentation of exogenous peptide antigen via MHC class II; TAS:Reactome.
DR GO; GO:0000045; P:autophagic vacuole assembly; IEA:Ensembl.
DR GO; GO:0008219; P:cell death; IEA:UniProtKB-KW.
DR GO; GO:0030574; P:collagen catabolic process; TAS:Reactome.
DR GO; GO:0022617; P:extracellular matrix disassembly; TAS:Reactome.
DR GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW.
DR Gene3D; 2.40.70.10; -; 2.
DR InterPro; IPR001461; Aspartic_peptidase.
DR InterPro; IPR001969; Aspartic_peptidase_AS.
DR InterPro; IPR012848; Aspartic_peptidase_N.
DR InterPro; IPR021109; Peptidase_aspartic_dom.
DR PANTHER; PTHR13683; PTHR13683; 1.
DR Pfam; PF07966; A1_Propeptide; 1.
DR Pfam; PF00026; Asp; 1.
DR PRINTS; PR00792; PEPSIN.
DR SUPFAM; SSF50630; SSF50630; 1.
DR PROSITE; PS00141; ASP_PROTEASE; 2.
PE 1: Evidence at protein level;
KW 3D-structure; Alzheimer disease; Aspartyl protease; Complete proteome;
KW Direct protein sequencing; Disease mutation; Disulfide bond;
KW Glycoprotein; Hydrolase; Lysosome; Neurodegeneration;
KW Neuronal ceroid lipofuscinosis; Polymorphism; Protease;
KW Reference proteome; Secreted; Signal; Zymogen.
FT SIGNAL 1 18
FT PROPEP 19 64 Activation peptide.
FT /FTId=PRO_0000025949.
FT CHAIN 65 412 Cathepsin D.
FT /FTId=PRO_0000025950.
FT CHAIN 65 161 Cathepsin D light chain (Probable).
FT /FTId=PRO_0000025951.
FT CHAIN 169 412 Cathepsin D heavy chain (Probable).
FT /FTId=PRO_0000025952.
FT ACT_SITE 97 97
FT ACT_SITE 295 295
FT CARBOHYD 63 63 O-linked (GalNAc...).
FT CARBOHYD 134 134 N-linked (GlcNAc...).
FT CARBOHYD 263 263 N-linked (GlcNAc...).
FT DISULFID 91 160
FT DISULFID 110 117
FT DISULFID 286 290
FT DISULFID 329 366
FT VARIANT 58 58 A -> V (associated with increased risk
FT for AD; possibly influences secretion and
FT intracellular maturation; dbSNP:rs17571).
FT /FTId=VAR_011621.
FT VARIANT 229 229 F -> I (in CLN10).
FT /FTId=VAR_029362.
FT VARIANT 282 282 G -> R (in dbSNP:rs147278302).
FT /FTId=VAR_058490.
FT VARIANT 383 383 W -> C (in CLN10).
FT /FTId=VAR_029363.
FT STRAND 67 74
FT TURN 75 77
FT STRAND 78 85
FT TURN 86 89
FT STRAND 90 97
FT STRAND 103 107
FT HELIX 115 118
FT HELIX 125 127
FT STRAND 132 141
FT STRAND 146 159
FT STRAND 172 184
FT TURN 189 191
FT STRAND 194 200
FT HELIX 204 206
FT HELIX 208 210
FT HELIX 214 220
FT STRAND 224 233
FT STRAND 236 238
FT STRAND 243 247
FT HELIX 252 254
FT STRAND 255 263
FT TURN 267 270
FT STRAND 271 279
FT TURN 280 282
FT STRAND 284 286
FT STRAND 290 294
FT STRAND 299 303
FT HELIX 305 315
FT STRAND 318 321
FT STRAND 324 328
FT HELIX 329 334
FT STRAND 338 342
FT STRAND 345 349
FT TURN 351 353
FT STRAND 354 358
FT TURN 359 362
FT STRAND 363 372
FT TURN 377 379
FT STRAND 383 385
FT HELIX 387 390
FT STRAND 393 398
FT TURN 399 402
FT STRAND 403 409
SQ SEQUENCE 412 AA; 44552 MW; 903FB8412E0CF0B0 CRC64;
MQPSSLLPLA LCLLAAPASA LVRIPLHKFT SIRRTMSEVG GSVEDLIAKG PVSKYSQAVP
AVTEGPIPEV LKNYMDAQYY GEIGIGTPPQ CFTVVFDTGS SNLWVPSIHC KLLDIACWIH
HKYNSDKSST YVKNGTSFDI HYGSGSLSGY LSQDTVSVPC QSASSASALG GVKVERQVFG
EATKQPGITF IAAKFDGILG MAYPRISVNN VLPVFDNLMQ QKLVDQNIFS FYLSRDPDAQ
PGGELMLGGT DSKYYKGSLS YLNVTRKAYW QVHLDQVEVA SGLTLCKEGC EAIVDTGTSL
MVGPVDEVRE LQKAIGAVPL IQGEYMIPCE KVSTLPAITL KLGGKGYKLS PEDYTLKVSQ
AGKTLCLSGF MGMDIPPPSG PLWILGDVFI GRYYTVFDRD NNRVGFAEAA RL
//
MIM
116840
*RECORD*
*FIELD* NO
116840
*FIELD* TI
*116840 CATHEPSIN D; CTSD
*FIELD* TX
DESCRIPTION
Cathepsin D (EC 3.4.23.5) is one of the lysosomal proteinases. It is
read moreubiquitously expressed and is involved in proteolytic degradation, cell
invasion, and apoptosis (Steinfeld et al., 2006).
CLONING
Faust et al. (1985) cloned human cathepsin D from a kidney cDNA library.
The cDNA encodes a 412-amino acid protein with 20 and 44 amino acids in
a pre- and prosegment, respectively.
MAPPING
By study of somatic cell hybrids, Hasilik et al. (1982) assigned the
structural gene for cathepsin D to chromosome 11 and specifically to the
region 11pter-11q12. By somatic cell hybrid deletion mapping and in situ
hybridization, Qin et al. (1987) mapped CTSD to 11p15. Henry et al.
(1989) likewise mapped CTSD to 11p15 using somatic cell hybrids with
specific deletions. CTSD mapped distal to a breakpoint at 11p15.4.
MOLECULAR GENETICS
In mice and sheep, cathepsin D deficiency causes a fatal
neurodegenerative disease. Steinfeld et al. (2006) reported a novel
disorder in a child with early blindness and progressive psychomotor
disability (CLN10; 610127). They found compound heterozygosity for
missense mutations in the CTSD gene, phe229 to ile (F229I; 116840.0001)
and trp383 to cys (W383C; 116840.0002). The mutations caused markedly
reduced proteolytic activity and a diminished amount of cathepsin D in
the patient's fibroblasts. Expression of cathepsin D mutants in
fibroblasts of Ctsd -/- mice revealed disturbed posttranslational
processing and intracellular targeting for W383C and diminished maximal
enzyme velocity for F229I. Computer modeling suggested larger structural
alterations for W383C than for F229I.
In a Pakistani infant with severe congenital CLN10, Siintola et al.
(2006) identified a homozygous null mutation (116840.0003) in the CTSD
gene.
ANIMAL MODEL
Tyynela et al. (2000) identified a mutation in ovine cathepsin D that
accounts for congenital ovine neuronal ceroid lipofuscinosis (CONCL). In
this disorder, which is transmitted as an autosomal recessive, newborn
lambs are weak, trembling, and unable to rise and support their bodies.
However, they are able to vocalize, support their heads, and to suckle
if bottle-fed. At autopsy, the brains of affected lambs are strikingly
small. The deep layers of the cerebral cortex show pronounced neuronal
loss, reactive astrocytosis, and infiltration of macrophages. There is
severe degeneration of hippocampal pyramidal neurons. The cerebellum is
less affected. The basal ganglia, thalamus, and brainstem are relatively
spared. Visceral tissues are unaffected. These animals have normal
palmitoyl protein thioesterase activity, indicating that the molecular
bases of human infantile neuronal ceroid lipofuscinosis (see 256730) and
CONCL are distinct. As the pathology of CONCL suggested a lysosomal
storage disease, Tyynela et al. (2000) measured a range of lysosomal
enzyme activities and found strikingly deficient cathepsin D activity,
which was about 40% of normal in heterozygous lambs. A G-to-A transition
at nucleotide 934 was found in homozygosity in all affected animals.
This mutation results in a substitution of an asparagine for aspartate
at the codon corresponding to human asp295 of cathepsin D and asp215 of
pepsin (see 169700). This residue is conserved among all aspartyl
proteinases and represents 1 of the 2 aspartate residues that are
essential for catalytic function of these proteins.
*FIELD* AV
.0001
CEROID LIPOFUSCINOSIS, NEURONAL, 10
CTSD, PHE229ILE
In a patient with cathepsin D-deficient neuronal ceroid lipofuscinosis
(610127), Steinfeld et al. (2006) found compound heterozygosity for
mutations in the CTSD gene. On the maternal allele, a 6517T-A
transversion in exon 5 resulted in a phe229-to-ile (F229I) substitution.
The paternal allele carried a 10267G-C transversion in exon 9, resulting
in a trp383-to-cys (W383C) substitution. The F229I substitution in the
cathepsin D precursor protein corresponds to F165I in the mature
protein. Phe229 belongs to a group of 15 amino acids that are strictly
conserved among the members of the pepsin family of peptidases.
.0002
CEROID LIPOFUSCINOSIS, NEURONAL, 10
CTSD, TRP383CYS
See 116840.0001 and Steinfeld et al. (2006). The W383C substitution in
the cathepsin D precursor protein corresponds to W319C in the mature
protein. The residue trp383 is conserved among all 12 human pepsin
peptidases and nearly all other mammalian members of this family but is
not conserved within pepsin peptidases from more distantly related
species.
.0003
CEROID LIPOFUSCINOSIS, NEURONAL, 10
CTSD, 1-BP DUP, 764A
In a Pakistani infant with congenital CLN (610127), Siintola et al.
(2006) identified homozygosity for a 1-bp duplication, 764dupA, in exon
6 of the CTSD gene, resulting in a premature stop codon at codon 255
(tyr255-to-ter; Y255X), truncation of the protein by 158 amino acids,
and deletion of the active site aspartic acid residue at position 295.
The mutation was not identified in 550 control chromosomes. In vitro
functional expression studies in baby hamster kidney cells showed that
the mutant protein had no enzymatic activity. The unaffected father was
heterozygous for the mutation; DNA from the mother, who is the first
cousin of the father, was not available. There were 2 other affected
brothers in the same family, but DNA was not available from these
patients either. The 3 boys died at ages 10, 1, and 4 days of age,
respectively, after demonstrating intractable seizures, spasticity, and
apnea immediately after birth.
*FIELD* RF
1. Faust, P. L.; Kornfeld, S.; Chirgwin, J. M.: Cloning and sequence
analysis of cDNA for human cathepsin D. Proc. Nat. Acad. Sci. 82:
4910-4914, 1985.
2. Hasilik, A.; von Figura, K.; Grzeschik, K.-H.: Assignment of a
gene for human cathepsin D to chromosome 11. (Abstract) Cytogenet.
Cell Genet. 32: 284 only, 1982.
3. Henry, I.; Puech, A.; Antignac, C.; Couillin, P.; Jeanpierre, M.;
Ahnine, L.; Barichard, F.; Boehm, T.; Augereau, P.; Scrable, H.; Rabbitts,
T. H.; Rochefort, H.; Cavenee, W.; Junien, C.: Subregional mapping
of BWS, CTSD, MYOD1, and a T-ALL breakpoint in 11p15. (Abstract) Cytogenet.
Cell Genet. 51: 1013 only, 1989.
4. Qin, S.; Nakai, H.; Byers, M. G.; Eddy, R. L.; Haley, L. L.; Henry,
W. M.; Wang, X.; Watkins, P. C.; Chirgwin, J. M.; Shows, T. B.: Mapping
FSHB, CAT, and CTSD to specific sites on 11p. (Abstract) Cytogenet.
Cell Genet. 46: 678 only, 1987.
5. Siintola, E.; Partanen, S.; Stromme, P.; Haapanen, A.; Haltia,
M.; Maehlen, J.; Lehesjoki, A.-E.; Tyynela, J.: Cathepsin D deficiency
underlies congenital human neuronal ceroid-lipofuscinosis. Brain 129:
1438-1445, 2006.
6. Steinfeld, R.; Reinhardt, K.; Schreiber, K.; Hillebrand, M.; Kraetzner,
R.; Bruck, W.; Saftig, P.; Gartner, J.: Cathepsin D deficiency is
associated with a human neurodegenerative disorder. Am. J. Hum. Genet. 78:
988-998, 2006.
7. Tyynela, J.; Sohar, I.; Sleat, D. E.; Gin, R. M.; Donnelly, R.
J.; Baumann, M.; Haltia, M.; Lobel, P.: A mutation in the ovine cathepsin
D gene causes a congenital lysosomal storage disease with profound
neurodegeneration. EMBO J. 19: 2786-2792, 2000.
*FIELD* CN
Cassandra L. Kniffin - updated: 7/14/2006
Victor A. McKusick - updated: 5/15/2006
Ada Hamosh - updated: 8/14/2000
*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
wwang: 07/31/2006
ckniffin: 7/14/2006
joanna: 5/31/2006
alopez: 5/17/2006
terry: 5/15/2006
carol: 3/24/2006
alopez: 8/18/2000
terry: 8/14/2000
supermim: 3/16/1992
supermim: 3/20/1990
supermim: 3/9/1990
ddp: 10/26/1989
marie: 3/25/1988
carol: 2/26/1988
*RECORD*
*FIELD* NO
116840
*FIELD* TI
*116840 CATHEPSIN D; CTSD
*FIELD* TX
DESCRIPTION
Cathepsin D (EC 3.4.23.5) is one of the lysosomal proteinases. It is
read moreubiquitously expressed and is involved in proteolytic degradation, cell
invasion, and apoptosis (Steinfeld et al., 2006).
CLONING
Faust et al. (1985) cloned human cathepsin D from a kidney cDNA library.
The cDNA encodes a 412-amino acid protein with 20 and 44 amino acids in
a pre- and prosegment, respectively.
MAPPING
By study of somatic cell hybrids, Hasilik et al. (1982) assigned the
structural gene for cathepsin D to chromosome 11 and specifically to the
region 11pter-11q12. By somatic cell hybrid deletion mapping and in situ
hybridization, Qin et al. (1987) mapped CTSD to 11p15. Henry et al.
(1989) likewise mapped CTSD to 11p15 using somatic cell hybrids with
specific deletions. CTSD mapped distal to a breakpoint at 11p15.4.
MOLECULAR GENETICS
In mice and sheep, cathepsin D deficiency causes a fatal
neurodegenerative disease. Steinfeld et al. (2006) reported a novel
disorder in a child with early blindness and progressive psychomotor
disability (CLN10; 610127). They found compound heterozygosity for
missense mutations in the CTSD gene, phe229 to ile (F229I; 116840.0001)
and trp383 to cys (W383C; 116840.0002). The mutations caused markedly
reduced proteolytic activity and a diminished amount of cathepsin D in
the patient's fibroblasts. Expression of cathepsin D mutants in
fibroblasts of Ctsd -/- mice revealed disturbed posttranslational
processing and intracellular targeting for W383C and diminished maximal
enzyme velocity for F229I. Computer modeling suggested larger structural
alterations for W383C than for F229I.
In a Pakistani infant with severe congenital CLN10, Siintola et al.
(2006) identified a homozygous null mutation (116840.0003) in the CTSD
gene.
ANIMAL MODEL
Tyynela et al. (2000) identified a mutation in ovine cathepsin D that
accounts for congenital ovine neuronal ceroid lipofuscinosis (CONCL). In
this disorder, which is transmitted as an autosomal recessive, newborn
lambs are weak, trembling, and unable to rise and support their bodies.
However, they are able to vocalize, support their heads, and to suckle
if bottle-fed. At autopsy, the brains of affected lambs are strikingly
small. The deep layers of the cerebral cortex show pronounced neuronal
loss, reactive astrocytosis, and infiltration of macrophages. There is
severe degeneration of hippocampal pyramidal neurons. The cerebellum is
less affected. The basal ganglia, thalamus, and brainstem are relatively
spared. Visceral tissues are unaffected. These animals have normal
palmitoyl protein thioesterase activity, indicating that the molecular
bases of human infantile neuronal ceroid lipofuscinosis (see 256730) and
CONCL are distinct. As the pathology of CONCL suggested a lysosomal
storage disease, Tyynela et al. (2000) measured a range of lysosomal
enzyme activities and found strikingly deficient cathepsin D activity,
which was about 40% of normal in heterozygous lambs. A G-to-A transition
at nucleotide 934 was found in homozygosity in all affected animals.
This mutation results in a substitution of an asparagine for aspartate
at the codon corresponding to human asp295 of cathepsin D and asp215 of
pepsin (see 169700). This residue is conserved among all aspartyl
proteinases and represents 1 of the 2 aspartate residues that are
essential for catalytic function of these proteins.
*FIELD* AV
.0001
CEROID LIPOFUSCINOSIS, NEURONAL, 10
CTSD, PHE229ILE
In a patient with cathepsin D-deficient neuronal ceroid lipofuscinosis
(610127), Steinfeld et al. (2006) found compound heterozygosity for
mutations in the CTSD gene. On the maternal allele, a 6517T-A
transversion in exon 5 resulted in a phe229-to-ile (F229I) substitution.
The paternal allele carried a 10267G-C transversion in exon 9, resulting
in a trp383-to-cys (W383C) substitution. The F229I substitution in the
cathepsin D precursor protein corresponds to F165I in the mature
protein. Phe229 belongs to a group of 15 amino acids that are strictly
conserved among the members of the pepsin family of peptidases.
.0002
CEROID LIPOFUSCINOSIS, NEURONAL, 10
CTSD, TRP383CYS
See 116840.0001 and Steinfeld et al. (2006). The W383C substitution in
the cathepsin D precursor protein corresponds to W319C in the mature
protein. The residue trp383 is conserved among all 12 human pepsin
peptidases and nearly all other mammalian members of this family but is
not conserved within pepsin peptidases from more distantly related
species.
.0003
CEROID LIPOFUSCINOSIS, NEURONAL, 10
CTSD, 1-BP DUP, 764A
In a Pakistani infant with congenital CLN (610127), Siintola et al.
(2006) identified homozygosity for a 1-bp duplication, 764dupA, in exon
6 of the CTSD gene, resulting in a premature stop codon at codon 255
(tyr255-to-ter; Y255X), truncation of the protein by 158 amino acids,
and deletion of the active site aspartic acid residue at position 295.
The mutation was not identified in 550 control chromosomes. In vitro
functional expression studies in baby hamster kidney cells showed that
the mutant protein had no enzymatic activity. The unaffected father was
heterozygous for the mutation; DNA from the mother, who is the first
cousin of the father, was not available. There were 2 other affected
brothers in the same family, but DNA was not available from these
patients either. The 3 boys died at ages 10, 1, and 4 days of age,
respectively, after demonstrating intractable seizures, spasticity, and
apnea immediately after birth.
*FIELD* RF
1. Faust, P. L.; Kornfeld, S.; Chirgwin, J. M.: Cloning and sequence
analysis of cDNA for human cathepsin D. Proc. Nat. Acad. Sci. 82:
4910-4914, 1985.
2. Hasilik, A.; von Figura, K.; Grzeschik, K.-H.: Assignment of a
gene for human cathepsin D to chromosome 11. (Abstract) Cytogenet.
Cell Genet. 32: 284 only, 1982.
3. Henry, I.; Puech, A.; Antignac, C.; Couillin, P.; Jeanpierre, M.;
Ahnine, L.; Barichard, F.; Boehm, T.; Augereau, P.; Scrable, H.; Rabbitts,
T. H.; Rochefort, H.; Cavenee, W.; Junien, C.: Subregional mapping
of BWS, CTSD, MYOD1, and a T-ALL breakpoint in 11p15. (Abstract) Cytogenet.
Cell Genet. 51: 1013 only, 1989.
4. Qin, S.; Nakai, H.; Byers, M. G.; Eddy, R. L.; Haley, L. L.; Henry,
W. M.; Wang, X.; Watkins, P. C.; Chirgwin, J. M.; Shows, T. B.: Mapping
FSHB, CAT, and CTSD to specific sites on 11p. (Abstract) Cytogenet.
Cell Genet. 46: 678 only, 1987.
5. Siintola, E.; Partanen, S.; Stromme, P.; Haapanen, A.; Haltia,
M.; Maehlen, J.; Lehesjoki, A.-E.; Tyynela, J.: Cathepsin D deficiency
underlies congenital human neuronal ceroid-lipofuscinosis. Brain 129:
1438-1445, 2006.
6. Steinfeld, R.; Reinhardt, K.; Schreiber, K.; Hillebrand, M.; Kraetzner,
R.; Bruck, W.; Saftig, P.; Gartner, J.: Cathepsin D deficiency is
associated with a human neurodegenerative disorder. Am. J. Hum. Genet. 78:
988-998, 2006.
7. Tyynela, J.; Sohar, I.; Sleat, D. E.; Gin, R. M.; Donnelly, R.
J.; Baumann, M.; Haltia, M.; Lobel, P.: A mutation in the ovine cathepsin
D gene causes a congenital lysosomal storage disease with profound
neurodegeneration. EMBO J. 19: 2786-2792, 2000.
*FIELD* CN
Cassandra L. Kniffin - updated: 7/14/2006
Victor A. McKusick - updated: 5/15/2006
Ada Hamosh - updated: 8/14/2000
*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
wwang: 07/31/2006
ckniffin: 7/14/2006
joanna: 5/31/2006
alopez: 5/17/2006
terry: 5/15/2006
carol: 3/24/2006
alopez: 8/18/2000
terry: 8/14/2000
supermim: 3/16/1992
supermim: 3/20/1990
supermim: 3/9/1990
ddp: 10/26/1989
marie: 3/25/1988
carol: 2/26/1988
MIM
610127
*RECORD*
*FIELD* NO
610127
*FIELD* TI
#610127 CEROID LIPOFUSCINOSIS, NEURONAL, 10; CLN10
;;CEROID LIPOFUSCINOSIS, NEURONAL, CATHEPSIN D-DEFICIENT;;
read moreNEURONAL CEROID LIPOFUSCINOSIS DUE TO CATHEPSIN D DEFICIENCY
NEURONAL CEROID LIPOFUSCINOSIS, CONGENITAL, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because this disorder is
caused by mutation in the cathepsin D gene (CTSD; 116840).
CLINICAL FEATURES
For a general phenotypic description and a discussion of genetic
heterogeneity of neuronal ceroid lipofuscinosis (NCL; CLN), see CLN1
(256730).
Various forms of CLN are characterized by developmental regression,
visual loss, and epilepsy in addition to the name-giving accumulation of
autofluorescent liposomal storage material. Steinfeld et al. (2006)
identified a patient with cathepsin D deficiency in a group of 25
infants and children with a nonidentified genetic cause of a CLN-like
disorder. The affected child had normal early psychomotor development
and first showed neurodegenerative symptoms, namely ataxia and visual
disturbances, at early school age. The ocular fundus showed retinitis
pigmentosa, and cranial MRI scans showed cerebral and cerebellar
atrophy. In the course of disease, she developed progressive cognitive
decline, loss of speech, retinal atrophy, and loss of motor functions.
At the age of 17 years, she was wheelchair-bound and severely mentally
retarded. Ultrastructural examination of skin biopsy material revealed
granular osmiophilic-like deposits and myelin-like lamellar structures
in nonmyelinated Schwann cells. In comparison with the granular deposits
characteristic of CLN1 (256730), these granular inclusions appeared more
heterogeneous and were less abundant within cells. The myelin-like
lamellar structures are less specific for CLN, being often found in
other storage diseases such as the mucopolysaccharidoses. Inclusions
were not found in patient endothelial cells, fibroblasts, sweat glands,
or peripheral lymphocytes.
- Congenital Neuronal Ceroid Lipofuscinosis
Barohn et al. (1992) noted that the clinical expression of CLN rarely
occurs at birth, the so-called 'congenital' form.
Norman and Wood (1941) and Brown et al. (1954) reported 2 sibs with
congenital CLN. The patient reported by Norman and Wood (1941) had
microcephaly and respiratory difficulties and died at age 18 days.
Postmortem examination showed multiple intracellular lipoid inclusions
throughout the brain and less so in the reticuloendothelial system. The
patient reported by Brown et al. (1954) showed microcephaly, rigidity,
and apnea from birth and died at 7 weeks of age. Postmortem examination
showed a small, firm brain with neuronal lipoid inclusions.
Sandbank (1968) reported the findings in 2 infants, born to a
consanguineous couple, who died at ages 24 and 48 hours. Six other
children of this couple had reportedly died within 48 hours of delivery.
The 2 infants, a male and a female, showed hyperkinetic movements,
tremor of the hands and legs, absence of pupillary reactions, and
absence of Moro and grasping reflexes. The brains of both infants were
small and firm with severe loss of neurons and extensive gliosis. There
were multiple large cells in the brain with an eosinophilic,
intracellular material; similar material was observed in cells of the
reticuloendothelial system. Sandbank (1968) noted the similarities to
the patient reported by Norman and Wood (1941).
Humphreys et al. (1985) reported an affected infant who died at age 29
hours from respiratory failure. The brain was small and firm with marked
neuronal loss and gliosis. Granular lipopigment material was identified
in astrocytes, macrophages, and residual neurons. Similar material was
observed in cells from the liver, spleen, thymus, and lung. Humphreys et
al. (1985) noted similarities to infantile and juvenile Batten disease
(see, e.g., CLN3, 204200).
Barohn et al. (1992) reported an affected infant who was microcephalic
and had generalized seizures at birth. He developed cyanosis and
bradycardia and died 36 hours after birth. Neuropathologic examination
showed severe cerebral atrophy and diffuse ballooning of neurons with
autofluorescent lipid accumulation. The white matter was gliotic, and no
myelin was observed.
Siintola et al. (2006) reported a Pakistani child, born of first-cousin
parents, with congenital CLN. He had 2 affected brothers. All 3 affected
fetuses demonstrated deceleration of head growth in the last trimester
and were born microcephalic with overriding sutures and obliterated
fontanels. Other dysmorphic features included low-set ears and broad
nasal bridge. The infants showed seizures, spasticity, and central apnea
from birth and died at ages 10, 1, and 4 days, respectively. Siintola et
al. (2006) also reported a fourth similarly affected infant from an
unrelated family who died within 29 hours after birth. Neuropathologic
examination of 3 of the patients showed severe neuronal loss in the
cerebral and cerebellar cortices, glial activation, and white matter
almost devoid of axons and myelin. Immunostaining for the cathepsin D
protein was almost absent in brain tissue. In 1 affected infant from the
first family, Siintola et al. (2006) identified a homozygous null
mutation in the CTSD gene (116840.0003).
MOLECULAR GENETICS
In a patient with cathepsin D deficiency manifesting as a CLN-like
disorder, Steinfeld et al. (2006) identified compound heterozygosity for
missense mutations in the CTSD gene. The maternal allele carried a
phe229-to-ile substitution (F229I; 116840.0001), and the paternal allele
a trp383-to-cys substitution (W383C; 116840.0002). The mutations caused
markedly reduced proteolytic activity, and a diminished amount of
cathepsin D was found in patient fibroblasts.
GENOTYPE/PHENOTYPE CORRELATIONS
In a Pakistani infant with severe congenital NCL, Siintola et al. (2006)
identified a homozygous null mutation in the CTSD gene (116840.0003).
The extreme clinical phenotype, including postnatal apnea, seizures, and
early death, were consistent with complete inactivation of the cathepsin
D protein.
*FIELD* RF
1. Barohn, R. J.; Dowd, D. C.; Kagan-Hallet, K. S.: Congenital ceroid-lipofuscinosis. Pediatr.
Neurol. 8: 54-59, 1992.
2. Brown, N. J.; Corner, B. D.; Dodgson, M. C. H.: A second case
in the same family of congenital familial cerebral lipoidosis resembling
amaurotic family idiocy. Arch. Dis. Child 29: 48-54, 1954.
3. Humphreys, S.; Lake, B. D.; Scholtz, C. L.: Congenital amaurotic
idiocy--a pathological, histochemical, biochemical and ultrastructural
study. Neuropath. Appl. Neurobiol. 11: 475-484, 1985.
4. Norman, R. M.; Wood, N.: A congenital form of amaurotic family
idiocy. J. Neurol. Psychiat. 4: 175-190, 1941.
5. Sandbank, U.: Congenital amaurotic idiocy. Path. Europ. 3: 226-229,
1968.
6. Siintola, E.; Partanen, S.; Stromme, P.; Haapanen, A.; Haltia,
M.; Maehlen, J.; Lehesjoki, A.-E.; Tyynela, J.: Cathepsin D deficiency
underlies congenital human neuronal ceroid-lipofuscinosis. Brain 129:
1438-1445, 2006.
7. Steinfeld, R.; Reinhardt, K.; Schreiber, K.; Hillebrand, M.; Kraetzner,
R.; Bruck, W.; Saftig, P.; Gartner, J.: Cathepsin D deficiency is
associated with a human neurodegenerative disorder. Am. J. Hum. Genet. 78:
988-998, 2006.
*FIELD* CS
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Head];
Microcephaly;
[Face];
Sloping forehead;
[Ears];
Low-set ears;
[Eyes];
Loss of vision, progressive;
Retinitis pigmentosa;
Retinal atrophy;
[Nose];
Broad nasal bridge
RESPIRATORY:
Apnea;
Respiratory failure
SKELETAL:
[Skull];
Overriding sutures;
Obliterated fontanelles
NEUROLOGIC:
[Central nervous system];
Spasticity;
Rigidity;
Seizures;
Status epilepticus;
Ataxia;
Some patients may show normal early development;
Mental retardation, severe;
Loss of motor functions;
MRI shows cerebral atrophy;
MRI shows cerebellar atrophy;
Neuronal loss in the cerebrum and cerebellum;
Glial activation;
White matter lacks axons and myelin;
Autofluorescent lipopigment in neurons;
Granular osmiophilic cytoplasmic deposits in Schwann cells;
Myelin-like lamellar structures in Schwann cells
LABORATORY ABNORMALITIES:
Decrease or absence of cathepsin D (CTSD) protein immunostaining
MISCELLANEOUS:
Onset at birth or early childhood;
Patients with null mutations in (CTSD) show a more severe phenotype
with onset at birth ('congenital NCL') and early death within days
MOLECULAR BASIS:
Caused by mutation in the cathepsin D gene (CTSD, 116840.0001).
*FIELD* CD
Cassandra L. Kniffin: 5/17/2006
*FIELD* ED
joanna: 10/31/2006
ckniffin: 7/14/2006
alopez: 5/17/2006
*FIELD* CN
Cassandra L. Kniffin - updated: 11/22/2006
Cassandra L. Kniffin - updated: 7/14/2006
*FIELD* CD
Victor A. McKusick: 5/17/2006
*FIELD* ED
terry: 08/09/2007
carol: 6/22/2007
carol: 1/5/2007
ckniffin: 11/22/2006
wwang: 8/1/2006
wwang: 7/31/2006
ckniffin: 7/14/2006
alopez: 5/24/2006
alopez: 5/17/2006
*RECORD*
*FIELD* NO
610127
*FIELD* TI
#610127 CEROID LIPOFUSCINOSIS, NEURONAL, 10; CLN10
;;CEROID LIPOFUSCINOSIS, NEURONAL, CATHEPSIN D-DEFICIENT;;
read moreNEURONAL CEROID LIPOFUSCINOSIS DUE TO CATHEPSIN D DEFICIENCY
NEURONAL CEROID LIPOFUSCINOSIS, CONGENITAL, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because this disorder is
caused by mutation in the cathepsin D gene (CTSD; 116840).
CLINICAL FEATURES
For a general phenotypic description and a discussion of genetic
heterogeneity of neuronal ceroid lipofuscinosis (NCL; CLN), see CLN1
(256730).
Various forms of CLN are characterized by developmental regression,
visual loss, and epilepsy in addition to the name-giving accumulation of
autofluorescent liposomal storage material. Steinfeld et al. (2006)
identified a patient with cathepsin D deficiency in a group of 25
infants and children with a nonidentified genetic cause of a CLN-like
disorder. The affected child had normal early psychomotor development
and first showed neurodegenerative symptoms, namely ataxia and visual
disturbances, at early school age. The ocular fundus showed retinitis
pigmentosa, and cranial MRI scans showed cerebral and cerebellar
atrophy. In the course of disease, she developed progressive cognitive
decline, loss of speech, retinal atrophy, and loss of motor functions.
At the age of 17 years, she was wheelchair-bound and severely mentally
retarded. Ultrastructural examination of skin biopsy material revealed
granular osmiophilic-like deposits and myelin-like lamellar structures
in nonmyelinated Schwann cells. In comparison with the granular deposits
characteristic of CLN1 (256730), these granular inclusions appeared more
heterogeneous and were less abundant within cells. The myelin-like
lamellar structures are less specific for CLN, being often found in
other storage diseases such as the mucopolysaccharidoses. Inclusions
were not found in patient endothelial cells, fibroblasts, sweat glands,
or peripheral lymphocytes.
- Congenital Neuronal Ceroid Lipofuscinosis
Barohn et al. (1992) noted that the clinical expression of CLN rarely
occurs at birth, the so-called 'congenital' form.
Norman and Wood (1941) and Brown et al. (1954) reported 2 sibs with
congenital CLN. The patient reported by Norman and Wood (1941) had
microcephaly and respiratory difficulties and died at age 18 days.
Postmortem examination showed multiple intracellular lipoid inclusions
throughout the brain and less so in the reticuloendothelial system. The
patient reported by Brown et al. (1954) showed microcephaly, rigidity,
and apnea from birth and died at 7 weeks of age. Postmortem examination
showed a small, firm brain with neuronal lipoid inclusions.
Sandbank (1968) reported the findings in 2 infants, born to a
consanguineous couple, who died at ages 24 and 48 hours. Six other
children of this couple had reportedly died within 48 hours of delivery.
The 2 infants, a male and a female, showed hyperkinetic movements,
tremor of the hands and legs, absence of pupillary reactions, and
absence of Moro and grasping reflexes. The brains of both infants were
small and firm with severe loss of neurons and extensive gliosis. There
were multiple large cells in the brain with an eosinophilic,
intracellular material; similar material was observed in cells of the
reticuloendothelial system. Sandbank (1968) noted the similarities to
the patient reported by Norman and Wood (1941).
Humphreys et al. (1985) reported an affected infant who died at age 29
hours from respiratory failure. The brain was small and firm with marked
neuronal loss and gliosis. Granular lipopigment material was identified
in astrocytes, macrophages, and residual neurons. Similar material was
observed in cells from the liver, spleen, thymus, and lung. Humphreys et
al. (1985) noted similarities to infantile and juvenile Batten disease
(see, e.g., CLN3, 204200).
Barohn et al. (1992) reported an affected infant who was microcephalic
and had generalized seizures at birth. He developed cyanosis and
bradycardia and died 36 hours after birth. Neuropathologic examination
showed severe cerebral atrophy and diffuse ballooning of neurons with
autofluorescent lipid accumulation. The white matter was gliotic, and no
myelin was observed.
Siintola et al. (2006) reported a Pakistani child, born of first-cousin
parents, with congenital CLN. He had 2 affected brothers. All 3 affected
fetuses demonstrated deceleration of head growth in the last trimester
and were born microcephalic with overriding sutures and obliterated
fontanels. Other dysmorphic features included low-set ears and broad
nasal bridge. The infants showed seizures, spasticity, and central apnea
from birth and died at ages 10, 1, and 4 days, respectively. Siintola et
al. (2006) also reported a fourth similarly affected infant from an
unrelated family who died within 29 hours after birth. Neuropathologic
examination of 3 of the patients showed severe neuronal loss in the
cerebral and cerebellar cortices, glial activation, and white matter
almost devoid of axons and myelin. Immunostaining for the cathepsin D
protein was almost absent in brain tissue. In 1 affected infant from the
first family, Siintola et al. (2006) identified a homozygous null
mutation in the CTSD gene (116840.0003).
MOLECULAR GENETICS
In a patient with cathepsin D deficiency manifesting as a CLN-like
disorder, Steinfeld et al. (2006) identified compound heterozygosity for
missense mutations in the CTSD gene. The maternal allele carried a
phe229-to-ile substitution (F229I; 116840.0001), and the paternal allele
a trp383-to-cys substitution (W383C; 116840.0002). The mutations caused
markedly reduced proteolytic activity, and a diminished amount of
cathepsin D was found in patient fibroblasts.
GENOTYPE/PHENOTYPE CORRELATIONS
In a Pakistani infant with severe congenital NCL, Siintola et al. (2006)
identified a homozygous null mutation in the CTSD gene (116840.0003).
The extreme clinical phenotype, including postnatal apnea, seizures, and
early death, were consistent with complete inactivation of the cathepsin
D protein.
*FIELD* RF
1. Barohn, R. J.; Dowd, D. C.; Kagan-Hallet, K. S.: Congenital ceroid-lipofuscinosis. Pediatr.
Neurol. 8: 54-59, 1992.
2. Brown, N. J.; Corner, B. D.; Dodgson, M. C. H.: A second case
in the same family of congenital familial cerebral lipoidosis resembling
amaurotic family idiocy. Arch. Dis. Child 29: 48-54, 1954.
3. Humphreys, S.; Lake, B. D.; Scholtz, C. L.: Congenital amaurotic
idiocy--a pathological, histochemical, biochemical and ultrastructural
study. Neuropath. Appl. Neurobiol. 11: 475-484, 1985.
4. Norman, R. M.; Wood, N.: A congenital form of amaurotic family
idiocy. J. Neurol. Psychiat. 4: 175-190, 1941.
5. Sandbank, U.: Congenital amaurotic idiocy. Path. Europ. 3: 226-229,
1968.
6. Siintola, E.; Partanen, S.; Stromme, P.; Haapanen, A.; Haltia,
M.; Maehlen, J.; Lehesjoki, A.-E.; Tyynela, J.: Cathepsin D deficiency
underlies congenital human neuronal ceroid-lipofuscinosis. Brain 129:
1438-1445, 2006.
7. Steinfeld, R.; Reinhardt, K.; Schreiber, K.; Hillebrand, M.; Kraetzner,
R.; Bruck, W.; Saftig, P.; Gartner, J.: Cathepsin D deficiency is
associated with a human neurodegenerative disorder. Am. J. Hum. Genet. 78:
988-998, 2006.
*FIELD* CS
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Head];
Microcephaly;
[Face];
Sloping forehead;
[Ears];
Low-set ears;
[Eyes];
Loss of vision, progressive;
Retinitis pigmentosa;
Retinal atrophy;
[Nose];
Broad nasal bridge
RESPIRATORY:
Apnea;
Respiratory failure
SKELETAL:
[Skull];
Overriding sutures;
Obliterated fontanelles
NEUROLOGIC:
[Central nervous system];
Spasticity;
Rigidity;
Seizures;
Status epilepticus;
Ataxia;
Some patients may show normal early development;
Mental retardation, severe;
Loss of motor functions;
MRI shows cerebral atrophy;
MRI shows cerebellar atrophy;
Neuronal loss in the cerebrum and cerebellum;
Glial activation;
White matter lacks axons and myelin;
Autofluorescent lipopigment in neurons;
Granular osmiophilic cytoplasmic deposits in Schwann cells;
Myelin-like lamellar structures in Schwann cells
LABORATORY ABNORMALITIES:
Decrease or absence of cathepsin D (CTSD) protein immunostaining
MISCELLANEOUS:
Onset at birth or early childhood;
Patients with null mutations in (CTSD) show a more severe phenotype
with onset at birth ('congenital NCL') and early death within days
MOLECULAR BASIS:
Caused by mutation in the cathepsin D gene (CTSD, 116840.0001).
*FIELD* CD
Cassandra L. Kniffin: 5/17/2006
*FIELD* ED
joanna: 10/31/2006
ckniffin: 7/14/2006
alopez: 5/17/2006
*FIELD* CN
Cassandra L. Kniffin - updated: 11/22/2006
Cassandra L. Kniffin - updated: 7/14/2006
*FIELD* CD
Victor A. McKusick: 5/17/2006
*FIELD* ED
terry: 08/09/2007
carol: 6/22/2007
carol: 1/5/2007
ckniffin: 11/22/2006
wwang: 8/1/2006
wwang: 7/31/2006
ckniffin: 7/14/2006
alopez: 5/24/2006
alopez: 5/17/2006