RBCC Red Blood Cell Collection

PEPD (PRD) [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Xaa-Pro dipeptidase; X-Pro dipeptidase; 3.4.13.9 (Imidodipeptidase; Peptidase D; Proline dipeptidase; Prolidase)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

hRBCD IPI00257882
IPI00257882 Xaa-Pro dipeptidase Splits dipeptides with a prolyl or hydroxyprolyl residue in the C-terminal position. Plays an important role in collagen metabolism because of the high level of iminoacids in collagen, metallocarboxypeptidase D activity amino acid metabolism proteolysis and peptidolysis soluble n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a cytoplasmic n/a found at its expected molecular weight found at molecular weight

UniProt P12955
ID PEPD_HUMAN Reviewed; 493 AA.
AC P12955; A8K3Z1; A8K416; A8K696; A8MX47; B4DDB7; B4DGJ1; E9PCE8;
read moreAC Q8TBN9; Q9BT75;
DT 01-JAN-1990, integrated into UniProtKB/Swiss-Prot.
DT 23-JAN-2007, sequence version 3.
DT 22-JAN-2014, entry version 165.
DE RecName: Full=Xaa-Pro dipeptidase;
DE Short=X-Pro dipeptidase;
DE EC=3.4.13.9;
DE AltName: Full=Imidodipeptidase;
DE AltName: Full=Peptidase D;
DE AltName: Full=Proline dipeptidase;
DE Short=Prolidase;
GN Name=PEPD; Synonyms=PRD;
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 1), AND PARTIAL PROTEIN SEQUENCE.
RC TISSUE=Liver, and Placenta;
RX PubMed=2925654;
RA Endo F., Tanoue A., Nakai H., Hata A., Indo Y., Titani K., Matsuda I.;
RT "Primary structure and gene localization of human prolidase.";
RL J. Biol. Chem. 264:4476-4481(1989).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
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 (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1; 2 AND 3), AND
RP VARIANT PHE-435.
RC TISSUE=Brain, and Kidney;
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 [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15057824; DOI=10.1038/nature02399;
RA Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J.,
RA Lamerdin J.E., Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M.,
RA Aerts A., Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E.,
RA Caenepeel S., Carrano A.V., Caoile C., Chan Y.M., Christensen M.,
RA Cleland C.A., Copeland A., Dalin E., Dehal P., Denys M., Detter J.C.,
RA Escobar J., Flowers D., Fotopulos D., Garcia C., Georgescu A.M.,
RA Glavina T., Gomez M., Gonzales E., Groza M., Hammon N., Hawkins T.,
RA Haydu L., Ho I., Huang W., Israni S., Jett J., Kadner K., Kimball H.,
RA Kobayashi A., Larionov V., Leem S.-H., Lopez F., Lou Y., Lowry S.,
RA Malfatti S., Martinez D., McCready P.M., Medina C., Morgan J.,
RA Nelson K., Nolan M., Ovcharenko I., Pitluck S., Pollard M.,
RA Popkie A.P., Predki P., Quan G., Ramirez L., Rash S., Retterer J.,
RA Rodriguez A., Rogers S., Salamov A., Salazar A., She X., Smith D.,
RA Slezak T., Solovyev V., Thayer N., Tice H., Tsai M., Ustaszewska A.,
RA Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J., Dubchak I.,
RA Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E.,
RA Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M.,
RA Rubin E.M., Lucas S.M.;
RT "The DNA sequence and biology of human chromosome 19.";
RL Nature 428:529-535(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT
RP PHE-435.
RC TISSUE=Kidney, Skin, and Uterus;
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 [6]
RP MASS SPECTROMETRY.
RC TISSUE=Mammary cancer;
RX PubMed=11840567;
RX DOI=10.1002/1615-9861(200202)2:2<212::AID-PROT212>3.0.CO;2-H;
RA Harris R.A., Yang A., Stein R.C., Lucy K., Brusten L., Herath A.,
RA Parekh R., Waterfield M.D., O'Hare M.J., Neville M.A., Page M.J.,
RA Zvelebil M.J.;
RT "Cluster analysis of an extensive human breast cancer cell line
RT protein expression map database.";
RL Proteomics 2:212-223(2002).
RN [7]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [8]
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 [9]
RP X-RAY CRYSTALLOGRAPHY (1.82 ANGSTROMS) IN COMPLEX WITH MANGANESE IONS,
RP AND COFACTOR.
RG Protein structure factory (PSF);
RT "Crystal structure of human prolidase: the molecular basis of PD
RT disease.";
RL Submitted (FEB-2009) to the PDB data bank.
RN [10]
RP VARIANT PD ASN-276.
RX PubMed=2365824; DOI=10.1172/JCI114708;
RA Tanoue A., Endo F., Kitano A., Matsuda I.;
RT "A single nucleotide change in the prolidase gene in fibroblasts from
RT two patients with polypeptide positive prolidase deficiency.
RT Expression of the mutant enzyme in NIH 3T3 cells.";
RL J. Clin. Invest. 86:351-355(1990).
RN [11]
RP VARIANTS PD ARG-448 AND GLU-452 DEL.
RX PubMed=8198124;
RA Ledoux P., Scriver C.R., Hechtman P.;
RT "Four novel PEPD alleles causing prolidase deficiency.";
RL Am. J. Hum. Genet. 54:1014-1021(1994).
RN [12]
RP VARIANTS PD GLN-184; ASP-278; ARG-448 AND GLU-452 DEL.
RX PubMed=8900231;
RA Ledoux P., Scriver C.R., Hechtman P.;
RT "Expression and molecular analysis of mutations in prolidase
RT deficiency.";
RL Am. J. Hum. Genet. 59:1035-1039(1996).
RN [13]
RP VARIANT PD ARG-448.
RX PubMed=12384772; DOI=10.1007/s00439-002-0792-5;
RA Forlino A., Lupi A., Vaghi P., Icaro Cornaglia A., Calligaro A.,
RA Campari E., Cetta G.;
RT "Mutation analysis of five new patients affected by prolidase
RT deficiency: the lack of enzyme activity causes necrosis-like cell
RT death in cultured fibroblasts.";
RL Hum. Genet. 111:314-322(2002).
CC -!- FUNCTION: Splits dipeptides with a prolyl or hydroxyprolyl residue
CC in the C-terminal position. Plays an important role in collagen
CC metabolism because the high level of iminoacids in collagen.
CC -!- CATALYTIC ACTIVITY: Hydrolysis of Xaa-|-Pro dipeptides; also acts
CC on aminoacyl-hydroxyproline analogs. No action on Pro-|-Pro.
CC -!- COFACTOR: Binds 2 manganese ions per subunit.
CC -!- SUBUNIT: Homodimer.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=P12955-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P12955-2; Sequence=VSP_042629;
CC Note=No experimental confirmation available;
CC Name=3;
CC IsoId=P12955-3; Sequence=VSP_045370;
CC Note=No experimental confirmation available;
CC -!- MASS SPECTROMETRY: Mass=54251.73; Method=MALDI; Range=2-493;
CC Source=PubMed:11840567;
CC -!- DISEASE: Prolidase deficiency (PD) [MIM:170100]: A multisystem
CC disorder associated with massive iminodipeptiduria and lack of or
CC reduced prolidase activity in erythrocytes, leukocytes, or
CC cultured fibroblasts. Clinical features include skin ulcers,
CC developmental delay, recurrent infections, and a characteristic
CC facies. Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- SIMILARITY: Belongs to the peptidase M24B family. Eukaryotic-type
CC prolidase subfamily.
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DR EMBL; J04605; AAA60064.1; -; mRNA.
DR EMBL; BT006692; AAP35338.1; -; mRNA.
DR EMBL; AK290756; BAF83445.1; -; mRNA.
DR EMBL; AK290781; BAF83470.1; -; mRNA.
DR EMBL; AK291561; BAF84250.1; -; mRNA.
DR EMBL; AK293126; BAG56678.1; -; mRNA.
DR EMBL; AK294619; BAG57802.1; -; mRNA.
DR EMBL; AC008744; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC010485; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC004305; AAH04305.1; -; mRNA.
DR EMBL; BC015027; AAH15027.1; -; mRNA.
DR EMBL; BC028295; AAH28295.1; -; mRNA.
DR PIR; A32454; A32454.
DR RefSeq; NP_000276.2; NM_000285.3.
DR RefSeq; NP_001159528.1; NM_001166056.1.
DR RefSeq; NP_001159529.1; NM_001166057.1.
DR UniGene; Hs.36473; -.
DR PDB; 2IW2; X-ray; 1.82 A; A/B=2-492.
DR PDB; 2OKN; X-ray; 2.45 A; A/B=2-492.
DR PDBsum; 2IW2; -.
DR PDBsum; 2OKN; -.
DR ProteinModelPortal; P12955; -.
DR SMR; P12955; 6-482.
DR IntAct; P12955; 8.
DR MINT; MINT-5000488; -.
DR STRING; 9606.ENSP00000244137; -.
DR BindingDB; P12955; -.
DR ChEMBL; CHEMBL4185; -.
DR MEROPS; M24.007; -.
DR PhosphoSite; P12955; -.
DR DMDM; 50403718; -.
DR REPRODUCTION-2DPAGE; IPI00257882; -.
DR PaxDb; P12955; -.
DR PeptideAtlas; P12955; -.
DR PRIDE; P12955; -.
DR DNASU; 5184; -.
DR Ensembl; ENST00000244137; ENSP00000244137; ENSG00000124299.
DR Ensembl; ENST00000397032; ENSP00000380226; ENSG00000124299.
DR Ensembl; ENST00000436370; ENSP00000391890; ENSG00000124299.
DR GeneID; 5184; -.
DR KEGG; hsa:5184; -.
DR UCSC; uc002nur.4; human.
DR CTD; 5184; -.
DR GeneCards; GC19M033877; -.
DR HGNC; HGNC:8840; PEPD.
DR HPA; HPA015599; -.
DR MIM; 170100; phenotype.
DR MIM; 613230; gene.
DR neXtProt; NX_P12955; -.
DR Orphanet; 742; Prolidase deficiency.
DR PharmGKB; PA33181; -.
DR eggNOG; COG0006; -.
DR HOGENOM; HOG000008763; -.
DR HOVERGEN; HBG053562; -.
DR InParanoid; P12955; -.
DR KO; K14213; -.
DR OMA; PIVACGE; -.
DR OrthoDB; EOG7FNC76; -.
DR PhylomeDB; P12955; -.
DR ChiTaRS; PEPD; human.
DR EvolutionaryTrace; P12955; -.
DR GeneWiki; PEPD; -.
DR GenomeRNAi; 5184; -.
DR NextBio; 20054; -.
DR PRO; PR:P12955; -.
DR ArrayExpress; P12955; -.
DR Bgee; P12955; -.
DR CleanEx; HS_PEPD; -.
DR Genevestigator; P12955; -.
DR GO; GO:0004177; F:aminopeptidase activity; IEA:InterPro.
DR GO; GO:0016805; F:dipeptidase activity; IEA:UniProtKB-KW.
DR GO; GO:0030145; F:manganese ion binding; IEA:InterPro.
DR GO; GO:0004181; F:metallocarboxypeptidase activity; TAS:ProtInc.
DR GO; GO:0006520; P:cellular amino acid metabolic process; TAS:ProtInc.
DR GO; GO:0030574; P:collagen catabolic process; IEA:UniProtKB-KW.
DR GO; GO:0006508; P:proteolysis; TAS:ProtInc.
DR Gene3D; 3.90.230.10; -; 1.
DR InterPro; IPR007865; Aminopep_P_N.
DR InterPro; IPR000994; Pept_M24_structural-domain.
DR InterPro; IPR001131; Peptidase_M24B_aminopep-P_CS.
DR Pfam; PF05195; AMP_N; 1.
DR Pfam; PF00557; Peptidase_M24; 1.
DR SMART; SM01011; AMP_N; 1.
DR SUPFAM; SSF55920; SSF55920; 1.
DR PROSITE; PS00491; PROLINE_PEPTIDASE; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Collagen degradation;
KW Complete proteome; Dipeptidase; Direct protein sequencing;
KW Disease mutation; Hydrolase; Manganese; Metal-binding;
KW Metalloprotease; Polymorphism; Protease; Reference proteome.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 493 Xaa-Pro dipeptidase.
FT /FTId=PRO_0000185087.
FT METAL 276 276 Manganese 1.
FT METAL 287 287 Manganese 1.
FT METAL 287 287 Manganese 2.
FT METAL 370 370 Manganese 2.
FT METAL 412 412 Manganese 2.
FT METAL 452 452 Manganese 1.
FT METAL 452 452 Manganese 2.
FT MOD_RES 2 2 N-acetylalanine.
FT VAR_SEQ 68 131 Missing (in isoform 3).
FT /FTId=VSP_045370.
FT VAR_SEQ 184 224 Missing (in isoform 2).
FT /FTId=VSP_042629.
FT VARIANT 184 184 R -> Q (in PD).
FT /FTId=VAR_011614.
FT VARIANT 276 276 D -> N (in PD).
FT /FTId=VAR_004404.
FT VARIANT 278 278 G -> D (in PD).
FT /FTId=VAR_011615.
FT VARIANT 388 388 R -> H (in dbSNP:rs2230062).
FT /FTId=VAR_051574.
FT VARIANT 435 435 L -> F (in dbSNP:rs17570).
FT /FTId=VAR_014723.
FT VARIANT 448 448 G -> R (in PD).
FT /FTId=VAR_004405.
FT VARIANT 452 452 Missing (in PD).
FT /FTId=VAR_004406.
FT CONFLICT 48 48 L -> R (in Ref. 3; BAF84250).
FT CONFLICT 66 66 R -> L (in Ref. 1; AAA60064).
FT CONFLICT 107 107 W -> R (in Ref. 3; BAF83470).
FT CONFLICT 108 108 M -> I (in Ref. 3; BAF83445).
FT CONFLICT 183 183 C -> S (in Ref. 1; AAA60064).
FT CONFLICT 221 221 E -> G (in Ref. 1; AAA60064).
FT CONFLICT 283 284 CF -> SV (in Ref. 1; AAA60064).
FT CONFLICT 294 294 A -> R (in Ref. 1; AAA60064).
FT CONFLICT 311 311 R -> L (in Ref. 1; AAA60064).
FT CONFLICT 324 324 V -> D (in Ref. 1; AAA60064).
FT CONFLICT 329 330 MH -> ID (in Ref. 1; AAA60064).
FT CONFLICT 408 408 V -> A (in Ref. 3; BAG56678).
FT CONFLICT 458 458 T -> I (in Ref. 1; AAA60064).
FT CONFLICT 478 478 C -> R (in Ref. 3; BAF83470).
FT HELIX 21 36
FT STRAND 45 49
FT STRAND 54 56
FT HELIX 69 75
FT STRAND 79 81
FT STRAND 83 87
FT TURN 88 90
FT STRAND 93 97
FT HELIX 102 104
FT TURN 105 107
FT HELIX 114 121
FT STRAND 124 128
FT HELIX 129 131
FT HELIX 132 138
FT TURN 152 154
FT HELIX 166 168
FT HELIX 176 185
FT HELIX 189 212
FT HELIX 219 234
FT STRAND 238 241
FT STRAND 244 247
FT HELIX 248 252
FT STRAND 272 277
FT STRAND 279 281
FT STRAND 288 293
FT HELIX 300 319
FT HELIX 326 343
FT HELIX 351 356
FT TURN 357 359
FT HELIX 360 363
FT STRAND 373 377
FT HELIX 394 396
FT STRAND 408 411
FT STRAND 414 416
FT HELIX 419 427
FT HELIX 429 432
FT HELIX 437 443
FT STRAND 448 450
FT STRAND 452 457
FT STRAND 459 464
FT HELIX 472 479
SQ SEQUENCE 493 AA; 54548 MW; E8C4A2497E44BA22 CRC64;
MAAATGPSFW LGNETLKVPL ALFALNRQRL CERLRKNPAV QAGSIVVLQG GEETQRYCTD
TGVLFRQESF FHWAFGVTEP GCYGVIDVDT GKSTLFVPRL PASHATWMGK IHSKEHFKEK
YAVDDVQYVD EIASVLTSQK PSVLLTLRGV NTDSGSVCRE ASFDGISKFE VNNTILHPEI
VECRVFKTDM ELEVLRYTNK ISSEAHREVM KAVKVGMKEY ELESLFEHYC YSRGGMRHSS
YTCICGSGEN SAVLHYGHAG APNDRTIQNG DMCLFDMGGE YYCFASDITC SFPANGKFTA
DQKAVYEAVL RSSRAVMGAM KPGVWWPDMH RLADRIHLEE LAHMGILSGS VDAMVQAHLG
AVFMPHGLGH FLGIDVHDVG GYPEGVERID EPGLRSLRTA RHLQPGMVLT VEPGIYFIDH
LLDEALADPA RASFLNREVL QRFRGFGGVR IEEDVVVTDS GIELLTCVPR TVEEIEACMA
GCDKAFTPFS GPK
//

MIM 170100
*RECORD*
*FIELD* NO
170100
*FIELD* TI
#170100 PROLIDASE DEFICIENCY
*FIELD* TX
A number sign (#) is used with this entry because prolidase deficiency
read moreis caused by mutation in the gene encoding peptidase D (PEPD; 613230).

DESCRIPTION

Prolidase deficiency is a rare autosomal recessive multisystem disorder
associated with massive imidodipeptiduria and lack of or reduced
prolidase activity in erythrocytes, leukocytes, or cultured fibroblasts.
The disorder is clinically heterogeneous and severity varies widely.
Features include chronic, slowly healing ulcerations, mainly on the legs
and feet. The ulcers are often preceded by other dermatologic
manifestations that may occur anywhere and include erythematous papular
eruptions, telangiectasias with pruritus and photosensitivity,
impetigo-like eruptions, pruritic eczematous lesions, and necrotic
papules. Mild to severe mental retardation is often a feature, and
recurrent respiratory tract infections, sometimes fatal, are common.
Facial dysmorphism may include low hairline and hirsutism, saddle nose,
ocular hypertelorism, micrognathia, a high-arched palate, mandibular
protrusion, and exophthalmos. Clinical manifestations are usually
detectable after birth or in early childhood, but late-onset cases have
been reported (summary by Lupi et al., 2008).

CLINICAL FEATURES

Powell et al. (1974) described a patient who excreted massive amounts of
glycyl-L-proline and other di- and tri-peptides containing proline.
Prolidase, the enzyme known to cleave the bond between the other amino
acid and proline (which is carboxyl-terminal), was found to be absent or
markedly decreased in the patient's red and white cells. The mother and
maternal grandfather had intermediate levels. The father was not
available for study. The parents were not known to be related. The
proband was a 7-year-old white male with dry, cracked erythematous palms
and soles and with obesity from an early age. Mild mental retardation
and 'mild diffuse demineralization' of long bones were described.

Powell et al. (1975) studied 2 children with prolidase deficiency.
Clinical features included chronic dermatitis, frequent infections,
splenomegaly, and massive imidodipeptiduria. Powell et al. (1977)
reported that chronic ear and sinus infections, chronic skin lesions,
and splenomegaly were features.

Sheffield et al. (1977) described an 11-year-old boy who was born of
consanguineous parents and presented distinctive clinical features of
recurrent skin ulceration, lymphedema, hepatosplenomegaly, and mild
mental retardation. Massive amounts of dipeptides, most of which had
proline or hydroxyproline as the carboxyl residue, were excreted in the
urine. Glycylproline predominated. Prolidase deficiency was demonstrable
in red cells, fibroblasts, and continuous lymphocyte cultures.

Myara et al. (1984) stated that about 20 cases of prolidase deficiency
had been reported. Dermatologic features, particularly severe leg
ulcers, and mental retardation of variable severity were the main
manifestations (Der Kaloustian et al., 1982). Recurrent infections might
be due to a disturbance of complement component C1q, which contains a
large amount of iminoacids. Most patients have an unusual facial
appearance as well as splenomegaly. After gelatin ingestion, excretion
of iminoacids in the urine is increased, indicating that iminoacid
absorption in the intestine is not modified even though prolidase is
deficient in the intestine. Freij et al. (1984) described affected
brothers.

Leoni et al. (1987) described prolidase deficiency in 2 sisters who
suffered from recurrent leg ulcers, which first appeared in early
childhood. Milligan et al. (1989) described a patient in whom chronic
leg ulceration was due to prolidase deficiency. They added erosive
cystitis as a feature of the disorder.

Shrinath et al. (1997) described 2 children with prolidase deficiency
who developed clinical and immunologic abnormalities consistent with a
diagnosis of systemic lupus erythematosus (SLE; 152700). The first child
died from septicemia, and SLE was diagnosed only during his terminal
illness. As a result of this diagnosis, his cousin, who was already
known to have prolidase deficiency, was investigated further and a
diagnosis of SLE was confirmed. Following treatment with oral
prednisolone, her clinical condition improved, although she had a
persistently raised erythrocyte sedimentation rate and florid facial
rash. Both prolidase deficiency and SLE are associated with disturbances
in immune function and have clinical features in common. Prolidase
deficiency may be a risk factor for SLE. Shrinath et al. (1997)
suggested that patients with SLE should be specifically investigated for
prolidase deficiency, especially where there is a family history of SLE
or presentation of SLE in childhood, since standard immunologic or
hematologic investigations will not identify the biochemical
abnormalities characteristic of prolidase deficiency.

Falik-Zaccai et al. (2010) reported 20 patients from 10 kindreds with
prolidase deficiency in northern Israel. There were 7 Druze and 3 Arab
Muslim families. All presented with some degree of developmental delay,
most with moderate cognitive or speech delay. All also had some degree
of facial dysmorphism, including ocular hypertelorism, exophthalmos,
upward or downward slanting palpebral fissures, small-beaked nose, low
posterior hairline, facial hirsutism, and a slender upper lip.
Dermatologic manifestations included erythematous papular eruptions,
impetigo-like eruptions, pseudo-psoriasis skin lesions, and pruritic
eczematous lesions. Other more variable features included splenomegaly,
hepatitis-like symptoms, osteomyelitis, recurrent lung infections, and
asthma. One patient had chronic lung disease resembling cystic fibrosis
(CF; 219700), and 2 developed SLE. The phenotype was highly
heterogeneous, and there was great inter- and intrafamilial variability.
In 1 family, the severity ranged from death in infancy to an essentially
asymptomatic adult with minor facial dysmorphism and mental deficits.

BIOCHEMICAL FEATURES

Endo et al. (1987) found absence of a subunit of prolidase in red cells
in a patient with prolidase deficiency.

Wysocki et al. (1988) described a 17-year-old girl with recurrent
ulceration, initially covering most of her body but later in life
confined mainly to her legs. Although she had an almost complete absence
of prolidase in plasma and erythrocytes, this patient did not excrete
hydroxyproline-containing dipeptides in her urine. One or more of the
symptoms of prolidase deficiency may reflect a tissue deficiency of
L-proline, which is not reclaimed in the absence of prolidase. Excretion
of this amino acid, in bound form, can be as high as 20 to 30 mmol/day.
Against the proposition that the failure of recovery of proline from
iminodipeptides has a major role in the pathogenesis of prolidase
deficiency is the fact that oral administration of L-proline does not
relieve the dermatologic lesions. Attempts at enzyme replacement with
normal matched erythrocytes have had no effect on iminodipeptiduria and
this appears to be due to the fact that prolidase occurs in erythrocytes
in an inactive form. Hechtman et al. (1988) found that brief exposure of
intact erythrocytes to low concentrations of manganese ion activated
intracellular prolidase without causing hemolysis. Hechtman et al.
(1988) showed that erythrocytes so treated retained high levels of
enzymatic activity for at least 2 weeks.

Ohhashi et al. (1988) reported prolidase serum activities against 6
different substrates from 2 patients with prolidase deficiency, their
mother, and controls.

Boright et al. (1988) demonstrated 3 classes of mutant prolidase
alleles. In 6 prolidase-deficient cell strains, Boright et al. (1989)
identified 3 types of mutations: half the cell lines showed a mutation
that conferred a CRM-negative phenotype, while the other 3 showed
CRM-positive mutations of 2 types, 1 mutation encoding an enlarged
subunit (60 kD as contrasted with the normal 58-kD polypeptide) and the
others associated with subunits of normal size. Complementation analysis
indicated that the mutations mapped to the same locus. Normal subjects
and obligate heterozygotes expressing CRM-negative mutations had
thermostable prolidase activity at 50 degrees C in cell extracts,
whereas heterozygotes expressing CRM-positive mutations had thermolabile
activity under the same conditions, implying negative allelic
complementation in the putative heterodimer. Alternative enzymatic
activity not encoded at the prolidase locus was indicated by the
occurrence of prolidase-like activity about 5% of normal in amount but
with a preference for substrate different from normal, in cells
homozygous (or compound) for CRM-negative mutations. Allelic
heterogeneity at the major locus and the amount of alternative peptidase
activity encoded elsewhere appeared to be determinants of the associated
and heterogeneous clinical phenotype.

Endo et al. (1990) demonstrated great biochemical heterogeneity in
prolidase deficiency. There was no apparent relation between the
clinical symptoms and the biochemical phenotypes, except that mental
retardation was present in the polypeptide-negative (CRM-negative)
patients. Berardesca et al. (1992) reported the case of a 15-year-old
boy with prolidase deficiency and marked urinary excretion of the
iminodipeptide gly-pro. After blood transfusion, prolidase activity in
erythrocytes against substrate glycyl-proline increased to 15.7% of
donor activity and declined to 12% and 3.4% of normal activity after 8
and 45 days, respectively. Urinary iminodipeptide levels following
transfusion remained unaltered. Transfusions of concentrated
erythrocytes led to at least partial healing of ulcers of the skin but
these recurred by 18 months after the last transfusion.

DIAGNOSIS

Kurien et al. (2006) described the biochemical diagnostic techniques for
prolidase deficiency.

INHERITANCE

Complementation studies indicated that a single genetic locus is
involved in prolidase deficiency (Boright et al., 1988).

Reports of multiple affected sibs, parental consanguinity, and equal sex
distribution indicate that prolidase deficiency is an autosomal
recessive disorder (Milligan et al., 1989).

MOLECULAR GENETICS

In 2 unrelated patients with prolidase deficiency, Tanoue et al. (1990)
identified homozygosity for a mutation in the PEPD gene (613230.0001).

Ledoux et al. (1994) described 4 mutant PEPD alleles associated with
prolidase deficiency and Ledoux et al. (1996) reported 2 additional
ones. Ledoux et al. (1996) developed a novel expression system to study
mutant PEPD alleles by using COS-1 cells and demonstrated that 4 of
these mutations were responsible for the enzyme deficiency
(613230.0003-613230.0006).

In 5 cases of prolidase deficiency, Forlino et al. (2002) provided
molecular characterization of 3 mutations, all of which resulted in loss
of prolidase activity. Long-term cultured fibroblasts from the patients
were used to develop an in vitro model that allowed investigation of the
affected cells. Light and electron microscopy revealed that
prolidase-deficient cells were more round and branched out than
controls, and had increased cytosolic vacuolization, interruptions of
the plasma membrane, mitochondrial swelling, and modifications of the
mitochondrial matrix and cristae. Forlino et al. (2002) interpreted
these findings as evidence that absence of prolidase activity causes the
activation of a necrosis-like cellular death, which could be responsible
for the skin lesions typical of prolidase deficiency.

Wang et al. (2006) reported 4 Geauga Amish children with prolidase
deficiency, born of consanguineous parents whose ancestry could be
traced to common ascendants 7 or 8 generations back, in whom they
identified a homozygous nonsense mutation in the PEPD gene
(613230.0008). All 4 patients had massive imidodipeptiduria and
clinically similar multisystem involvement, with typical facial features
of prominent forehead, low nasal root, ocular hypertelorism, and
proptosis. Splenomegaly and elevated immunoglobulins, especially of IgE,
were observed in 3 patients, who also had asthma-like chronic reactive
airway disease. There was neonatal jaundice and hepatomegaly in all 4
patients, and 3 had anemia, thrombocytopenia, and petechiae. Wang et al.
(2006) stated that this was the first report of prolidase deficiency in
the Amish as well as in the United States.

POPULATION GENETICS

Falik-Zaccai et al. (2010) identified the same PEPD mutation (S202F;
613230.0011) in 17 patients from northern Israel with prolidase
deficiency. The patients were from 6 Druze kindreds living in 4
different villages and from 2 Arab Muslim kindreds living in 2 different
villages. The separate practices of consanguinity and endogamy reduce
the likelihood of genetic interchange between these 2 groups, but
haplotype analysis indicated a founder effect. The findings refuted the
possibility of the Druze being a homogeneous population, and suggested
that the mutation arose before the establishment of the Druze community.

*FIELD* SA
Butterwork and Priestman (1986); Endo et al. (1987); Hechtman (2001);
Martiniuk et al. (1985)
*FIELD* RF
1. Berardesca, E.; Fideli, D.; Bellosta, M.; Dyne, K. M.; Zanaboni,
G.; Cetta, G.: Blood transfusions in the therapy of a case of prolidase
deficiency. Brit. J. Derm. 126: 193-195, 1992.

2. Boright, A. P.; Lancaster, G. A.; Scriver, C. R.: A classification
of rare alleles causing prolidase deficiency. (Abstract) Am. J. Hum.
Genet. 43: A3 only, 1988.

3. Boright, A. P.; Scriver, C. R.; Lancaster, G. A.; Choy, F.: Prolidase
deficiency: biochemical classification of alleles. Am. J. Hum. Genet. 44:
731-740, 1989.

4. Butterwork, J.; Priestman, D. A.: Presence in human cells and
tissues of two prolidases and their alteration in prolidase deficiency. J.
Inherit. Metab. Dis. 8: 193-197, 1986.

5. Der Kaloustian, V. M.; Freij, B. J.; Kurban, A. K.: Prolidase
deficiency: an inborn error of metabolism with major dermatological
manifestations. Dermatologica 164: 293-304, 1982.

6. Endo, F.; Motohara, K.; Indo, Y.; Matsuda, I.: Immunochemical
studies of human prolidase with monoclonal and polyclonal antibodies:
absence of the subunit of prolidase in erythrocytes from a patient
with prolidase deficiency. Pediat. Res. 22: 627-633, 1987.

7. Endo, F.; Motohara, K.; Indo, Y.; Matsuda, I.: Absence of the
subunit of prolidase in a patient with prolidase deficiency. J. Inherit.
Metab. Dis. 10 (suppl. 2): 317-318, 1987.

8. Endo, F.; Tanoue, A.; Kitano, A.; Arata, J.; Danks, D. M.; Lapiere,
C. M.; Sei, Y.; Wadman, S. K.; Matsuda, I.: Biochemical basis of
prolidase deficiency: polypeptide acid RNA phenotypes and the relation
to clinical phenotypes. J. Clin. Invest. 85: 162-169, 1990.

9. Falik-Zaccai, T. C.; Khayat, M.; Luder, A.; Frenkel, P.; Magen,
D.; Brik, R.; Gershoni-Baruch, R.; Mandel, H.: A broad spectrum of
developmental delay in a large cohort of prolidase deficiency patients
demonstrates marked interfamilial and intrafamilial phenotypic variability. Am.
J. Med. Genet. 153B: 46-56, 2010.

10. Forlino, A.; Lupi, A.; Vaghi, P.; Cornaglia, A. I.; Calligaro,
A.; Campari, E.; Cetta, G.: Mutation analysis of five new patients
affected by prolidase deficiency: the lack of enzyme activity causes
necrosis-like cell death in cultured fibroblasts. Hum. Genet. 111:
314-322, 2002.

11. Freij, B. J.; Levy, H. L.; Dudin, G.; Mutasim, D.; Deeb, M.; Der
Kaloustian, V. M.: Clinical and biochemical characteristics of prolidase
deficiency in siblings. Am. J. Med. Genet. 19: 561-571, 1984.

12. Hechtman, P.: Prolidase deficiency.In: Scriver, C. R.; Beaudet,
A. L.; Sly, W. S.; Valle, D. (eds.): The Metabolic & Molecular Bases
of Inherited Disease. Vol. II. 8th ed. New York: McGraw-Hill
2001. Pp. 1839-1856.

13. Hechtman, P.; Richter, A.; Corman, N.; Leong, Y.-M.: In situ
activation of human erythrocyte prolidase: potential for enzyme replacement
therapy in prolidase deficiency. Pediat. Res. 24: 709-712, 1988.

14. Kurien, B. T.; Patel, N. C.; Porter, A. C.; D'Souza, A.; Miller,
D.; Matsumoto, H.; Wang, H.; Scofield, R. H.: Prolidase deficiency
and the biochemical assays used in its diagnosis. Anal. Biochem. 349:
165-175, 2006.

15. Ledoux, P.; Scriver, C.; Hechtman, P.: Four novel PEPD alleles
causing prolidase deficiency. Am. J. Hum. Genet. 54: 1014-1021,
1994.

16. Ledoux, P.; Scriver, C. R.; Hechtman, P.: Expression and molecular
analysis of mutations in prolidase deficiency. Am. J. Hum. Genet. 59:
1035-1039, 1996.

17. Leoni, A.; Cetta, G.; Tenni, R.; Pasquali-Ronchetti, I.; Bertolini,
F.; Guerra, D.; Dyne, K.; Castellani, A.: Prolidase deficiency in
two siblings with chronic leg ulcerations: clinical, biochemical,
and morphologic aspects. Arch. Derm. 123: 493-499, 1987.

18. Lupi, A.; Tenni, R.; Rossi, A.; Cetta, G.; Forlino, A.: Human
prolidase and prolidase deficiency: an overview on the characterization
of the enzyme involved in proline recycling and on the effects of
its mutations. Amino Acids 35: 739-752, 2008.

19. Martiniuk, F.; Ellenbogen, A.; Hirschhorn, K.; Hirschhorn, R.
: Further regional localization of the genes for human acid alpha
glucosidase (GAA), peptidase D (PEPD), and alpha mannosidase B (MANB)
by somatic cell hybridization. Hum. Genet. 69: 109-111, 1985.

20. Milligan, A.; Graham-Brown, R. A. C.; Burns, D. A.; Anderson,
I.: Prolidase deficiency: a case report and literature review. Brit.
J. Derm. 121: 405-409, 1989.

21. Myara, I.; Charpentier, C.; Lemonnier, A.: Prolidase and prolidase
deficiency. Life Sci. 34: 1985-1998, 1984.

22. Ohhashi, T.; Ohno, T.; Arata, J.; Kodama, H.: Biochemical studies
on prolidase in sera from control, patients with prolidase deficiency
and their mother. J. Inherit. Metab. Dis. 11: 166-173, 1988.

23. Powell, G. F.; Kurosky, A.; Maniscalco, R. M.: Prolidase deficiency:
report of a second case with quantitation of the excessively excreted
amino acids. J. Pediat. 91: 242-246, 1977.

24. Powell, G. F.; Maniscalco, R. M.; Kurosky, A.: Source of imidodipeptides
in prolidase deficiency. (Abstract) Am. J. Hum. Genet. 27: 73A only,
1975.

25. Powell, G. F.; Rasco, M. A.; Maniscalco, R. M.: A prolidase deficiency
in man with iminopeptiduria. Metabolism 23: 505-513, 1974.

26. Sheffield, L. J.; Schlesinger, P.; Faull, K.; Halpern, B. J.;
Schier, G. M.; Cotton, R. G. H.; Hammond, J.; Danks, D. M.: Iminopeptiduria,
recurrent skin ulcerations and edema in a boy with prolidase deficiency. J.
Pediat. 91: 578-583, 1977.

27. Shrinath, M.; Walter, J. H.; Haeney, M.; Couriel, J. M.; Lewis,
M. A.; Herrick, A. L.: Prolidase deficiency and systemic lupus erythematosus. Arch.
Dis. Child. 76: 441-444, 1997.

28. Tanoue, A.; Endo, F.; Matsuda, I.: Structural organization of
the gene for human prolidase (peptidase D) and demonstration of a
partial gene deletion in a patient with prolidase deficiency. J.
Biol. Chem. 265: 11306-11311, 1990.

29. Wang, H.; Kurien, B. T.; Lundgren, D.; Patel, N. C.; Kaufman,
K. M.; Miller, D. L.; Porter, A. C.; D'Souza, A.; Nye, L.; Tumbush,
J.; Hupertz, V.; Kerr, D. S.; Kurono, S.; Matsumoto, H.; Scofield,
R. H.: A nonsense mutation of PEPD in four Amish children with prolidase
deficiency. Am. J. Med. Genet. 140A: 580-585, 2006.

30. Wysocki, S. J.; Hahnel, R.; Mahoney, T.; Wilson, R. G.; Panegyres,
P. K.: Prolidase deficiency: a patient without hydroxyproline-containing
iminodipeptides in urine. J. Inherit. Metab. Dis. 11: 161-165, 1988.

*FIELD* CS
INHERITANCE:
Autosomal recessive

HEAD AND NECK:
[Face];
Prominent forehead;
Facial dysmorphism;
[Eyes];
Hypertelorism;
Ptosis;
Ocular proptosis;
Exophthalmos;
Upward or downward slanting palpebral fissures;
[Nose];
Small nose;
Low nasal root;
Beaked nose;
[Mouth];
Slender upper lip

RESPIRATORY:
[Lungs];
Pulmonary infections, recurrent;
Chronic lung disease;
Asthma

ABDOMEN:
[Liver];
Jaundice, neonatal;
Hepatomegaly;
[Spleen];
Splenomegaly

SKIN, NAILS, HAIR:
[Skin];
Diffuse telangiectases;
Crusting erythematous dermatitis;
Impetigo-like eruptions;
Pruritic eczematous lesions;
Severe progressive ulceration of lower extremities;
[Hair];
Low posterior hairline

NEUROLOGIC:
[Central nervous system];
Developmental delay

HEMATOLOGY:
Thrombocytopenia;
Petechiae;
Anemia

IMMUNOLOGY:
Elevated immunoglobulins, particularly IgE;
Increased frequency of infection;
Systemic lupus erythematosus

LABORATORY ABNORMALITIES:
Hyperimidodipeptiduria;
Deficiency of prolidase activity in erythrocytes, leukocytes, or fibroblasts

MISCELLANEOUS:
Median age at diagnosis 7 years;
Highly variable expression

MOLECULAR BASIS:
Caused by mutation in the peptidase D gene (PEPD, 613230.0001)

*FIELD* CN
Marla J. F. O'Neill - updated: 08/03/2012
Cassandra L. Kniffin - updated: 7/30/2010
Ada Hamosh - reviewed: 4/19/2000

*FIELD* CD
Kelly A. Przylepa: 4/7/2000

*FIELD* ED
joanna: 08/03/2012
joanna: 9/26/2011
ckniffin: 7/30/2010
joanna: 9/16/2003
joanna: 4/19/2000
kayiaros: 4/7/2000

*FIELD* CN
Cassandra L. Kniffin - updated: 7/30/2010
Marla J. F. O'Neill - updated: 6/20/2006
Victor A. McKusick - updated: 11/9/2004
Victor A. McKusick - updated: 11/13/2002
Victor A. McKusick - updated: 6/26/1997

*FIELD* CD
Victor A. McKusick: 6/2/1986

*FIELD* ED
wwang: 07/30/2010
ckniffin: 7/30/2010
carol: 1/26/2010
terry: 1/25/2010
carol: 1/25/2010
wwang: 6/22/2006
terry: 6/20/2006
tkritzer: 11/10/2004
terry: 11/9/2004
mgross: 3/17/2004
ckniffin: 9/24/2003
tkritzer: 11/14/2002
terry: 11/13/2002
carol: 6/3/1998
terry: 6/3/1998
dholmes: 6/3/1998
jenny: 7/1/1997
terry: 6/26/1997
terry: 12/30/1996
terry: 12/19/1996
terry: 7/15/1994
pfoster: 4/27/1994
warfield: 3/4/1994
carol: 5/11/1992
supermim: 3/16/1992
carol: 1/26/1992

MIM 613230
*RECORD*
*FIELD* NO
613230
*FIELD* TI
*613230 PEPTIDASE D; PEPD
;;PROLIDASE;;
IMIDODIPEPTIDASE
*FIELD* TX

DESCRIPTION

Peptidase D (EC 3.4.13.9), also known as prolidase, imidodipeptidase,
read moreproline dipeptidase, and aminoacyl-L-proline hydrolase, specifically
splits iminodipeptides with C-terminal proline or hydroxyproline. The
enzyme prolinase (EC 3.4.13.8) splits iminodipeptides with N-terminal
proline or hydroxyproline. The 2 dipeptidases play an important role in
collagen metabolism because of the high level of iminoacids in collagen
(proline and hydroxyproline constitute 25%) (Royce and Steinmann, 2002)
and seem to be important for protein catabolism in general (Lupi et al.,
2008).

CLONING

Endo et al. (1989) isolated prolidase cDNA clones from human liver and
placenta cDNA libraries. The deduced mature enzyme contains 492 amino
acids with a calculated molecular mass of 54.3 kD. Northern blot
analysis detected a single mRNA of approximately 2.1 kb.

GENE STRUCTURE

Tanoue et al. (1990) demonstrated that the prolidase gene contains 15
exons and spans more than 130 kb. All of the splice donor and acceptor
sites conform to the GT/AG rule. By nuclease S1 mapping and primer
extension, they determined that the transcription initiation site is
located 131 bases upstream from the initiation codon. A 'CAAT' box-like
sequence was found 67 bases from the cap site, but there was no 'TATA'
box-like sequence. There were 7 sets of sequences resembling the
transcription factor Sp1 binding sites.

MAPPING

Peptidase D was assigned to chromosome 19 by McAlpine et al. (1976) and
by Brown et al. (1978). Eiberg et al. (1983) showed that PEPD is
probably linked to the C3-LE-DM-SE-LU linkage group, thus corroborating
the assignment of this large group to chromosome 19. They found a lod
score (male and female) for PEPD-Se of 2.14 at theta 0.05; a previous
score of 0.94 at theta 0.20 was reported in other families. PEPD-C3
(male) gave positive scores. GPI and PEPD, which are on chromosome 19 in
man, are on chromosome 9 of the Chinese hamster, and TPI, which is on
chromosome 12 of man, is on Chinese hamster chromosome 8 (Siciliano et
al., 1983). Linkage of peptidase D to myotonic dystrophy (O'Brien et
al., 1983) proves the assignment of the Lutheran-secretor linkage group
to chromosome 19 and provides regional assignment to 19pter-q13. Brook
et al. (1985) gave a regionalization of 19p13.2-q13.2. Ball et al.
(1985) found close linkage between PEPD and APOC2 (608083). Lusis et al.
(1986) used a reciprocal whole arm translocation between the long arm of
chromosome 19 and the short arm of chromosome 1 to determine that the
APOC1, APOC2, APOE and GPI loci are on the long arm and the LDLR, C3 and
PEPD loci on the short arm. They isolated a single lambda phage carrying
APOC1 and part of APOE. These genes are 6 kb apart and arranged
tandemly. APOC2 and APOE were previously shown to be tightly linked.
Friedrich et al. (1987) cited evidence from somatic cell hybrid studies
using cells with various chromosome 19 rearrangements that the PEPD
locus is unequivocally on the long arm of chromosome 19. Thus, PEPD is
located at 19cen-q13.11. Using a panel of human-rodent somatic cell
hybrids containing different regions of chromosome 19, Davis et al.
(1987) also assigned PEPD to the long arm of chromosome 19.

Hartz (2010) mapped the PEPD gene to chromosome 19q13.11 based on an
alignment of the PEPD sequence (GenBank GENBANK BT006692) with the
genomic sequence (GRCh37).

GENE FUNCTION

Prolidase is involved in the final stage of degradation of endogenous
and dietary proteins, in particular in collagen catabolism (Cunningham
and O'Connor, 1997).

MOLECULAR GENETICS

Lewis and Harris (1969) identified a number of electrophoretic variants
of peptidase D of red cells.

Data on gene frequencies of allelic variants were tabulated by
Roychoudhury and Nei (1988).

In 2 unrelated patients with prolidase deficiency (170100), Tanoue et
al. (1990) identified homozygosity for a mutation in the PEPD gene
(613230.0001).

Wang et al. (2006) reported 4 Geauga Amish children with prolidase
deficiency, born of consanguineous parents whose ancestry could be
traced to common ascendants 7 or 8 generations back, in whom they
identified a homozygous nonsense mutation in the PEPD gene
(613230.0008).

Falik-Zaccai et al. (2010) identified the same PEPD mutation (S202F;
613230.0011) in 17 patients from northern Israel with prolidase
deficiency. The patients were from 6 Druze kindreds living in 4
different villages and from 2 Arab Muslim kindreds living in 2 different
villages. The separate practices of consanguinity and endogamy reduce
the likelihood of genetic interchange between these 2 groups, but
haplotype analysis indicated a founder effect. The findings refuted the
possibility of the Druze being a homogeneous population, and suggested
that the mutation arose before the establishment of the Druze community.

HISTORY

Endo et al. (1989) sequenced a cDNA that codes for the entire mature
protein of prolidase. They assigned the gene to 19p13.2 by in situ
hybridization.

*FIELD* AV
.0001
PROLIDASE DEFICIENCY
PEPD, ASP276ASN

In 2 unrelated patients with polypeptide-positive (CRM-positive)
prolidase deficiency (170100), Tanoue et al. (1990) demonstrated a
G-to-A substitution at nucleotide 826 in exon 12, resulting in
replacement of aspartic acid by asparagine at amino acid residue 276.
Both patients were homozygous for this mutation.

.0002
PROLIDASE DEFICIENCY
PEPD, EX14DEL

Tanoue et al. (1990) analyzed DNA from 3 patients with prolidase
deficiency (170100) by Southern blot analysis after TaqI or BamHI
digestion. A partial deletion of several hundred basepairs in the PEPD
gene, which eliminated exon 14, was found in a patient and her affected
sister, who were the offspring of a consanguineous mating (Endo et al.,
1990). The defect appeared to be homozygous. No major abnormality in
gene structure was found in 2 other patients. Tanoue et al. (1991) gave
further details: the 774-bp deletion had termini within short, direct
repeats. 'Slipped mispairing' was thought to have been involved in the
generation of the deletion. The mutation caused a 192-bp in-frame
deletion of prolidase mRNA. The parents were consanguineous. The oldest
sister, 25 years of age at the time of report, developed skin lesions at
the age of 19 months and required specific treatment. Her homozygous
sister had no prominent changes in the skin until age 18 years. Both
were negative for immunologic crossreacting material, and there was no
residual activity of prolidase in the fibroblasts. Both excreted massive
amounts of imidodipeptide in the urine. Erythrocyte prolidase activities
were about 50% of the control value in the first-cousin parents.

.0003
PROLIDASE DEFICIENCY
PEPD, ARG184GLN

In an individual with prolidase deficiency (170100) who was asymptomatic
at age 11 years, Ledoux et al. (1996) demonstrated compound
heterozygosity for a G-to-A transition of nucleotide 551 in exon 8
(R184Q) and a G-to-A transition of nucleotide 833 in exon 123 (G278D;
613230.0004) in the PEPD gene. To assess the biochemical phenotypes of
these in 2 previously identified PEPD mutations (G448R, 613230.0005 and
E452DEL, 613230.0006), they designed a transient expression system for
prolidase in COS-1 cells. The enzyme was expressed as a fusion protein
carrying an N-terminal tag, allowing its immunologic discrimination from
the endogenous enzyme with a monoclonal antibody. Expression of the
R184Q mutation produced 7.4% of control enzymatic activity, whereas the
expression of the other 3 mutations produced inactive enzymes. Western
analysis of the R184Q, G278D, and G448R prolidases revealed stable
immunoreactive material whereas the E452DEL prolidase was not
detectable. Pulse-chase metabolic labeling of cells followed by
immunoprecipitation revealed that the E452DEL mutant protein was
synthesized but had an increased rate of degradation.

.0004
PROLIDASE DEFICIENCY
PEPD, GLY278ASP

See 613230.0003 and Ledoux et al. (1996).

.0005
PROLIDASE DEFICIENCY
PEPD, GLY448ARG

See 613230.0003 and Ledoux et al. (1996).

Forlino et al. (2002) identified the gly448-to-arg (G448R) mutation,
which resulted from a G-to-A transition at nucleotide 1342 in the PEPD
gene, in 2 brothers with prolidase deficiency (170100).

.0006
PROLIDASE DEFICIENCY
PEPD, 3-BP DEL, GLU452DEL

See 613230.0003 and Ledoux et al. (1996).

.0007
PROLIDASE DEFICIENCY
PEPD, 3-BP DEL, 707TAC

In 2 unrelated Portuguese patients with prolidase deficiency (170100),
Lupi et al. (2004) identified a homozygous 3-bp deletion in exon 10 of
the PEPD gene, 707delTAC, resulting in deletion of a tyrosine at codon
231 (tyr231).

.0008
PROLIDASE DEFICIENCY
PEPD, ARG265TER

In 4 Geauga Amish children with prolidase deficiency (170100), born of
consanguineous parents and whose ancestry could be traced to common
ascendants 7 or 8 generations back, Wang et al. (2006) identified
homozygosity for a 793T-C transition in exon 11 of the PEPD gene,
resulting in an arg265-to-ter (R265X) substitution. The authors stated
that the phenotype in these patients appeared to be more severe than in
previously reported patients, and noted that prolidase activity was
nearly undetectable in these patients.

.0009
PROLIDASE DEFICIENCY
PEPD, GLU412LYS

In 2 Turkish sisters with prolidase deficiency (170100), Lupi et al.
(2006) identified homozygosity for a 1234G-A transition in the PEPD
gene, resulting in a glu412-to-lys (E412K) substitution. The 21-year-old
proband had eczema-like lesions on the face during childhood; following
trauma after puberty, she had recurrent severe leg ulcers. She had no
prolidase activity in her erythrocytes or serum. Her 29-year-old sister
had no ulcers or any other typical symptoms of prolidase deficiency but
had no prolidase activity in her serum or erythrocytes. Their parents
were heterozygous for the mutation, which was not found in their healthy
brother. Glu412 is a highly conserved residue among different species.

.0010
PROLIDASE DEFICIENCY
PEPD, 13-BP DUP

In a Turkish woman with prolidase deficiency (170100), originally
described by Pedersen et al. (1983), Lupi et al. (2006) identified a
homozygous 13-bp duplication in exon 8 of the PEPD gene, generating a
premature stop codon after 18 amino acids from the insertion site and
resulting in the absence of prolidase. She had presented in the first
year of life with developmental delay, skin ulcers, and failure to
thrive. She was diagnosed with prolidase deficiency at age 4 years.

.0011
PROLIDASE DEFICIENCY
PEPD, SER202PHE

In 17 patients with prolidase deficiency (170100), Falik-Zaccai et al.
(2010) identified a homozygous 605C-T transition in exon 8 of the PEPD
gene, resulting in a ser202-to-phe (S202F) substitution in a highly
conserved residue. All patients with this mutation resided in a small
geographic area in northern Israel, and there was a shared haplotype
between Druze and Arab Muslims, suggesting a founder effect. There was
marked intra- and interfamilial clinical variability, ranging from death
in infancy to mild developmental delay or facial dysmorphism.

*FIELD* RF
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A somatic cell hybrid panel for chromosome 19: localization of known
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Cell Genet. 40: 590-591, 1985.

3. Brown, S.; Lalley, P. A.; Minna, J. D.: Assignment of the gene
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314-322, 2002.

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12. Hartz, P. A.: Personal Communication. Baltimore, Md. 1/25/2010.

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generating symptomatic and asymptomatic outcomes within the same family. J.
Med. Genet. 43: e58, 2006. Note: Electronic Article.

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its mutations. Amino Acids 35: 739-752, 2008.

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24. Siciliano, M. J.; Stallings, R. L.; Adair, G. M.; Humphrey, R.
M.; Siciliano, J.: Provisional assignment of TPI, GPI, and PEPD to
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25. Tanoue, A.; Endo, F.; Akaboshi, I.; Oono, T.; Arata, J.; Matsuda,
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1991.

26. Tanoue, A.; Endo, F.; Kitano, A.; Matsuda, I.: A single nucleotide
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27. Tanoue, A.; Endo, F.; Matsuda, I.: Structural organization of
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28. Wang, H.; Kurien, B. T.; Lundgren, D.; Patel, N. C.; Kaufman,
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*FIELD* CN
Cassandra L. Kniffin - updated: 7/30/2010

*FIELD* CD
Carol A. Bocchini: 1/25/2010

*FIELD* ED
joanna: 08/05/2013
wwang: 7/30/2010
ckniffin: 7/30/2010
terry: 2/2/2010
carol: 1/26/2010
terry: 1/25/2010
carol: 1/25/2010