Full text data of PEX5
PEX5
(PXR1)
[Confidence: low (only semi-automatic identification from reviews)]
Peroxisomal targeting signal 1 receptor; PTS1 receptor; PTS1R (PTS1-BP; Peroxin-5; Peroxisomal C-terminal targeting signal import receptor; Peroxisome receptor 1)
Peroxisomal targeting signal 1 receptor; PTS1 receptor; PTS1R (PTS1-BP; Peroxin-5; Peroxisomal C-terminal targeting signal import receptor; Peroxisome receptor 1)
UniProt
P50542
ID PEX5_HUMAN Reviewed; 639 AA.
AC P50542; A8K891; B4DZ45; B7ZAD5; D3DUT8; Q15115; Q15266; Q96FN7;
read moreDT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
DT 12-DEC-2006, sequence version 3.
DT 22-JAN-2014, entry version 150.
DE RecName: Full=Peroxisomal targeting signal 1 receptor;
DE Short=PTS1 receptor;
DE Short=PTS1R;
DE AltName: Full=PTS1-BP;
DE AltName: Full=Peroxin-5;
DE AltName: Full=Peroxisomal C-terminal targeting signal import receptor;
DE AltName: Full=Peroxisome receptor 1;
GN Name=PEX5; Synonyms=PXR1;
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 2), INVOLVEMENT IN PBD2A, VARIANT
RP PBD2B LYS-526, FUNCTION, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=7719337; DOI=10.1038/ng0295-115;
RA Dodt G., Braverman N., Wong C., Moser A., Moser H.W., Watkins P.,
RA Valle D., Gould S.J.;
RT "Mutations in the PTS1 receptor gene, PXR1, define complementation
RT group 2 of the peroxisome biogenesis disorders.";
RL Nat. Genet. 9:115-125(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), FUNCTION, AND TISSUE
RP SPECIFICITY.
RC TISSUE=Liver;
RX PubMed=7790377; DOI=10.1083/jcb.130.1.51;
RA Wiemer E.A.C., Nuttley W.M., Bertolaet B.L., Li X., Francke U.,
RA Wheelock M.J., Anne U.K., Johnson K.R., Subramani S.;
RT "Human peroxisomal targeting signal-1 receptor restores peroxisomal
RT protein import in cells from patients with fatal peroxisomal
RT disorders.";
RL J. Cell Biol. 130:51-65(1995).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, TISSUE SPECIFICITY,
RP AND SUBCELLULAR LOCATION.
RC TISSUE=Liver;
RX PubMed=7706321; DOI=10.1074/jbc.270.13.7731;
RA Fransen M., Brees C., Baumgart E., Vanhooren J.C.T., Baes M.,
RA Mannaerts G.P., van Veldhoven P.P.;
RT "Identification and characterization of the putative human peroxisomal
RT C-terminal targeting signal import receptor.";
RL J. Biol. Chem. 270:7731-7736(1995).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1; 2 AND 4).
RC TISSUE=Testis;
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 [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16541075; DOI=10.1038/nature04569;
RA Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y.,
RA Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C.,
RA Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M.,
RA Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L.,
RA Milosavljevic A., Miner G.R., Montgomery K.T., Morgan M.B.,
RA Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D.,
RA Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y., Zhang Z.,
RA Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z.,
RA Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H., Draper H.,
RA Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S., Kelly S.H.,
RA Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V.,
RA Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H., Santibanez J.,
RA Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q., Williams G.A.,
RA Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V., Bailey M.,
RA Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E., Burkett C.E.,
RA Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K.,
RA Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D.,
RA Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M.,
RA Dathorne S.R., David R., Davis C.M., Davy-Carroll L., Deshazo D.R.,
RA Donlin J.E., D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J.,
RA Escotto M., Flagg N., Forbes L.D., Gabisi A.M., Garza M., Hamilton C.,
RA Henderson N., Hernandez O., Hines S., Hogues M.E., Huang M.,
RA Idlebird D.G., Johnson R., Jolivet A., Jones S., Kagan R., King L.M.,
RA Leal B., Lebow H., Lee S., LeVan J.M., Lewis L.C., London P.,
RA Lorensuhewa L.M., Loulseged H., Lovett D.A., Lucier A., Lucier R.L.,
RA Ma J., Madu R.C., Mapua P., Martindale A.D., Martinez E., Massey E.,
RA Mawhiney S., Meador M.G., Mendez S., Mercado C., Mercado I.C.,
RA Merritt C.E., Miner Z.L., Minja E., Mitchell T., Mohabbat F.,
RA Mohabbat K., Montgomery B., Moore N., Morris S., Munidasa M.,
RA Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O., Nwokenkwo S.,
RA Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J.,
RA Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A.,
RA Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M.,
RA Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I.,
RA Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A.,
RA Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D.,
RA Trejos Z.Y., Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I.,
RA Vera V.A., Villasana D.M., Wang L., Ward-Moore S., Warren J.T.,
RA Wei X., White F., Williamson A.L., Wleczyk R., Wooden H.S.,
RA Wooden S.H., Yen J., Yoon L., Yoon V., Zorrilla S.E., Nelson D.,
RA Kucherlapati R., Weinstock G., Gibbs R.A.;
RT "The finished DNA sequence of human chromosome 12.";
RL Nature 440:346-351(2006).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
RC TISSUE=Eye;
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 [8]
RP INTERACTION WITH PEX12.
RX PubMed=10562279; DOI=10.1083/jcb.147.4.761;
RA Chang C.C., Warren D.S., Sacksteder K.A., Gould S.J.;
RT "PEX12 interacts with PEX5 and PEX10 and acts downstream of receptor
RT docking in peroxisomal matrix protein import.";
RL J. Cell Biol. 147:761-774(1999).
RN [9]
RP INTERACTION WITH PEX14, AND MUTAGENESIS OF TRP-118 AND PHE-122.
RX PubMed=11438541; DOI=10.1074/jbc.M104647200;
RA Saidowsky J., Dodt G., Kirchberg K., Wegner A., Nastainczyk W.,
RA Kunau W.-H., Schliebs W.;
RT "The di-aromatic pentapeptide repeats of the human peroxisome import
RT receptor PEX5 are separate high affinity binding sites for the
RT peroxisomal membrane protein PEX14.";
RL J. Biol. Chem. 276:34524-34529(2001).
RN [10]
RP INTERACTION WITH ZFAND6.
RX PubMed=21980954; DOI=10.1111/j.1600-0854.2011.01298.x;
RA Miyata N., Okumoto K., Mukai S., Noguchi M., Fujiki Y.;
RT "AWP1/ZFAND6 functions in Pex5 export by interacting with cys-
RT monoubiquitinated Pex5 and Pex6 AAA ATPase.";
RL Traffic 13:168-183(2012).
RN [11]
RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 272-639 IN COMPLEX WITH
RP TARGETING PEPTIDE.
RX PubMed=11101887; DOI=10.1038/81930;
RA Gatto G.J. Jr., Geisbrecht B.V., Gould S.J., Berg J.M.;
RT "Peroxisomal targeting signal-1 recognition by the TPR domains of
RT human PEX5.";
RL Nat. Struct. Biol. 7:1091-1095(2000).
RN [12]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 321-639 IN COMPLEX WITH
RP TARGETING PEPTIDE.
RX PubMed=17157249; DOI=10.1016/j.molcel.2006.10.024;
RA Stanley W.A., Filipp F.V., Kursula P., Schueller N., Erdmann R.,
RA Schliebs W., Sattler M., Wilmanns M.;
RT "Recognition of a functional peroxisome type 1 target by the dynamic
RT import receptor Pex5p.";
RL Mol. Cell 24:653-663(2006).
RN [13]
RP X-RAY CRYSTALLOGRAPHY (2.65 ANGSTROMS) OF 315-639, AND BINDING TO
RP C-TERMINAL TARGETING PEPTIDES.
RX PubMed=17428317; DOI=10.1186/1472-6807-7-24;
RA Stanley W.A., Pursiainen N.V., Garman E.F., Juffer A.H., Wilmanns M.,
RA Kursula P.;
RT "A previously unobserved conformation for the human Pex5p receptor
RT suggests roles for intrinsic flexibility and rigid domain motions in
RT ligand binding.";
RL BMC Struct. Biol. 7:24-24(2007).
RN [14]
RP STRUCTURE BY NMR OF 108-127 IN COMPLEX WITH PEX14.
RX PubMed=19197237; DOI=10.1038/emboj.2009.7;
RA Neufeld C., Filipp F.V., Simon B., Neuhaus A., Schueller N., David C.,
RA Kooshapur H., Madl T., Erdmann R., Schliebs W., Wilmanns M.,
RA Sattler M.;
RT "Structural basis for competitive interactions of Pex14 with the
RT import receptors Pex5 and Pex19.";
RL EMBO J. 28:745-754(2009).
RN [15]
RP VARIANTS PBD2B LYS-526 AND TRP-600, AND CHARACTERIZATION OF VARIANTS
RP PBD2B LYS-526 AND TRP-600.
RX PubMed=10462504; DOI=10.1006/bbrc.1999.1232;
RA Shimozawa N., Zhang Z., Suzuki Y., Imamura A., Tsukamoto T., Osumi T.,
RA Fujiki Y., Orii T., Barth P.G., Wanders R.J., Kondo N.;
RT "Functional heterogeneity of C-terminal peroxisome targeting signal 1
RT in PEX5-defective patients.";
RL Biochem. Biophys. Res. Commun. 262:504-508(1999).
CC -!- FUNCTION: Binds to the C-terminal PTS1-type tripeptide peroxisomal
CC targeting signal (SKL-type) and plays an essential role in
CC peroxisomal protein import.
CC -!- SUBUNIT: Interacts with PEX7 and PEX13 (By similarity). Interacts
CC with PEX12 and PEX14. Interacts (Cys-linked ubiquitinated) with
CC ZFAND6.
CC -!- INTERACTION:
CC O00623:PEX12; NbExp=4; IntAct=EBI-597835, EBI-594836;
CC O75381:PEX14; NbExp=13; IntAct=EBI-597835, EBI-594898;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Peroxisome membrane; Peripheral
CC membrane protein. Note=Its distribution appears to be dynamic. It
CC is probably a cycling receptor found mainly in the cytoplasm and
CC as well associated to the peroxisomal membrane through a docking
CC factor (PEX13).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=1;
CC IsoId=P50542-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P50542-2; Sequence=VSP_021880;
CC Name=3;
CC IsoId=P50542-3; Sequence=VSP_024106;
CC Name=4;
CC IsoId=P50542-4; Sequence=VSP_043639;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Detected in heart, brain, placenta, lung,
CC liver, skeletal muscle, kidney and pancreas.
CC -!- PTM: Monoubiquitination at Cys-11 is required for proper export
CC from peroxisomes and recycling (By similarity).
CC -!- DISEASE: Peroxisome biogenesis disorder 2A (PBD2A) [MIM:214110]: A
CC fatal peroxisome biogenesis disorder belonging to the Zellweger
CC disease spectrum and characterized clinically by severe neurologic
CC dysfunction with profound psychomotor retardation, severe
CC hypotonia and neonatal seizures, craniofacial abnormalities, liver
CC dysfunction, and biochemically by the absence of peroxisomes.
CC Additional features include cardiovascular and skeletal defects,
CC renal cysts, ocular abnormalities, and hearing impairment. Most
CC severely affected individuals with the classic form of the disease
CC (classic Zellweger syndrome) die within the first year of life.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- DISEASE: Peroxisome biogenesis disorder 2B (PBD2B) [MIM:202370]: A
CC peroxisome biogenesis disorder that includes neonatal
CC adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD),
CC two milder manifestations of the Zellweger disease spectrum. The
CC clinical course of patients with the NALD and IRD presentation is
CC variable and may include developmental delay, hypotonia, liver
CC dysfunction, sensorineural hearing loss, retinal dystrophy and
CC vision impairment. Children with the NALD presentation may reach
CC their teens, while patients with the IRD presentation may reach
CC adulthood. The clinical conditions are often slowly progressive in
CC particular with respect to loss of hearing and vision. The
CC biochemical abnormalities include accumulation of phytanic acid,
CC very long chain fatty acids (VLCFA), di- and
CC trihydroxycholestanoic acid and pipecolic acid. Note=The disease
CC is caused by mutations affecting the gene represented in this
CC entry.
CC -!- SIMILARITY: Belongs to the peroxisomal targeting signal receptor
CC family.
CC -!- SIMILARITY: Contains 7 TPR repeats.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/PEX5";
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DR EMBL; U19721; AAC50103.1; -; mRNA.
DR EMBL; Z48054; CAA88131.1; -; mRNA.
DR EMBL; X84899; CAA59324.1; -; mRNA.
DR EMBL; AK292256; BAF84945.1; -; mRNA.
DR EMBL; AK302742; BAG63957.1; -; mRNA.
DR EMBL; AK316250; BAH14621.1; -; mRNA.
DR EMBL; AC018653; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471116; EAW88671.1; -; Genomic_DNA.
DR EMBL; CH471116; EAW88674.1; -; Genomic_DNA.
DR EMBL; CH471116; EAW88672.1; -; Genomic_DNA.
DR EMBL; BC010621; AAH10621.1; -; mRNA.
DR PIR; A56126; A56126.
DR RefSeq; NP_000310.2; NM_000319.4.
DR RefSeq; NP_001124495.1; NM_001131023.1.
DR RefSeq; NP_001124496.1; NM_001131024.1.
DR RefSeq; NP_001124497.1; NM_001131025.1.
DR RefSeq; NP_001124498.1; NM_001131026.1.
DR RefSeq; XP_005253511.1; XM_005253454.1.
DR UniGene; Hs.567327; -.
DR PDB; 1FCH; X-ray; 2.20 A; A/B=272-639.
DR PDB; 2C0L; X-ray; 2.30 A; A=335-639.
DR PDB; 2C0M; X-ray; 2.50 A; A/B/C/F=321-639.
DR PDB; 2J9Q; X-ray; 2.65 A; A/B=315-639.
DR PDB; 2W84; NMR; -; B=108-127.
DR PDB; 3R9A; X-ray; 2.35 A; B/D=315-639.
DR PDBsum; 1FCH; -.
DR PDBsum; 2C0L; -.
DR PDBsum; 2C0M; -.
DR PDBsum; 2J9Q; -.
DR PDBsum; 2W84; -.
DR PDBsum; 3R9A; -.
DR DisProt; DP00472; -.
DR ProteinModelPortal; P50542; -.
DR SMR; P50542; 335-639.
DR DIP; DIP-34654N; -.
DR IntAct; P50542; 18.
DR MINT; MINT-241634; -.
DR STRING; 9606.ENSP00000407401; -.
DR PhosphoSite; P50542; -.
DR DMDM; 119364633; -.
DR PaxDb; P50542; -.
DR PRIDE; P50542; -.
DR DNASU; 5830; -.
DR Ensembl; ENST00000266563; ENSP00000266563; ENSG00000139197.
DR Ensembl; ENST00000266564; ENSP00000266564; ENSG00000139197.
DR Ensembl; ENST00000420616; ENSP00000410159; ENSG00000139197.
DR Ensembl; ENST00000434354; ENSP00000407401; ENSG00000139197.
DR Ensembl; ENST00000455147; ENSP00000400647; ENSG00000139197.
DR GeneID; 5830; -.
DR KEGG; hsa:5830; -.
DR UCSC; uc001qsw.3; human.
DR CTD; 5830; -.
DR GeneCards; GC12P007341; -.
DR HGNC; HGNC:9719; PEX5.
DR HPA; HPA039259; -.
DR MIM; 202370; phenotype.
DR MIM; 214110; phenotype.
DR MIM; 600414; gene.
DR neXtProt; NX_P50542; -.
DR Orphanet; 772; Infantile Refsum disease.
DR Orphanet; 44; Neonatal adrenoleukodystrophy.
DR Orphanet; 912; Zellweger syndrome.
DR PharmGKB; PA34063; -.
DR eggNOG; COG0457; -.
DR HOGENOM; HOG000158146; -.
DR HOVERGEN; HBG053575; -.
DR InParanoid; P50542; -.
DR KO; K13342; -.
DR OrthoDB; EOG793B77; -.
DR ChiTaRS; PEX5; human.
DR EvolutionaryTrace; P50542; -.
DR GeneWiki; PEX5; -.
DR GenomeRNAi; 5830; -.
DR NextBio; 22716; -.
DR PRO; PR:P50542; -.
DR ArrayExpress; P50542; -.
DR Bgee; P50542; -.
DR CleanEx; HS_PEX5; -.
DR Genevestigator; P50542; -.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0005794; C:Golgi apparatus; IDA:HPA.
DR GO; GO:0005782; C:peroxisomal matrix; IDA:UniProtKB.
DR GO; GO:0005778; C:peroxisomal membrane; IDA:UniProtKB.
DR GO; GO:0043234; C:protein complex; IDA:UniProtKB.
DR GO; GO:0005052; F:peroxisome matrix targeting signal-1 binding; IDA:UniProtKB.
DR GO; GO:0048468; P:cell development; IEA:Ensembl.
DR GO; GO:0021795; P:cerebral cortex cell migration; IEA:Ensembl.
DR GO; GO:0021895; P:cerebral cortex neuron differentiation; IEA:Ensembl.
DR GO; GO:0007029; P:endoplasmic reticulum organization; IEA:Ensembl.
DR GO; GO:0006635; P:fatty acid beta-oxidation; IEA:Ensembl.
DR GO; GO:0007006; P:mitochondrial membrane organization; IEA:Ensembl.
DR GO; GO:1901094; P:negative regulation of protein homotetramerization; IDA:UniProtKB.
DR GO; GO:0050905; P:neuromuscular process; IEA:Ensembl.
DR GO; GO:0001764; P:neuron migration; IEA:Ensembl.
DR GO; GO:0040018; P:positive regulation of multicellular organism growth; IEA:Ensembl.
DR GO; GO:0016558; P:protein import into peroxisome matrix; IGI:UniProtKB.
DR GO; GO:0016560; P:protein import into peroxisome matrix, docking; IDA:UniProtKB.
DR GO; GO:0016561; P:protein import into peroxisome matrix, translocation; IDA:UniProtKB.
DR GO; GO:0045046; P:protein import into peroxisome membrane; IMP:UniProtKB.
DR GO; GO:0051262; P:protein tetramerization; IDA:UniProtKB.
DR GO; GO:0000038; P:very long-chain fatty acid metabolic process; IEA:Ensembl.
DR Gene3D; 1.25.40.10; -; 2.
DR InterPro; IPR024111; PTS1R_family.
DR InterPro; IPR013026; TPR-contain_dom.
DR InterPro; IPR011990; TPR-like_helical.
DR InterPro; IPR001440; TPR_1.
DR InterPro; IPR019734; TPR_repeat.
DR PANTHER; PTHR10130; PTHR10130; 1.
DR Pfam; PF00515; TPR_1; 3.
DR SMART; SM00028; TPR; 4.
DR PROSITE; PS50005; TPR; 5.
DR PROSITE; PS50293; TPR_REGION; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Complete proteome; Cytoplasm;
KW Disease mutation; Membrane; Peroxisome;
KW Peroxisome biogenesis disorder; Protein transport; Reference proteome;
KW Repeat; Thioester bond; TPR repeat; Transport; Ubl conjugation;
KW Zellweger syndrome.
FT CHAIN 1 639 Peroxisomal targeting signal 1 receptor.
FT /FTId=PRO_0000106305.
FT REPEAT 335 368 TPR 1.
FT REPEAT 369 402 TPR 2.
FT REPEAT 403 436 TPR 3.
FT REPEAT 452 485 TPR 4.
FT REPEAT 488 521 TPR 5.
FT REPEAT 522 555 TPR 6.
FT REPEAT 556 589 TPR 7.
FT CROSSLNK 11 11 Glycyl cysteine thioester (Cys-Gly)
FT (interchain with G-Cter in ubiquitin) (By
FT similarity).
FT VAR_SEQ 45 45 P -> PASEAVSVLEVESPGA (in isoform 4).
FT /FTId=VSP_043639.
FT VAR_SEQ 215 251 Missing (in isoform 2).
FT /FTId=VSP_021880.
FT VAR_SEQ 283 290 Missing (in isoform 3).
FT /FTId=VSP_024106.
FT VARIANT 526 526 N -> K (in PBD2B; neonatal
FT adrenoleukodystrophy; strongly affects
FT peroxisomal protein import).
FT /FTId=VAR_007543.
FT VARIANT 600 600 S -> W (in PBD2B; infantile Refsum
FT disease; mildly affects peroxisomal
FT protein import).
FT /FTId=VAR_031328.
FT MUTAGEN 118 118 W->A: Strongly reduced interaction with
FT PEX14.
FT MUTAGEN 122 122 F->A: Strongly reduced interaction with
FT PEX14.
FT CONFLICT 425 425 T -> I (in Ref. 1; AAC50103).
FT HELIX 109 124
FT HELIX 318 321
FT TURN 331 334
FT HELIX 338 347
FT HELIX 351 363
FT HELIX 369 381
FT HELIX 385 398
FT HELIX 403 415
FT HELIX 419 431
FT TURN 434 436
FT HELIX 437 439
FT HELIX 460 481
FT HELIX 488 500
FT HELIX 504 517
FT HELIX 522 534
FT HELIX 538 551
FT HELIX 556 569
FT HELIX 572 587
FT STRAND 593 595
FT HELIX 601 614
FT HELIX 617 619
FT HELIX 620 624
FT HELIX 628 634
SQ SEQUENCE 639 AA; 70865 MW; 9D6951F58AED31AC CRC64;
MAMRELVEAE CGGANPLMKL AGHFTQDKAL RQEGLRPGPW PPGAPASEAA SKPLGVASED
ELVAEFLQDQ NAPLVSRAPQ TFKMDDLLAE MQQIEQSNFR QAPQRAPGVA DLALSENWAQ
EFLAAGDAVD VTQDYNETDW SQEFISEVTD PLSVSPARWA EEYLEQSEEK LWLGEPEGTA
TDRWYDEYHP EEDLQHTASD FVAKVDDPKL ANSEFLKFVR QIGEGQVSLE SGAGSGRAQA
EQWAAEFIQQ QGTSDAWVDQ FTRPVNTSAL DMEFERAKSA IESDVDFWDK LQAELEEMAK
RDAEAHPWLS DYDDLTSATY DKGYQFEEEN PLRDHPQPFE EGLRRLQEGD LPNAVLLFEA
AVQQDPKHME AWQYLGTTQA ENEQELLAIS ALRRCLELKP DNQTALMALA VSFTNESLQR
QACETLRDWL RYTPAYAHLV TPAEEGAGGA GLGPSKRILG SLLSDSLFLE VKELFLAAVR
LDPTSIDPDV QCGLGVLFNL SGEYDKAVDC FTAALSVRPN DYLLWNKLGA TLANGNQSEE
AVAAYRRALE LQPGYIRSRY NLGISCINLG AHREAVEHFL EALNMQRKSR GPRGEGGAMS
ENIWSTLRLA LSMLGQSDAY GAADARDLST LLTMFGLPQ
//
ID PEX5_HUMAN Reviewed; 639 AA.
AC P50542; A8K891; B4DZ45; B7ZAD5; D3DUT8; Q15115; Q15266; Q96FN7;
read moreDT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
DT 12-DEC-2006, sequence version 3.
DT 22-JAN-2014, entry version 150.
DE RecName: Full=Peroxisomal targeting signal 1 receptor;
DE Short=PTS1 receptor;
DE Short=PTS1R;
DE AltName: Full=PTS1-BP;
DE AltName: Full=Peroxin-5;
DE AltName: Full=Peroxisomal C-terminal targeting signal import receptor;
DE AltName: Full=Peroxisome receptor 1;
GN Name=PEX5; Synonyms=PXR1;
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 2), INVOLVEMENT IN PBD2A, VARIANT
RP PBD2B LYS-526, FUNCTION, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=7719337; DOI=10.1038/ng0295-115;
RA Dodt G., Braverman N., Wong C., Moser A., Moser H.W., Watkins P.,
RA Valle D., Gould S.J.;
RT "Mutations in the PTS1 receptor gene, PXR1, define complementation
RT group 2 of the peroxisome biogenesis disorders.";
RL Nat. Genet. 9:115-125(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), FUNCTION, AND TISSUE
RP SPECIFICITY.
RC TISSUE=Liver;
RX PubMed=7790377; DOI=10.1083/jcb.130.1.51;
RA Wiemer E.A.C., Nuttley W.M., Bertolaet B.L., Li X., Francke U.,
RA Wheelock M.J., Anne U.K., Johnson K.R., Subramani S.;
RT "Human peroxisomal targeting signal-1 receptor restores peroxisomal
RT protein import in cells from patients with fatal peroxisomal
RT disorders.";
RL J. Cell Biol. 130:51-65(1995).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, TISSUE SPECIFICITY,
RP AND SUBCELLULAR LOCATION.
RC TISSUE=Liver;
RX PubMed=7706321; DOI=10.1074/jbc.270.13.7731;
RA Fransen M., Brees C., Baumgart E., Vanhooren J.C.T., Baes M.,
RA Mannaerts G.P., van Veldhoven P.P.;
RT "Identification and characterization of the putative human peroxisomal
RT C-terminal targeting signal import receptor.";
RL J. Biol. Chem. 270:7731-7736(1995).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1; 2 AND 4).
RC TISSUE=Testis;
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 [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16541075; DOI=10.1038/nature04569;
RA Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y.,
RA Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C.,
RA Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M.,
RA Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L.,
RA Milosavljevic A., Miner G.R., Montgomery K.T., Morgan M.B.,
RA Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D.,
RA Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y., Zhang Z.,
RA Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z.,
RA Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H., Draper H.,
RA Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S., Kelly S.H.,
RA Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V.,
RA Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H., Santibanez J.,
RA Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q., Williams G.A.,
RA Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V., Bailey M.,
RA Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E., Burkett C.E.,
RA Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K.,
RA Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D.,
RA Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M.,
RA Dathorne S.R., David R., Davis C.M., Davy-Carroll L., Deshazo D.R.,
RA Donlin J.E., D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J.,
RA Escotto M., Flagg N., Forbes L.D., Gabisi A.M., Garza M., Hamilton C.,
RA Henderson N., Hernandez O., Hines S., Hogues M.E., Huang M.,
RA Idlebird D.G., Johnson R., Jolivet A., Jones S., Kagan R., King L.M.,
RA Leal B., Lebow H., Lee S., LeVan J.M., Lewis L.C., London P.,
RA Lorensuhewa L.M., Loulseged H., Lovett D.A., Lucier A., Lucier R.L.,
RA Ma J., Madu R.C., Mapua P., Martindale A.D., Martinez E., Massey E.,
RA Mawhiney S., Meador M.G., Mendez S., Mercado C., Mercado I.C.,
RA Merritt C.E., Miner Z.L., Minja E., Mitchell T., Mohabbat F.,
RA Mohabbat K., Montgomery B., Moore N., Morris S., Munidasa M.,
RA Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O., Nwokenkwo S.,
RA Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J.,
RA Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A.,
RA Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M.,
RA Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I.,
RA Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A.,
RA Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D.,
RA Trejos Z.Y., Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I.,
RA Vera V.A., Villasana D.M., Wang L., Ward-Moore S., Warren J.T.,
RA Wei X., White F., Williamson A.L., Wleczyk R., Wooden H.S.,
RA Wooden S.H., Yen J., Yoon L., Yoon V., Zorrilla S.E., Nelson D.,
RA Kucherlapati R., Weinstock G., Gibbs R.A.;
RT "The finished DNA sequence of human chromosome 12.";
RL Nature 440:346-351(2006).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
RC TISSUE=Eye;
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 [8]
RP INTERACTION WITH PEX12.
RX PubMed=10562279; DOI=10.1083/jcb.147.4.761;
RA Chang C.C., Warren D.S., Sacksteder K.A., Gould S.J.;
RT "PEX12 interacts with PEX5 and PEX10 and acts downstream of receptor
RT docking in peroxisomal matrix protein import.";
RL J. Cell Biol. 147:761-774(1999).
RN [9]
RP INTERACTION WITH PEX14, AND MUTAGENESIS OF TRP-118 AND PHE-122.
RX PubMed=11438541; DOI=10.1074/jbc.M104647200;
RA Saidowsky J., Dodt G., Kirchberg K., Wegner A., Nastainczyk W.,
RA Kunau W.-H., Schliebs W.;
RT "The di-aromatic pentapeptide repeats of the human peroxisome import
RT receptor PEX5 are separate high affinity binding sites for the
RT peroxisomal membrane protein PEX14.";
RL J. Biol. Chem. 276:34524-34529(2001).
RN [10]
RP INTERACTION WITH ZFAND6.
RX PubMed=21980954; DOI=10.1111/j.1600-0854.2011.01298.x;
RA Miyata N., Okumoto K., Mukai S., Noguchi M., Fujiki Y.;
RT "AWP1/ZFAND6 functions in Pex5 export by interacting with cys-
RT monoubiquitinated Pex5 and Pex6 AAA ATPase.";
RL Traffic 13:168-183(2012).
RN [11]
RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 272-639 IN COMPLEX WITH
RP TARGETING PEPTIDE.
RX PubMed=11101887; DOI=10.1038/81930;
RA Gatto G.J. Jr., Geisbrecht B.V., Gould S.J., Berg J.M.;
RT "Peroxisomal targeting signal-1 recognition by the TPR domains of
RT human PEX5.";
RL Nat. Struct. Biol. 7:1091-1095(2000).
RN [12]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 321-639 IN COMPLEX WITH
RP TARGETING PEPTIDE.
RX PubMed=17157249; DOI=10.1016/j.molcel.2006.10.024;
RA Stanley W.A., Filipp F.V., Kursula P., Schueller N., Erdmann R.,
RA Schliebs W., Sattler M., Wilmanns M.;
RT "Recognition of a functional peroxisome type 1 target by the dynamic
RT import receptor Pex5p.";
RL Mol. Cell 24:653-663(2006).
RN [13]
RP X-RAY CRYSTALLOGRAPHY (2.65 ANGSTROMS) OF 315-639, AND BINDING TO
RP C-TERMINAL TARGETING PEPTIDES.
RX PubMed=17428317; DOI=10.1186/1472-6807-7-24;
RA Stanley W.A., Pursiainen N.V., Garman E.F., Juffer A.H., Wilmanns M.,
RA Kursula P.;
RT "A previously unobserved conformation for the human Pex5p receptor
RT suggests roles for intrinsic flexibility and rigid domain motions in
RT ligand binding.";
RL BMC Struct. Biol. 7:24-24(2007).
RN [14]
RP STRUCTURE BY NMR OF 108-127 IN COMPLEX WITH PEX14.
RX PubMed=19197237; DOI=10.1038/emboj.2009.7;
RA Neufeld C., Filipp F.V., Simon B., Neuhaus A., Schueller N., David C.,
RA Kooshapur H., Madl T., Erdmann R., Schliebs W., Wilmanns M.,
RA Sattler M.;
RT "Structural basis for competitive interactions of Pex14 with the
RT import receptors Pex5 and Pex19.";
RL EMBO J. 28:745-754(2009).
RN [15]
RP VARIANTS PBD2B LYS-526 AND TRP-600, AND CHARACTERIZATION OF VARIANTS
RP PBD2B LYS-526 AND TRP-600.
RX PubMed=10462504; DOI=10.1006/bbrc.1999.1232;
RA Shimozawa N., Zhang Z., Suzuki Y., Imamura A., Tsukamoto T., Osumi T.,
RA Fujiki Y., Orii T., Barth P.G., Wanders R.J., Kondo N.;
RT "Functional heterogeneity of C-terminal peroxisome targeting signal 1
RT in PEX5-defective patients.";
RL Biochem. Biophys. Res. Commun. 262:504-508(1999).
CC -!- FUNCTION: Binds to the C-terminal PTS1-type tripeptide peroxisomal
CC targeting signal (SKL-type) and plays an essential role in
CC peroxisomal protein import.
CC -!- SUBUNIT: Interacts with PEX7 and PEX13 (By similarity). Interacts
CC with PEX12 and PEX14. Interacts (Cys-linked ubiquitinated) with
CC ZFAND6.
CC -!- INTERACTION:
CC O00623:PEX12; NbExp=4; IntAct=EBI-597835, EBI-594836;
CC O75381:PEX14; NbExp=13; IntAct=EBI-597835, EBI-594898;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Peroxisome membrane; Peripheral
CC membrane protein. Note=Its distribution appears to be dynamic. It
CC is probably a cycling receptor found mainly in the cytoplasm and
CC as well associated to the peroxisomal membrane through a docking
CC factor (PEX13).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=1;
CC IsoId=P50542-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P50542-2; Sequence=VSP_021880;
CC Name=3;
CC IsoId=P50542-3; Sequence=VSP_024106;
CC Name=4;
CC IsoId=P50542-4; Sequence=VSP_043639;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Detected in heart, brain, placenta, lung,
CC liver, skeletal muscle, kidney and pancreas.
CC -!- PTM: Monoubiquitination at Cys-11 is required for proper export
CC from peroxisomes and recycling (By similarity).
CC -!- DISEASE: Peroxisome biogenesis disorder 2A (PBD2A) [MIM:214110]: A
CC fatal peroxisome biogenesis disorder belonging to the Zellweger
CC disease spectrum and characterized clinically by severe neurologic
CC dysfunction with profound psychomotor retardation, severe
CC hypotonia and neonatal seizures, craniofacial abnormalities, liver
CC dysfunction, and biochemically by the absence of peroxisomes.
CC Additional features include cardiovascular and skeletal defects,
CC renal cysts, ocular abnormalities, and hearing impairment. Most
CC severely affected individuals with the classic form of the disease
CC (classic Zellweger syndrome) die within the first year of life.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- DISEASE: Peroxisome biogenesis disorder 2B (PBD2B) [MIM:202370]: A
CC peroxisome biogenesis disorder that includes neonatal
CC adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD),
CC two milder manifestations of the Zellweger disease spectrum. The
CC clinical course of patients with the NALD and IRD presentation is
CC variable and may include developmental delay, hypotonia, liver
CC dysfunction, sensorineural hearing loss, retinal dystrophy and
CC vision impairment. Children with the NALD presentation may reach
CC their teens, while patients with the IRD presentation may reach
CC adulthood. The clinical conditions are often slowly progressive in
CC particular with respect to loss of hearing and vision. The
CC biochemical abnormalities include accumulation of phytanic acid,
CC very long chain fatty acids (VLCFA), di- and
CC trihydroxycholestanoic acid and pipecolic acid. Note=The disease
CC is caused by mutations affecting the gene represented in this
CC entry.
CC -!- SIMILARITY: Belongs to the peroxisomal targeting signal receptor
CC family.
CC -!- SIMILARITY: Contains 7 TPR repeats.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/PEX5";
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DR EMBL; U19721; AAC50103.1; -; mRNA.
DR EMBL; Z48054; CAA88131.1; -; mRNA.
DR EMBL; X84899; CAA59324.1; -; mRNA.
DR EMBL; AK292256; BAF84945.1; -; mRNA.
DR EMBL; AK302742; BAG63957.1; -; mRNA.
DR EMBL; AK316250; BAH14621.1; -; mRNA.
DR EMBL; AC018653; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471116; EAW88671.1; -; Genomic_DNA.
DR EMBL; CH471116; EAW88674.1; -; Genomic_DNA.
DR EMBL; CH471116; EAW88672.1; -; Genomic_DNA.
DR EMBL; BC010621; AAH10621.1; -; mRNA.
DR PIR; A56126; A56126.
DR RefSeq; NP_000310.2; NM_000319.4.
DR RefSeq; NP_001124495.1; NM_001131023.1.
DR RefSeq; NP_001124496.1; NM_001131024.1.
DR RefSeq; NP_001124497.1; NM_001131025.1.
DR RefSeq; NP_001124498.1; NM_001131026.1.
DR RefSeq; XP_005253511.1; XM_005253454.1.
DR UniGene; Hs.567327; -.
DR PDB; 1FCH; X-ray; 2.20 A; A/B=272-639.
DR PDB; 2C0L; X-ray; 2.30 A; A=335-639.
DR PDB; 2C0M; X-ray; 2.50 A; A/B/C/F=321-639.
DR PDB; 2J9Q; X-ray; 2.65 A; A/B=315-639.
DR PDB; 2W84; NMR; -; B=108-127.
DR PDB; 3R9A; X-ray; 2.35 A; B/D=315-639.
DR PDBsum; 1FCH; -.
DR PDBsum; 2C0L; -.
DR PDBsum; 2C0M; -.
DR PDBsum; 2J9Q; -.
DR PDBsum; 2W84; -.
DR PDBsum; 3R9A; -.
DR DisProt; DP00472; -.
DR ProteinModelPortal; P50542; -.
DR SMR; P50542; 335-639.
DR DIP; DIP-34654N; -.
DR IntAct; P50542; 18.
DR MINT; MINT-241634; -.
DR STRING; 9606.ENSP00000407401; -.
DR PhosphoSite; P50542; -.
DR DMDM; 119364633; -.
DR PaxDb; P50542; -.
DR PRIDE; P50542; -.
DR DNASU; 5830; -.
DR Ensembl; ENST00000266563; ENSP00000266563; ENSG00000139197.
DR Ensembl; ENST00000266564; ENSP00000266564; ENSG00000139197.
DR Ensembl; ENST00000420616; ENSP00000410159; ENSG00000139197.
DR Ensembl; ENST00000434354; ENSP00000407401; ENSG00000139197.
DR Ensembl; ENST00000455147; ENSP00000400647; ENSG00000139197.
DR GeneID; 5830; -.
DR KEGG; hsa:5830; -.
DR UCSC; uc001qsw.3; human.
DR CTD; 5830; -.
DR GeneCards; GC12P007341; -.
DR HGNC; HGNC:9719; PEX5.
DR HPA; HPA039259; -.
DR MIM; 202370; phenotype.
DR MIM; 214110; phenotype.
DR MIM; 600414; gene.
DR neXtProt; NX_P50542; -.
DR Orphanet; 772; Infantile Refsum disease.
DR Orphanet; 44; Neonatal adrenoleukodystrophy.
DR Orphanet; 912; Zellweger syndrome.
DR PharmGKB; PA34063; -.
DR eggNOG; COG0457; -.
DR HOGENOM; HOG000158146; -.
DR HOVERGEN; HBG053575; -.
DR InParanoid; P50542; -.
DR KO; K13342; -.
DR OrthoDB; EOG793B77; -.
DR ChiTaRS; PEX5; human.
DR EvolutionaryTrace; P50542; -.
DR GeneWiki; PEX5; -.
DR GenomeRNAi; 5830; -.
DR NextBio; 22716; -.
DR PRO; PR:P50542; -.
DR ArrayExpress; P50542; -.
DR Bgee; P50542; -.
DR CleanEx; HS_PEX5; -.
DR Genevestigator; P50542; -.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0005794; C:Golgi apparatus; IDA:HPA.
DR GO; GO:0005782; C:peroxisomal matrix; IDA:UniProtKB.
DR GO; GO:0005778; C:peroxisomal membrane; IDA:UniProtKB.
DR GO; GO:0043234; C:protein complex; IDA:UniProtKB.
DR GO; GO:0005052; F:peroxisome matrix targeting signal-1 binding; IDA:UniProtKB.
DR GO; GO:0048468; P:cell development; IEA:Ensembl.
DR GO; GO:0021795; P:cerebral cortex cell migration; IEA:Ensembl.
DR GO; GO:0021895; P:cerebral cortex neuron differentiation; IEA:Ensembl.
DR GO; GO:0007029; P:endoplasmic reticulum organization; IEA:Ensembl.
DR GO; GO:0006635; P:fatty acid beta-oxidation; IEA:Ensembl.
DR GO; GO:0007006; P:mitochondrial membrane organization; IEA:Ensembl.
DR GO; GO:1901094; P:negative regulation of protein homotetramerization; IDA:UniProtKB.
DR GO; GO:0050905; P:neuromuscular process; IEA:Ensembl.
DR GO; GO:0001764; P:neuron migration; IEA:Ensembl.
DR GO; GO:0040018; P:positive regulation of multicellular organism growth; IEA:Ensembl.
DR GO; GO:0016558; P:protein import into peroxisome matrix; IGI:UniProtKB.
DR GO; GO:0016560; P:protein import into peroxisome matrix, docking; IDA:UniProtKB.
DR GO; GO:0016561; P:protein import into peroxisome matrix, translocation; IDA:UniProtKB.
DR GO; GO:0045046; P:protein import into peroxisome membrane; IMP:UniProtKB.
DR GO; GO:0051262; P:protein tetramerization; IDA:UniProtKB.
DR GO; GO:0000038; P:very long-chain fatty acid metabolic process; IEA:Ensembl.
DR Gene3D; 1.25.40.10; -; 2.
DR InterPro; IPR024111; PTS1R_family.
DR InterPro; IPR013026; TPR-contain_dom.
DR InterPro; IPR011990; TPR-like_helical.
DR InterPro; IPR001440; TPR_1.
DR InterPro; IPR019734; TPR_repeat.
DR PANTHER; PTHR10130; PTHR10130; 1.
DR Pfam; PF00515; TPR_1; 3.
DR SMART; SM00028; TPR; 4.
DR PROSITE; PS50005; TPR; 5.
DR PROSITE; PS50293; TPR_REGION; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Complete proteome; Cytoplasm;
KW Disease mutation; Membrane; Peroxisome;
KW Peroxisome biogenesis disorder; Protein transport; Reference proteome;
KW Repeat; Thioester bond; TPR repeat; Transport; Ubl conjugation;
KW Zellweger syndrome.
FT CHAIN 1 639 Peroxisomal targeting signal 1 receptor.
FT /FTId=PRO_0000106305.
FT REPEAT 335 368 TPR 1.
FT REPEAT 369 402 TPR 2.
FT REPEAT 403 436 TPR 3.
FT REPEAT 452 485 TPR 4.
FT REPEAT 488 521 TPR 5.
FT REPEAT 522 555 TPR 6.
FT REPEAT 556 589 TPR 7.
FT CROSSLNK 11 11 Glycyl cysteine thioester (Cys-Gly)
FT (interchain with G-Cter in ubiquitin) (By
FT similarity).
FT VAR_SEQ 45 45 P -> PASEAVSVLEVESPGA (in isoform 4).
FT /FTId=VSP_043639.
FT VAR_SEQ 215 251 Missing (in isoform 2).
FT /FTId=VSP_021880.
FT VAR_SEQ 283 290 Missing (in isoform 3).
FT /FTId=VSP_024106.
FT VARIANT 526 526 N -> K (in PBD2B; neonatal
FT adrenoleukodystrophy; strongly affects
FT peroxisomal protein import).
FT /FTId=VAR_007543.
FT VARIANT 600 600 S -> W (in PBD2B; infantile Refsum
FT disease; mildly affects peroxisomal
FT protein import).
FT /FTId=VAR_031328.
FT MUTAGEN 118 118 W->A: Strongly reduced interaction with
FT PEX14.
FT MUTAGEN 122 122 F->A: Strongly reduced interaction with
FT PEX14.
FT CONFLICT 425 425 T -> I (in Ref. 1; AAC50103).
FT HELIX 109 124
FT HELIX 318 321
FT TURN 331 334
FT HELIX 338 347
FT HELIX 351 363
FT HELIX 369 381
FT HELIX 385 398
FT HELIX 403 415
FT HELIX 419 431
FT TURN 434 436
FT HELIX 437 439
FT HELIX 460 481
FT HELIX 488 500
FT HELIX 504 517
FT HELIX 522 534
FT HELIX 538 551
FT HELIX 556 569
FT HELIX 572 587
FT STRAND 593 595
FT HELIX 601 614
FT HELIX 617 619
FT HELIX 620 624
FT HELIX 628 634
SQ SEQUENCE 639 AA; 70865 MW; 9D6951F58AED31AC CRC64;
MAMRELVEAE CGGANPLMKL AGHFTQDKAL RQEGLRPGPW PPGAPASEAA SKPLGVASED
ELVAEFLQDQ NAPLVSRAPQ TFKMDDLLAE MQQIEQSNFR QAPQRAPGVA DLALSENWAQ
EFLAAGDAVD VTQDYNETDW SQEFISEVTD PLSVSPARWA EEYLEQSEEK LWLGEPEGTA
TDRWYDEYHP EEDLQHTASD FVAKVDDPKL ANSEFLKFVR QIGEGQVSLE SGAGSGRAQA
EQWAAEFIQQ QGTSDAWVDQ FTRPVNTSAL DMEFERAKSA IESDVDFWDK LQAELEEMAK
RDAEAHPWLS DYDDLTSATY DKGYQFEEEN PLRDHPQPFE EGLRRLQEGD LPNAVLLFEA
AVQQDPKHME AWQYLGTTQA ENEQELLAIS ALRRCLELKP DNQTALMALA VSFTNESLQR
QACETLRDWL RYTPAYAHLV TPAEEGAGGA GLGPSKRILG SLLSDSLFLE VKELFLAAVR
LDPTSIDPDV QCGLGVLFNL SGEYDKAVDC FTAALSVRPN DYLLWNKLGA TLANGNQSEE
AVAAYRRALE LQPGYIRSRY NLGISCINLG AHREAVEHFL EALNMQRKSR GPRGEGGAMS
ENIWSTLRLA LSMLGQSDAY GAADARDLST LLTMFGLPQ
//
MIM
202370
*RECORD*
*FIELD* NO
202370
*FIELD* TI
#202370 PEROXISOME BIOGENESIS DISORDER 2B; PBD2B
*FIELD* TX
A number sign (#) is used with this entry because this form of
read moreperoxisome biogenesis disorder (PBD2B) is caused by homozygous mutation
in the PEX5 gene (600414) on chromosome 12p13.3. Mutations in the PEX5
gene also cause Zellweger syndrome (PBD2A; 214110).
DESCRIPTION
The overlapping phenotypes of neonatal adrenoleukodystrophy (NALD) and
infantile Refsum disease (IRD) represent the milder manifestations of
the Zellweger syndrome spectrum (ZSS) of peroxisome biogenesis
disorders. The clinical course of patients with the NALD and IRD
presentation is variable and may include developmental delay, hypotonia,
liver dysfunction, sensorineural hearing loss, retinal dystrophy, and
visual impairment. Children with the NALD presentation may reach their
teens, and those with the IRD presentation may reach adulthood (summary
by Waterham and Ebberink, 2012).
For a complete phenotypic description and a discussion of genetic
heterogeneity of PBD(NALD/IRD), see 601539.
Individuals with mutations in the PEX5 gene have cells of
complementation group 2 (CG2). For information on the history of PBD
complementation groups, see 214100.
MOLECULAR GENETICS
Dodt et al. (1995) reported a homozygous mutation in the PEX5 gene in a
cell line from a patient with NALD (600414.0001).
*FIELD* RF
1. Dodt, G.; Braverman, N.; Wong, C.; Moser, A.; Moser, H. W.; Watkins,
P.; Valle, D.; Gould, S. J.: Mutations in the PTS1 receptor gene,
PXR1, define complementation group 2 of the peroxisome biogenesis
disorders. Nature Genet. 9: 115-125, 1995.
2. Waterham, H. R.; Ebberink, M. S.: Genetics and molecular basis
of human peroxisome biogenesis disorders. Biochim. Biophys. Acta 1822:
1430-1441, 2012.
*FIELD* CS
Head:
Dolichocephaly;
Forehead prominent;
Forehead high
Eye:
Cataracts, neonatal polar;
Esotropia;
Epicanthal folds
Nose:
Nasal bridge broad;
Nostrils anteverted
Mouth:
Palate high-arched
Ears:
Low-set
Skin:
Tanning
Facies:
Peculiar facies
Neuro:
Mental retardation;
Seizures
Endo:
Adrenal insufficiency
Lab:
Elevated long chain fatty acids
Inheritance:
Autosomal recessive
*FIELD* CD
Victor A. McKusick: 6/2/1986
*FIELD* ED
alopez: 10/26/2012
alopez: 10/24/2012
wwang: 5/29/2007
terry: 4/6/2005
mgross: 5/18/2004
tkritzer: 4/8/2003
carol: 8/26/1999
alopez: 7/17/1998
terry: 7/17/1998
mark: 12/10/1997
mimadm: 11/12/1995
carol: 2/16/1995
warfield: 4/14/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
*RECORD*
*FIELD* NO
202370
*FIELD* TI
#202370 PEROXISOME BIOGENESIS DISORDER 2B; PBD2B
*FIELD* TX
A number sign (#) is used with this entry because this form of
read moreperoxisome biogenesis disorder (PBD2B) is caused by homozygous mutation
in the PEX5 gene (600414) on chromosome 12p13.3. Mutations in the PEX5
gene also cause Zellweger syndrome (PBD2A; 214110).
DESCRIPTION
The overlapping phenotypes of neonatal adrenoleukodystrophy (NALD) and
infantile Refsum disease (IRD) represent the milder manifestations of
the Zellweger syndrome spectrum (ZSS) of peroxisome biogenesis
disorders. The clinical course of patients with the NALD and IRD
presentation is variable and may include developmental delay, hypotonia,
liver dysfunction, sensorineural hearing loss, retinal dystrophy, and
visual impairment. Children with the NALD presentation may reach their
teens, and those with the IRD presentation may reach adulthood (summary
by Waterham and Ebberink, 2012).
For a complete phenotypic description and a discussion of genetic
heterogeneity of PBD(NALD/IRD), see 601539.
Individuals with mutations in the PEX5 gene have cells of
complementation group 2 (CG2). For information on the history of PBD
complementation groups, see 214100.
MOLECULAR GENETICS
Dodt et al. (1995) reported a homozygous mutation in the PEX5 gene in a
cell line from a patient with NALD (600414.0001).
*FIELD* RF
1. Dodt, G.; Braverman, N.; Wong, C.; Moser, A.; Moser, H. W.; Watkins,
P.; Valle, D.; Gould, S. J.: Mutations in the PTS1 receptor gene,
PXR1, define complementation group 2 of the peroxisome biogenesis
disorders. Nature Genet. 9: 115-125, 1995.
2. Waterham, H. R.; Ebberink, M. S.: Genetics and molecular basis
of human peroxisome biogenesis disorders. Biochim. Biophys. Acta 1822:
1430-1441, 2012.
*FIELD* CS
Head:
Dolichocephaly;
Forehead prominent;
Forehead high
Eye:
Cataracts, neonatal polar;
Esotropia;
Epicanthal folds
Nose:
Nasal bridge broad;
Nostrils anteverted
Mouth:
Palate high-arched
Ears:
Low-set
Skin:
Tanning
Facies:
Peculiar facies
Neuro:
Mental retardation;
Seizures
Endo:
Adrenal insufficiency
Lab:
Elevated long chain fatty acids
Inheritance:
Autosomal recessive
*FIELD* CD
Victor A. McKusick: 6/2/1986
*FIELD* ED
alopez: 10/26/2012
alopez: 10/24/2012
wwang: 5/29/2007
terry: 4/6/2005
mgross: 5/18/2004
tkritzer: 4/8/2003
carol: 8/26/1999
alopez: 7/17/1998
terry: 7/17/1998
mark: 12/10/1997
mimadm: 11/12/1995
carol: 2/16/1995
warfield: 4/14/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
MIM
214110
*RECORD*
*FIELD* NO
214110
*FIELD* TI
#214110 PEROXISOME BIOGENESIS DISORDER 2A (ZELLWEGER); PBD2A
PEROXISOME BIOGENESIS DISORDER, COMPLEMENTATION GROUP 2, INCLUDED;
read moreCG2, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because this form of Zellweger
syndrome (PBD2A) is caused by homozygous mutation in the PEX5 gene
(600414) on chromosome 12p13.3.
DESCRIPTION
The peroxisome biogenesis disorder (PBD) Zellweger syndrome (ZS) is an
autosomal recessive multiple congenital anomaly syndrome. Affected
children present in the newborn period with profound hypotonia,
seizures, and inability to feed. Characteristic craniofacial anomalies,
eye abnormalities, neuronal migration defects, hepatomegaly, and
chondrodysplasia punctata are present. Children with this condition do
not show any significant development and usually die in the first year
of life (summary by Steinberg et al., 2006).
For a complete phenotypic description and a discussion of genetic
heterogeneity of Zellweger syndrome, see 214100.
Individuals with PBDs of complementation group 2 (CG2) have mutations in
the PEX5 gene. For information on the history of PBD complementation
groups, see 214100.
CLINICAL FEATURES
Thomas et al. (1975) described a male patient with hyperpipecolic
acidemia. Features were persistent hepatomegaly, severe mental
retardation, progressive loss of developmental milestones, and
diminished visual acuity associated with nystagmus, abnormal discs, and
retinal changes. He died at age 2 years following a progressive loss of
neurologic function. Pipecolic acid was present in the serum at a
concentration of 4 to 5 mg percent and trace amounts were detected in
the urine. The complementation studies of Brul et al. (1988) assigned
this patient to complementation group 2 (CG2).
MOLECULAR GENETICS
Dodt et al. (1995) reported a homozygous mutation in the PEX5 gene in a
cell line from a patient with Zellweger syndrome (600414.0002).
*FIELD* RF
1. Brul, S.; Westerveld, A.; Strijland, A.; Wanders, R. J. A.; Schram,
A. W.; Heymans, H. S. A.; Schutgens, R. B. H.; van den Bosch, H.;
Tager, J. M.: Genetic heterogeneity in the cerebrohepatorenal (Zellweger)
syndrome and other inherited disorders with a generalized impairment
of peroxisomal functions: a study using complementation analysis. J.
Clin. Invest. 81: 1710-1715, 1988.
2. Dodt, G.; Braverman, N.; Wong, C.; Moser, A.; Moser, H. W.; Watkins,
P.; Valle, D.; Gould, S. J.: Mutations in the PTS1 receptor gene,
PXR1, define complementation group 2 of the peroxisome biogenesis
disorders. Nature Genet. 9: 115-125, 1995.
3. Steinberg, S. J.; Dodt, G.; Raymond, G. V.; Braverman, N. E.; Moser,
A. B.; Moser, H. W.: Peroxisome biogenesis disorders. Biochim. Biophys.
Acta 1763: 1733-1748, 2006.
4. Thomas, G. H.; Haslam, R. H. A.; Batshaw, M. L.; Capute, A. J.;
Neidengard, L.; Ransom, J. L.: Hyperpipecolic acidemia associated
with hepatomegaly, mental retardation, optic nerve dysplasia and progressive
neurological disease. Clin. Genet. 8: 376-382, 1975.
*FIELD* CS
Growth:
Prenatal growth failure;
Poor suck;
Failure to thrive;
Early death
Head:
High forehead;
Dolichoturricephaly;
Large fontanels
Facies:
Flat;
Round
Eyes:
Puffy lids;
Hypertelorism;
Epicanthic folds;
Brushfield spots;
Cloudy cornea;
Cataracts;
Pigmentary retinopathy;
Optic nerve dysplasia
Mouth:
Cleft palate;
Mandible:Micrognathia
Ears:
Low set;
Helix abnormal
Limbs:
Cubitus valgus;
Camptodactyly;
Transverse palmar crease;
Metatarsus adductus;
Talipes equinovarus
GU:
Polycystic kidneys;
Cryptorchidism;
Clitoromegaly
Resp:
Apnea
Thorax:
Thymus hypoplasia
Cardiac:
Congenital heart defect
Neuro:
Hypotonia;
Areflexia;
Absent Moro response;
Mental retardation;
Seizures
Liver:
Intrahepatic biliary dysgenesis;
Jaundice;
Mitochondrial abnormalities;
Hepatomegaly
Skel:
Stippled chondral calcification
Lab:
Elevated long chain fatty acids in plasma, fibroblasts and amniocytes;
Serum iron and iron binding capacity high;
Peroxisomes abnormal;
Pipecolic aciduria;
Serum pipecolic acid elevated
Inheritance:
Autosomal recessive, several forms
*FIELD* ED
joanna: 07/17/2013
*FIELD* CD
Victor A. McKusick: 7/11/1989
*FIELD* ED
alopez: 10/25/2012
alopez: 10/24/2012
mgross: 3/17/2004
mimadm: 2/19/1994
carol: 5/21/1993
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
root: 7/11/1989
*RECORD*
*FIELD* NO
214110
*FIELD* TI
#214110 PEROXISOME BIOGENESIS DISORDER 2A (ZELLWEGER); PBD2A
PEROXISOME BIOGENESIS DISORDER, COMPLEMENTATION GROUP 2, INCLUDED;
read moreCG2, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because this form of Zellweger
syndrome (PBD2A) is caused by homozygous mutation in the PEX5 gene
(600414) on chromosome 12p13.3.
DESCRIPTION
The peroxisome biogenesis disorder (PBD) Zellweger syndrome (ZS) is an
autosomal recessive multiple congenital anomaly syndrome. Affected
children present in the newborn period with profound hypotonia,
seizures, and inability to feed. Characteristic craniofacial anomalies,
eye abnormalities, neuronal migration defects, hepatomegaly, and
chondrodysplasia punctata are present. Children with this condition do
not show any significant development and usually die in the first year
of life (summary by Steinberg et al., 2006).
For a complete phenotypic description and a discussion of genetic
heterogeneity of Zellweger syndrome, see 214100.
Individuals with PBDs of complementation group 2 (CG2) have mutations in
the PEX5 gene. For information on the history of PBD complementation
groups, see 214100.
CLINICAL FEATURES
Thomas et al. (1975) described a male patient with hyperpipecolic
acidemia. Features were persistent hepatomegaly, severe mental
retardation, progressive loss of developmental milestones, and
diminished visual acuity associated with nystagmus, abnormal discs, and
retinal changes. He died at age 2 years following a progressive loss of
neurologic function. Pipecolic acid was present in the serum at a
concentration of 4 to 5 mg percent and trace amounts were detected in
the urine. The complementation studies of Brul et al. (1988) assigned
this patient to complementation group 2 (CG2).
MOLECULAR GENETICS
Dodt et al. (1995) reported a homozygous mutation in the PEX5 gene in a
cell line from a patient with Zellweger syndrome (600414.0002).
*FIELD* RF
1. Brul, S.; Westerveld, A.; Strijland, A.; Wanders, R. J. A.; Schram,
A. W.; Heymans, H. S. A.; Schutgens, R. B. H.; van den Bosch, H.;
Tager, J. M.: Genetic heterogeneity in the cerebrohepatorenal (Zellweger)
syndrome and other inherited disorders with a generalized impairment
of peroxisomal functions: a study using complementation analysis. J.
Clin. Invest. 81: 1710-1715, 1988.
2. Dodt, G.; Braverman, N.; Wong, C.; Moser, A.; Moser, H. W.; Watkins,
P.; Valle, D.; Gould, S. J.: Mutations in the PTS1 receptor gene,
PXR1, define complementation group 2 of the peroxisome biogenesis
disorders. Nature Genet. 9: 115-125, 1995.
3. Steinberg, S. J.; Dodt, G.; Raymond, G. V.; Braverman, N. E.; Moser,
A. B.; Moser, H. W.: Peroxisome biogenesis disorders. Biochim. Biophys.
Acta 1763: 1733-1748, 2006.
4. Thomas, G. H.; Haslam, R. H. A.; Batshaw, M. L.; Capute, A. J.;
Neidengard, L.; Ransom, J. L.: Hyperpipecolic acidemia associated
with hepatomegaly, mental retardation, optic nerve dysplasia and progressive
neurological disease. Clin. Genet. 8: 376-382, 1975.
*FIELD* CS
Growth:
Prenatal growth failure;
Poor suck;
Failure to thrive;
Early death
Head:
High forehead;
Dolichoturricephaly;
Large fontanels
Facies:
Flat;
Round
Eyes:
Puffy lids;
Hypertelorism;
Epicanthic folds;
Brushfield spots;
Cloudy cornea;
Cataracts;
Pigmentary retinopathy;
Optic nerve dysplasia
Mouth:
Cleft palate;
Mandible:Micrognathia
Ears:
Low set;
Helix abnormal
Limbs:
Cubitus valgus;
Camptodactyly;
Transverse palmar crease;
Metatarsus adductus;
Talipes equinovarus
GU:
Polycystic kidneys;
Cryptorchidism;
Clitoromegaly
Resp:
Apnea
Thorax:
Thymus hypoplasia
Cardiac:
Congenital heart defect
Neuro:
Hypotonia;
Areflexia;
Absent Moro response;
Mental retardation;
Seizures
Liver:
Intrahepatic biliary dysgenesis;
Jaundice;
Mitochondrial abnormalities;
Hepatomegaly
Skel:
Stippled chondral calcification
Lab:
Elevated long chain fatty acids in plasma, fibroblasts and amniocytes;
Serum iron and iron binding capacity high;
Peroxisomes abnormal;
Pipecolic aciduria;
Serum pipecolic acid elevated
Inheritance:
Autosomal recessive, several forms
*FIELD* ED
joanna: 07/17/2013
*FIELD* CD
Victor A. McKusick: 7/11/1989
*FIELD* ED
alopez: 10/25/2012
alopez: 10/24/2012
mgross: 3/17/2004
mimadm: 2/19/1994
carol: 5/21/1993
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
root: 7/11/1989
MIM
600414
*RECORD*
*FIELD* NO
600414
*FIELD* TI
*600414 PEROXISOME BIOGENESIS FACTOR 5; PEX5
;;PEROXISOME RECEPTOR 1; PXR1;;
PEROXIN 5;;
read morePTS1 RECEPTOR; PTS1R
*FIELD* TX
CLONING
Peroxisomal matrix enzymes are synthesized on free polyribosomes and
imported into the peroxisome posttranslationally. Import of the matrix
proteins requires cis-acting peroxisomal targeting signals (PTSs), the 2
best-characterized being PTS1 and PTS2 (Subramani, 1993). The C-terminal
PTS1 motif is present on most peroxisomal matrix proteins and is found
in mammals, insects, plants, yeast, and protozoans. In mammals, the
consensus PTS1 is ser-lys-leu-COOH, but some variability is allowed,
with ala or cys also possible at the -3 position; arg or his at the -2
position; and met at the -1 position. PTS1-mediated peroxisomal protein
import requires ATP and one or more cytosolic factors, and is stimulated
by HSP70 heat-shock proteins. PTS2, which has been identified in only a
few proteins (peroxisomal thiolase from numerous species, a glyoxysomal
malate dehydrogenase from watermelon, and human phytanic acid oxidase),
is located within 40 amino acids of the N terminus and has a consensus
of arg/lys-leu-X5-gln/his-leu. Mutants deficient in peroxisome assembly,
previously called pas mutants and now known as pex mutants, have been
identified in several yeast species. Among the 10 or more
complementation groups of pas mutants in the yeast Pichia pastoris, the
phenotype of the pas8 mutant is unique in that it displays a selective
defect in the import of PTS1 proteins. PAS8 encodes a 68-kD protein with
multiple tetratricopeptide repeat motifs. Because of the phenotype of
the pas8 mutant and the fact that the protein that is missing in that
mutant has PTS1-binding activity in vitro, it was proposed that PAS8
encodes the PTS1 receptor of P. pastoris. Dodt et al. (1995) identified
and characterized the human gene PXR1, a homolog of P. pastoris PAS8,
and demonstrated that it is indeed the human PTS1 receptor. PXR1, like
PAS8, encodes a receptor for proteins with the type 1 peroxisomal
targeting signal (PTS1). Mutations in PXR1 define complementation group
2 of the peroxisome biogenesis disorders (PBDs), and expression of PXR1
rescues the PTS1 import defect of fibroblasts from these patients. Based
on the observation that PXR1 exists both in the cytosol and in
association with peroxisomes, Dodt et al. (1995) proposed that PXR1
protein recognizes PTS1-containing proteins in the cytosol and directs
them to the peroxisome. In the revised nomenclature (vide infra) both
PAS8 and PXR1 are designated PEX5.
Wiemer et al. (1995) cloned a human liver cDNA encoding PEX5, which they
called PTS1R. The predicted 602-amino acid protein has a calculated
molecular mass of 67 kD but an 80-kD mass by immunoblot analysis; the
authors indicated that the discrepancy is due to aberrant migration on
SDS-polyacrylamide gels. Northern blot analysis detected an
approximately 3.4-kb transcript in all human tissues examined.
Shepard et al. (2007) identified long and short isoforms of PTS1R by
yeast 2-hybrid analysis of human trabecular meshwork and heart cell cDNA
libraries using C-terminal MYOC (601652) as bait. The long splice
variant contains 639 amino acids, and the short splice variant contains
602 amino acids.
MAPPING
By somatic cell hybrid and fluorescence in situ hybridization analyses,
Wiemer et al. (1995) mapped the human PEX5 gene to chromosome 12p13.3.
Marynen et al. (1995) mapped the PEX5 gene to chromosome 12p13 by in
situ hybridization using a cosmid containing the gene as a probe. A
radiation hybrid DNA panel was used to map the gene between TPI1
(190450) and the marker D12S1089.
BIOCHEMICAL FEATURES
- Crystal Structure
Stanley et al. (2006) solved the crystal structure of PXR1 at
2.3-angstrom resolution in the presence and absence of a cargo protein,
SCP2 (184755). PXR1 showed major structural changes from an open,
snail-like conformation in the absence of cargo into a closed, circular
conformation when bound by SCP2. These changes occurred within a long
loop C-terminal to the 7-fold tetratricopeptide repeat segments. Stanley
et al. (2006) identified residues within this loop that were critical
for in vivo cargo import, and their mutation led to defective cargo
import into peroxisomes.
GENE FUNCTION
Dammai and Subramani (2001) showed that human PEX5 does not just bind
cargo and deliver it to the peroxisome membrane, but instead
participates in multiple rounds of entry into the peroxisome matrix and
export to the cytosol independent of the PTS2 import pathway. The
authors noted that this unusual shuttling mechanism for the PTS1
receptor distinguishes protein import into peroxisomes from that into
most other organelles, with the exception of the nucleus.
Shepard et al. (2007) identified PTS1R as a binding partner for
misfolded mutant MYOC and demonstrated that glaucoma (137750)-causing
mutations in human MYOC induce exposure of a cryptic peroxisomal
targeting sequence, which must interact with PTS1R to elevate
intraocular pressure.
MOLECULAR GENETICS
Dodt et al. (1995) found that of the 2 reported patients in
complementation group 2 showing mutations in PEX5, cells from the
patient homozygous for N489K (600414.0001) were defective in the import
of PTS1 proteins into peroxisomes, as expected. However, cells from the
patient homozygous for the nonsense mutation R390X (600414.0002) were
defective in the import of both PTS1 and PTS2 proteins, suggesting that
the PTS1 receptor also mediates PTS2-targeted protein import. To
investigate this possibility, Braverman et al. (1998) characterized PEX5
expression and found that it undergoes alternative splicing, producing 2
transcripts, 1 containing and 1 lacking a 111-bp internal exon.
Fibroblasts from the patient with the nonsense mutation had greatly
reduced levels of PEX5 transcript and protein as compared with the
patient with the missense mutation N489K. Transfection of the R390X
cells with PEX5 cDNA lacking the 1 exon restored PTS1 but not PTS2
import; transfection with the long form of PEX5 cDNA restored both PTS1
and PTS2 protein import. Furthermore, transfection of the R390X cells
with PEX5 cDNAs containing the mutations, which are located downstream
of the additional exon, restored PTS2 but not PTS1 import. Taken
together, these data provided an explanation for the different protein
import defects in CG2 patients and showed that the long isoform of the
PEX5 protein is required for peroxisomal import of PTS2 proteins.
ANIMAL MODEL
Patients with Zellweger syndrome have an inability to assemble
functional peroxisomes, resulting in a multiorgan defect during fetal
development and death, usually within the first year of life. Patients
suffer from extreme hypotonia, neonatal seizures, and severe mental
retardation and accumulate very-long-chain fatty acids (VLCFAs),
pristanic acid, phytanic acid, and bile acid intermediates. At the time
of death, liver fibrosis, renal cysts, and severe brain malformations
are among the most prominent organ abnormalities. The thin cortical
plates and subcortical heterotopias are attributed to a partial
impediment to gliophilic neuronal migration. To investigate the
pleiotropic role of peroxisomes in vivo, Baes et al. (1997) generated an
animal model of peroxisome deficiency through inactivation of the Pxr1
gene in mice. Homozygous Pxr1 knockout mice lacked morphologically
identifiable peroxisomes and exhibited the typical biochemical
abnormalities of Zellweger patients. They displayed intrauterine growth
retardation, were severely hypotonic at birth, and died within 72 hours.
Analysis of the neocortex revealed impaired neuronal migration and
maturation and extensive apoptotic death of neurons.
NOMENCLATURE
Distel et al. (1996) provided a unified nomenclature for peroxisome
biogenesis. By the use of genetic approaches in a wide variety of
experimental organisms, 13 proteins required for peroxisome biogenesis
had been identified in the previous 10 years. Three of these had been
shown to be defective in lethal peroxisome biogenesis disorders (PBDs).
However, the diverse experimental systems had led to a profusion of
names for peroxisome assembly genes and proteins. Distel et al. (1996)
suggested that proteins involved in peroxisome biogenesis should be
designated 'peroxins,' with PEX representing the gene acronym. Even
though defects in peroxisomal metabolic enzymes or transcription factors
may affect peroxisome proliferation and/or morphology, such proteins
should not, they recommended, be included in this group. The proteins
and genes were to be numbered by date of published characterization,
both for known factors and those identified in the future. When
necessary, species of origin could be specified by 1-letter
abbreviations for genus and species (e.g., hsPEX2).
*FIELD* AV
.0001
PEROXISOME BIOGENESIS DISORDER 2B
PEX5, ASN489LYS
In a cell line from a patient with neonatal adrenoleukodystrophy (see
PBD2B, 202370), Dodt et al. (1995) identified a specific defect in
PTS1-mediated uptake of peroxisomal proteins and examined the PXR1 gene
in this patient by RT-PCR amplification of fibroblast RNA followed by
SSCP analysis. Sequencing of an abnormally migrating fragment
demonstrated a PXR1 allele with a T-to-G transversion at basepair 1467,
producing an asn489-to-lys (N489K) substitution. The patient appeared to
be homozygous for the mutant allele, but family studies were not
performed. The N489K substitution was not found in 130 unrelated control
individuals. Transfection of the normal gene into the patient's cells
restored normal import of PTS1-containing proteins into peroxisomes, as
well as normal peroxisome morphology. In contrast, normal cells
transfected with PXR1 carrying the N489K mutation were unable to import
PTS1-containing proteins into peroxisomes. (The cells of the patient
showed normal import of the PTS2 marker protein, thiolase, into
peroxisomal structures.)
.0002
PEROXISOME BIOGENESIS DISORDER 2A (ZELLWEGER)
PEX5, ARG390TER
In a cell line from a patient with Zellweger syndrome (PBD2A; 214110),
Dodt et al. (1995) identified a C-to-T transition at nucleotide 1168
resulting in an arg390-to-ter substitution. The patient was homozygous
for the mutation.
*FIELD* RF
1. Baes, M.; Gressens, P.; Baumgart, E.; Carmeliet, P.; Casteels,
M.; Fransen, M.; Evrard, P.; Fahimi, D.; Declercq, P. E.; Collen,
D.; van Veldhoven, P. P.; Mannaerts, G. P.: A mouse model for Zellweger
syndrome. Nature Genet. 17: 49-57, 1997.
2. Braverman, N.; Dodt, G.; Gould, S. J.; Valle, D.: An isoform of
Pex5p, the human PTS1 receptor, is required for the import of PTS2
proteins into peroxisomes. Hum. Molec. Genet. 7: 1195-1205, 1998.
3. Dammai, V.; Subramani, S.: The human peroxisomal targeting signal
receptor, Pex5p, is translocated into the peroxisomal matrix and recycled
to the cytosol. Cell 105: 187-196, 2001. Note: Erratum: Cell 105:
695 only, 2001.
4. Distel, B.; Erdmann, R.; Gould, S. J.; Blobel, G.; Crane, D. I.;
Cregg, J. M.; Dodt, G.; Fujiki, Y.; Goodman, J. M.; Just, W. W.; Kiel,
J. A. K. W.; Kunau, W.-H.; Lazarow, P. B.; Mannaerts, G. P.; Moser,
H. W.; Osumi, T.; Rachubinski, R. A.; Roscher, A.; Subramani, S.;
Tabak, H. F.; Tsukamoto, T.; Valle, D.; van der Klei, I.; van Veldhoven,
P. P.; Veenhuis, M.: A unified nomenclature for peroxisome biogenesis
factors. J. Cell Biol.. 135: 1-3, 1996.
5. Dodt, G.; Braverman, N.; Wong, C.; Moser, A.; Moser, H. W.; Watkins,
P.; Valle, D.; Gould, S. J.: Mutations in the PTS1 receptor gene,
PXR1, define complementation group 2 of the peroxisome biogenesis
disorders. Nature Genet. 9: 115-125, 1995.
6. Marynen, P.; Fransen, M.; Raeymaekers, P.; Mannaerts, G. P.; Van
Veldhoven, P. P.: The gene for the peroxisomal targeting signal import
receptor (PXR1) is located on human chromosome 12p13, flanked by TPI1
and D12S1089. Genomics 30: 366-368, 1995.
7. Shepard, A. R.; Jacobson, N.; Millar, J. C.; Pang, I.-H.; Steely,
H. T.; Searby, C. C.; Sheffield, V. C.; Stone, E. M.; Clark, A. F.
: Glaucoma-causing myocilin mutants require the peroxisomal targeting
signal-1 receptor (PTS1R) to elevate intraocular pressure. Hum. Molec.
Genet. 16: 609-617, 2007.
8. Stanley, W. A.; Filipp, F. V.; Kursula, P.; Schuller, N.; Erdmann,
R.; Schliebs, W.; Sattler, M.; Wilmanns, M.: Recognition of a functional
peroxisome type 1 target by the dynamic import receptor Pex5p. Molec.
Cell 24: 653-663, 2006.
9. Subramani, S.: Protein import into peroxisomes and biogenesis
of the organelle. Annu. Rev. Cell Biol. 9: 445-478, 1993.
10. Wiemer, E. A. C.; Nuttley, W. M.; Bertolaet, B. L.; Li, X.; Francke,
U.; Wheelock, M. J.; Anne, U. K.; Johnson, K. R.; Subramani, S.:
Human peroxisomal targeting signal-1 receptor restores peroxisomal
protein import in cells from patients with fatal peroxisomal disorders. J.
Cell Biol. 130: 51-65, 1995.
*FIELD* CN
Marla J. F. O'Neill - updated: 1/14/2011
Patricia A. Hartz - updated: 1/24/2007
Stylianos E. Antonarakis - updated: 6/5/2001
Carol A. Bocchini - updated: 8/7/1998
Victor A. McKusick - updated: 8/6/1998
Patti M. Sherman - updated: 7/17/1998
Victor A. McKusick - updated: 8/28/1997
David Valle - edited: 6/23/1997
Alan F. Scott - updated: 1/15/1996
*FIELD* CD
Victor A. McKusick: 2/16/1995
*FIELD* ED
carol: 04/03/2013
alopez: 10/25/2012
alopez: 10/24/2012
wwang: 1/28/2011
terry: 1/14/2011
wwang: 5/29/2007
alopez: 1/24/2007
mgross: 6/5/2001
terry: 8/11/1998
terry: 8/7/1998
terry: 8/6/1998
carol: 7/23/1998
carol: 7/17/1998
carol: 3/21/1998
jenny: 9/1/1997
terry: 8/28/1997
alopez: 7/10/1997
mark: 6/23/1997
joanna: 6/23/1997
jenny: 12/12/1996
terry: 12/9/1996
terry: 11/27/1996
terry: 11/26/1996
terry: 4/17/1996
mark: 1/15/1996
mimadm: 9/23/1995
carol: 2/17/1995
carol: 2/16/1995
*RECORD*
*FIELD* NO
600414
*FIELD* TI
*600414 PEROXISOME BIOGENESIS FACTOR 5; PEX5
;;PEROXISOME RECEPTOR 1; PXR1;;
PEROXIN 5;;
read morePTS1 RECEPTOR; PTS1R
*FIELD* TX
CLONING
Peroxisomal matrix enzymes are synthesized on free polyribosomes and
imported into the peroxisome posttranslationally. Import of the matrix
proteins requires cis-acting peroxisomal targeting signals (PTSs), the 2
best-characterized being PTS1 and PTS2 (Subramani, 1993). The C-terminal
PTS1 motif is present on most peroxisomal matrix proteins and is found
in mammals, insects, plants, yeast, and protozoans. In mammals, the
consensus PTS1 is ser-lys-leu-COOH, but some variability is allowed,
with ala or cys also possible at the -3 position; arg or his at the -2
position; and met at the -1 position. PTS1-mediated peroxisomal protein
import requires ATP and one or more cytosolic factors, and is stimulated
by HSP70 heat-shock proteins. PTS2, which has been identified in only a
few proteins (peroxisomal thiolase from numerous species, a glyoxysomal
malate dehydrogenase from watermelon, and human phytanic acid oxidase),
is located within 40 amino acids of the N terminus and has a consensus
of arg/lys-leu-X5-gln/his-leu. Mutants deficient in peroxisome assembly,
previously called pas mutants and now known as pex mutants, have been
identified in several yeast species. Among the 10 or more
complementation groups of pas mutants in the yeast Pichia pastoris, the
phenotype of the pas8 mutant is unique in that it displays a selective
defect in the import of PTS1 proteins. PAS8 encodes a 68-kD protein with
multiple tetratricopeptide repeat motifs. Because of the phenotype of
the pas8 mutant and the fact that the protein that is missing in that
mutant has PTS1-binding activity in vitro, it was proposed that PAS8
encodes the PTS1 receptor of P. pastoris. Dodt et al. (1995) identified
and characterized the human gene PXR1, a homolog of P. pastoris PAS8,
and demonstrated that it is indeed the human PTS1 receptor. PXR1, like
PAS8, encodes a receptor for proteins with the type 1 peroxisomal
targeting signal (PTS1). Mutations in PXR1 define complementation group
2 of the peroxisome biogenesis disorders (PBDs), and expression of PXR1
rescues the PTS1 import defect of fibroblasts from these patients. Based
on the observation that PXR1 exists both in the cytosol and in
association with peroxisomes, Dodt et al. (1995) proposed that PXR1
protein recognizes PTS1-containing proteins in the cytosol and directs
them to the peroxisome. In the revised nomenclature (vide infra) both
PAS8 and PXR1 are designated PEX5.
Wiemer et al. (1995) cloned a human liver cDNA encoding PEX5, which they
called PTS1R. The predicted 602-amino acid protein has a calculated
molecular mass of 67 kD but an 80-kD mass by immunoblot analysis; the
authors indicated that the discrepancy is due to aberrant migration on
SDS-polyacrylamide gels. Northern blot analysis detected an
approximately 3.4-kb transcript in all human tissues examined.
Shepard et al. (2007) identified long and short isoforms of PTS1R by
yeast 2-hybrid analysis of human trabecular meshwork and heart cell cDNA
libraries using C-terminal MYOC (601652) as bait. The long splice
variant contains 639 amino acids, and the short splice variant contains
602 amino acids.
MAPPING
By somatic cell hybrid and fluorescence in situ hybridization analyses,
Wiemer et al. (1995) mapped the human PEX5 gene to chromosome 12p13.3.
Marynen et al. (1995) mapped the PEX5 gene to chromosome 12p13 by in
situ hybridization using a cosmid containing the gene as a probe. A
radiation hybrid DNA panel was used to map the gene between TPI1
(190450) and the marker D12S1089.
BIOCHEMICAL FEATURES
- Crystal Structure
Stanley et al. (2006) solved the crystal structure of PXR1 at
2.3-angstrom resolution in the presence and absence of a cargo protein,
SCP2 (184755). PXR1 showed major structural changes from an open,
snail-like conformation in the absence of cargo into a closed, circular
conformation when bound by SCP2. These changes occurred within a long
loop C-terminal to the 7-fold tetratricopeptide repeat segments. Stanley
et al. (2006) identified residues within this loop that were critical
for in vivo cargo import, and their mutation led to defective cargo
import into peroxisomes.
GENE FUNCTION
Dammai and Subramani (2001) showed that human PEX5 does not just bind
cargo and deliver it to the peroxisome membrane, but instead
participates in multiple rounds of entry into the peroxisome matrix and
export to the cytosol independent of the PTS2 import pathway. The
authors noted that this unusual shuttling mechanism for the PTS1
receptor distinguishes protein import into peroxisomes from that into
most other organelles, with the exception of the nucleus.
Shepard et al. (2007) identified PTS1R as a binding partner for
misfolded mutant MYOC and demonstrated that glaucoma (137750)-causing
mutations in human MYOC induce exposure of a cryptic peroxisomal
targeting sequence, which must interact with PTS1R to elevate
intraocular pressure.
MOLECULAR GENETICS
Dodt et al. (1995) found that of the 2 reported patients in
complementation group 2 showing mutations in PEX5, cells from the
patient homozygous for N489K (600414.0001) were defective in the import
of PTS1 proteins into peroxisomes, as expected. However, cells from the
patient homozygous for the nonsense mutation R390X (600414.0002) were
defective in the import of both PTS1 and PTS2 proteins, suggesting that
the PTS1 receptor also mediates PTS2-targeted protein import. To
investigate this possibility, Braverman et al. (1998) characterized PEX5
expression and found that it undergoes alternative splicing, producing 2
transcripts, 1 containing and 1 lacking a 111-bp internal exon.
Fibroblasts from the patient with the nonsense mutation had greatly
reduced levels of PEX5 transcript and protein as compared with the
patient with the missense mutation N489K. Transfection of the R390X
cells with PEX5 cDNA lacking the 1 exon restored PTS1 but not PTS2
import; transfection with the long form of PEX5 cDNA restored both PTS1
and PTS2 protein import. Furthermore, transfection of the R390X cells
with PEX5 cDNAs containing the mutations, which are located downstream
of the additional exon, restored PTS2 but not PTS1 import. Taken
together, these data provided an explanation for the different protein
import defects in CG2 patients and showed that the long isoform of the
PEX5 protein is required for peroxisomal import of PTS2 proteins.
ANIMAL MODEL
Patients with Zellweger syndrome have an inability to assemble
functional peroxisomes, resulting in a multiorgan defect during fetal
development and death, usually within the first year of life. Patients
suffer from extreme hypotonia, neonatal seizures, and severe mental
retardation and accumulate very-long-chain fatty acids (VLCFAs),
pristanic acid, phytanic acid, and bile acid intermediates. At the time
of death, liver fibrosis, renal cysts, and severe brain malformations
are among the most prominent organ abnormalities. The thin cortical
plates and subcortical heterotopias are attributed to a partial
impediment to gliophilic neuronal migration. To investigate the
pleiotropic role of peroxisomes in vivo, Baes et al. (1997) generated an
animal model of peroxisome deficiency through inactivation of the Pxr1
gene in mice. Homozygous Pxr1 knockout mice lacked morphologically
identifiable peroxisomes and exhibited the typical biochemical
abnormalities of Zellweger patients. They displayed intrauterine growth
retardation, were severely hypotonic at birth, and died within 72 hours.
Analysis of the neocortex revealed impaired neuronal migration and
maturation and extensive apoptotic death of neurons.
NOMENCLATURE
Distel et al. (1996) provided a unified nomenclature for peroxisome
biogenesis. By the use of genetic approaches in a wide variety of
experimental organisms, 13 proteins required for peroxisome biogenesis
had been identified in the previous 10 years. Three of these had been
shown to be defective in lethal peroxisome biogenesis disorders (PBDs).
However, the diverse experimental systems had led to a profusion of
names for peroxisome assembly genes and proteins. Distel et al. (1996)
suggested that proteins involved in peroxisome biogenesis should be
designated 'peroxins,' with PEX representing the gene acronym. Even
though defects in peroxisomal metabolic enzymes or transcription factors
may affect peroxisome proliferation and/or morphology, such proteins
should not, they recommended, be included in this group. The proteins
and genes were to be numbered by date of published characterization,
both for known factors and those identified in the future. When
necessary, species of origin could be specified by 1-letter
abbreviations for genus and species (e.g., hsPEX2).
*FIELD* AV
.0001
PEROXISOME BIOGENESIS DISORDER 2B
PEX5, ASN489LYS
In a cell line from a patient with neonatal adrenoleukodystrophy (see
PBD2B, 202370), Dodt et al. (1995) identified a specific defect in
PTS1-mediated uptake of peroxisomal proteins and examined the PXR1 gene
in this patient by RT-PCR amplification of fibroblast RNA followed by
SSCP analysis. Sequencing of an abnormally migrating fragment
demonstrated a PXR1 allele with a T-to-G transversion at basepair 1467,
producing an asn489-to-lys (N489K) substitution. The patient appeared to
be homozygous for the mutant allele, but family studies were not
performed. The N489K substitution was not found in 130 unrelated control
individuals. Transfection of the normal gene into the patient's cells
restored normal import of PTS1-containing proteins into peroxisomes, as
well as normal peroxisome morphology. In contrast, normal cells
transfected with PXR1 carrying the N489K mutation were unable to import
PTS1-containing proteins into peroxisomes. (The cells of the patient
showed normal import of the PTS2 marker protein, thiolase, into
peroxisomal structures.)
.0002
PEROXISOME BIOGENESIS DISORDER 2A (ZELLWEGER)
PEX5, ARG390TER
In a cell line from a patient with Zellweger syndrome (PBD2A; 214110),
Dodt et al. (1995) identified a C-to-T transition at nucleotide 1168
resulting in an arg390-to-ter substitution. The patient was homozygous
for the mutation.
*FIELD* RF
1. Baes, M.; Gressens, P.; Baumgart, E.; Carmeliet, P.; Casteels,
M.; Fransen, M.; Evrard, P.; Fahimi, D.; Declercq, P. E.; Collen,
D.; van Veldhoven, P. P.; Mannaerts, G. P.: A mouse model for Zellweger
syndrome. Nature Genet. 17: 49-57, 1997.
2. Braverman, N.; Dodt, G.; Gould, S. J.; Valle, D.: An isoform of
Pex5p, the human PTS1 receptor, is required for the import of PTS2
proteins into peroxisomes. Hum. Molec. Genet. 7: 1195-1205, 1998.
3. Dammai, V.; Subramani, S.: The human peroxisomal targeting signal
receptor, Pex5p, is translocated into the peroxisomal matrix and recycled
to the cytosol. Cell 105: 187-196, 2001. Note: Erratum: Cell 105:
695 only, 2001.
4. Distel, B.; Erdmann, R.; Gould, S. J.; Blobel, G.; Crane, D. I.;
Cregg, J. M.; Dodt, G.; Fujiki, Y.; Goodman, J. M.; Just, W. W.; Kiel,
J. A. K. W.; Kunau, W.-H.; Lazarow, P. B.; Mannaerts, G. P.; Moser,
H. W.; Osumi, T.; Rachubinski, R. A.; Roscher, A.; Subramani, S.;
Tabak, H. F.; Tsukamoto, T.; Valle, D.; van der Klei, I.; van Veldhoven,
P. P.; Veenhuis, M.: A unified nomenclature for peroxisome biogenesis
factors. J. Cell Biol.. 135: 1-3, 1996.
5. Dodt, G.; Braverman, N.; Wong, C.; Moser, A.; Moser, H. W.; Watkins,
P.; Valle, D.; Gould, S. J.: Mutations in the PTS1 receptor gene,
PXR1, define complementation group 2 of the peroxisome biogenesis
disorders. Nature Genet. 9: 115-125, 1995.
6. Marynen, P.; Fransen, M.; Raeymaekers, P.; Mannaerts, G. P.; Van
Veldhoven, P. P.: The gene for the peroxisomal targeting signal import
receptor (PXR1) is located on human chromosome 12p13, flanked by TPI1
and D12S1089. Genomics 30: 366-368, 1995.
7. Shepard, A. R.; Jacobson, N.; Millar, J. C.; Pang, I.-H.; Steely,
H. T.; Searby, C. C.; Sheffield, V. C.; Stone, E. M.; Clark, A. F.
: Glaucoma-causing myocilin mutants require the peroxisomal targeting
signal-1 receptor (PTS1R) to elevate intraocular pressure. Hum. Molec.
Genet. 16: 609-617, 2007.
8. Stanley, W. A.; Filipp, F. V.; Kursula, P.; Schuller, N.; Erdmann,
R.; Schliebs, W.; Sattler, M.; Wilmanns, M.: Recognition of a functional
peroxisome type 1 target by the dynamic import receptor Pex5p. Molec.
Cell 24: 653-663, 2006.
9. Subramani, S.: Protein import into peroxisomes and biogenesis
of the organelle. Annu. Rev. Cell Biol. 9: 445-478, 1993.
10. Wiemer, E. A. C.; Nuttley, W. M.; Bertolaet, B. L.; Li, X.; Francke,
U.; Wheelock, M. J.; Anne, U. K.; Johnson, K. R.; Subramani, S.:
Human peroxisomal targeting signal-1 receptor restores peroxisomal
protein import in cells from patients with fatal peroxisomal disorders. J.
Cell Biol. 130: 51-65, 1995.
*FIELD* CN
Marla J. F. O'Neill - updated: 1/14/2011
Patricia A. Hartz - updated: 1/24/2007
Stylianos E. Antonarakis - updated: 6/5/2001
Carol A. Bocchini - updated: 8/7/1998
Victor A. McKusick - updated: 8/6/1998
Patti M. Sherman - updated: 7/17/1998
Victor A. McKusick - updated: 8/28/1997
David Valle - edited: 6/23/1997
Alan F. Scott - updated: 1/15/1996
*FIELD* CD
Victor A. McKusick: 2/16/1995
*FIELD* ED
carol: 04/03/2013
alopez: 10/25/2012
alopez: 10/24/2012
wwang: 1/28/2011
terry: 1/14/2011
wwang: 5/29/2007
alopez: 1/24/2007
mgross: 6/5/2001
terry: 8/11/1998
terry: 8/7/1998
terry: 8/6/1998
carol: 7/23/1998
carol: 7/17/1998
carol: 3/21/1998
jenny: 9/1/1997
terry: 8/28/1997
alopez: 7/10/1997
mark: 6/23/1997
joanna: 6/23/1997
jenny: 12/12/1996
terry: 12/9/1996
terry: 11/27/1996
terry: 11/26/1996
terry: 4/17/1996
mark: 1/15/1996
mimadm: 9/23/1995
carol: 2/17/1995
carol: 2/16/1995