Full text data of PNPLA6
PNPLA6
(NTE)
[Confidence: high (present in two of the MS resources)]
Neuropathy target esterase; 3.1.1.5 (Patatin-like phospholipase domain-containing protein 6)
Neuropathy target esterase; 3.1.1.5 (Patatin-like phospholipase domain-containing protein 6)
hRBCD
IPI00217600
IPI00217600 Neuropathy target esterase Neuropathy target esterase membrane 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 2 n/a n/a 4 n/a n/a not mentioned n/a found at its expected molecular weight found at molecular weight
IPI00217600 Neuropathy target esterase Neuropathy target esterase membrane 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 2 n/a n/a 4 n/a n/a not mentioned n/a found at its expected molecular weight found at molecular weight
Comments
Isoform Q8IY17-2 was detected.
Isoform Q8IY17-2 was detected.
UniProt
Q8IY17
ID PLPL6_HUMAN Reviewed; 1366 AA.
AC Q8IY17; A6NGQ0; B4DFB9; B7Z7T2; F5H5K9; J3KQS3; O60859; Q86W58;
read moreAC Q9UG58;
DT 26-JUN-2007, integrated into UniProtKB/Swiss-Prot.
DT 26-JUN-2007, sequence version 2.
DT 22-JAN-2014, entry version 86.
DE RecName: Full=Neuropathy target esterase;
DE EC=3.1.1.5;
DE AltName: Full=Patatin-like phospholipase domain-containing protein 6;
GN Name=PNPLA6; Synonyms=NTE;
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), GLYCOSYLATION, AND TISSUE
RP SPECIFICITY.
RC TISSUE=Fetal brain;
RX PubMed=9576844;
RA Lush M.J., Li Y., Read D.J., Willis A.C., Glynn P.;
RT "Neuropathy target esterase and a homologous Drosophila
RT neurodegeneration-associated mutant protein contain a novel domain
RT conserved from bacteria to man.";
RL Biochem. J. 332:1-4(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 4 AND 5), AND VARIANT
RP PRO-403.
RC TISSUE=Cerebellum;
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 [3]
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 [4]
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 [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), NUCLEOTIDE
RP SEQUENCE [LARGE SCALE MRNA] OF 34-1366 (ISOFORM 3), AND VARIANTS
RP PRO-403 AND ARG-1024.
RC TISSUE=Brain, Duodenum, and Testis;
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 NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 985-1366 (ISOFORMS 1/2).
RC TISSUE=Brain;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [7]
RP FUNCTION.
RX PubMed=1666291;
RA Lotti M.;
RT "The pathogenesis of organophosphate polyneuropathy.";
RL Crit. Rev. Toxicol. 21:465-487(1991).
RN [8]
RP FUNCTION, ENZYME REGULATION, AND SUBCELLULAR LOCATION.
RX PubMed=15044461; DOI=10.1074/jbc.M400830200;
RA Zaccheo O., Dinsdale D., Meacock P.A., Glynn P.;
RT "Neuropathy target esterase and its yeast homologue degrade
RT phosphatidylcholine to glycerophosphocholine in living cells.";
RL J. Biol. Chem. 279:24024-24033(2004).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-345, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-345; THR-352 AND
RP SER-353, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-345, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [12]
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 [13]
RP VARIANTS SPG39 HIS-929 AND VAL-1051.
RX PubMed=18313024; DOI=10.1016/j.ajhg.2007.12.018;
RA Rainier S., Bui M., Mark E., Thomas D., Tokarz D., Ming L.,
RA Delaney C., Richardson R.J., Albers J.W., Matsunami N., Stevens J.,
RA Coon H., Leppert M., Fink J.K.;
RT "Neuropathy target esterase gene mutations cause motor neuron
RT disease.";
RL Am. J. Hum. Genet. 82:780-785(2008).
CC -!- FUNCTION: Phospholipase B that deacylates intracellular
CC phosphatidylcholine (PtdCho), generating glycerophosphocholine
CC (GroPtdCho). This deacylation occurs at both sn-2 and sn-1
CC positions of PtdCho. Its specific chemical modification by certain
CC organophosphorus (OP) compounds leads to distal axonopathy.
CC -!- CATALYTIC ACTIVITY: 2-lysophosphatidylcholine + H(2)O =
CC glycerophosphocholine + a carboxylate.
CC -!- ENZYME REGULATION: Inhibited by a series a OPs such as mipafox
CC (MPX), phenyl saligenin phosphate (PSP), phenyl dipentyl
CC phosphinate (PDPP), diisopropyl fluorophosphate and paraoxon.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane; Single-pass
CC type I membrane protein; Cytoplasmic side. Note=Anchored to the
CC cytoplasmic face of the endoplasmic reticulum by its amino-
CC terminal transmembrane segment.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=5;
CC Name=1;
CC IsoId=Q8IY17-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q8IY17-2; Sequence=VSP_026388;
CC Name=3;
CC IsoId=Q8IY17-3; Sequence=VSP_026389;
CC Note=No experimental confirmation available;
CC Name=4;
CC IsoId=Q8IY17-4; Sequence=VSP_046064;
CC Note=No experimental confirmation available;
CC Name=5;
CC IsoId=Q8IY17-5; Sequence=VSP_026388, VSP_046975, VSP_026389;
CC -!- TISSUE SPECIFICITY: Expressed in brain, placenta, kidney, neuron
CC and skeletal muscle.
CC -!- PTM: Glycosylated.
CC -!- DISEASE: Spastic paraplegia 39, autosomal recessive (SPG39)
CC [MIM:612020]: A form of spastic paraplegia, a neurodegenerative
CC disorder characterized by a slow, gradual, progressive weakness
CC and spasticity of the lower limbs. Rate of progression and the
CC severity of symptoms are quite variable. Initial symptoms may
CC include difficulty with balance, weakness and stiffness in the
CC legs, muscle spasms, and dragging the toes when walking. In some
CC forms of the disorder, bladder symptoms (such as incontinence) may
CC appear, or the weakness and stiffness may spread to other parts of
CC the body. SPG39 is associated with a motor axonopathy affecting
CC upper and lower limbs and resulting in progressive wasting of
CC distal upper and lower extremity muscles. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the NTE family.
CC -!- SIMILARITY: Contains 3 cyclic nucleotide-binding domains.
CC -!- SIMILARITY: Contains 1 patatin domain.
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DR EMBL; AJ004832; CAA06164.1; -; mRNA.
DR EMBL; AK294021; BAG57380.1; -; mRNA.
DR EMBL; AK302462; BAH13718.1; -; mRNA.
DR EMBL; AC008878; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC009003; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471139; EAW69029.1; -; Genomic_DNA.
DR EMBL; BC038229; AAH38229.1; -; mRNA.
DR EMBL; BC050553; AAH50553.1; -; mRNA.
DR EMBL; BC051768; AAH51768.1; -; mRNA.
DR EMBL; AL050362; CAB43674.1; -; mRNA.
DR RefSeq; NP_001159583.1; NM_001166111.1.
DR RefSeq; NP_001159584.1; NM_001166112.1.
DR RefSeq; NP_001159585.1; NM_001166113.1.
DR RefSeq; NP_001159586.1; NM_001166114.1.
DR RefSeq; NP_006693.3; NM_006702.4.
DR RefSeq; XP_005272512.1; XM_005272455.1.
DR RefSeq; XP_005272514.1; XM_005272457.1.
DR UniGene; Hs.631863; -.
DR ProteinModelPortal; Q8IY17; -.
DR SMR; Q8IY17; 527-714.
DR STRING; 9606.ENSP00000221249; -.
DR ChEMBL; CHEMBL2189129; -.
DR PhosphoSite; Q8IY17; -.
DR DMDM; 150403921; -.
DR PaxDb; Q8IY17; -.
DR PRIDE; Q8IY17; -.
DR Ensembl; ENST00000221249; ENSP00000221249; ENSG00000032444.
DR Ensembl; ENST00000414982; ENSP00000407509; ENSG00000032444.
DR Ensembl; ENST00000450331; ENSP00000394348; ENSG00000032444.
DR Ensembl; ENST00000545201; ENSP00000443323; ENSG00000032444.
DR Ensembl; ENST00000600737; ENSP00000473211; ENSG00000032444.
DR GeneID; 10908; -.
DR KEGG; hsa:10908; -.
DR UCSC; uc010xjq.2; human.
DR CTD; 10908; -.
DR GeneCards; GC19P007598; -.
DR HGNC; HGNC:16268; PNPLA6.
DR HPA; HPA007522; -.
DR MIM; 603197; gene.
DR MIM; 612020; phenotype.
DR neXtProt; NX_Q8IY17; -.
DR Orphanet; 139480; Autosomal recessive spastic paraplegia type 39.
DR PharmGKB; PA145148268; -.
DR eggNOG; COG0664; -.
DR HOVERGEN; HBG053067; -.
DR InParanoid; Q8IY17; -.
DR KO; K14676; -.
DR OMA; KQRAREW; -.
DR OrthoDB; EOG7QRQT1; -.
DR GeneWiki; Neuropathy_target_esterase; -.
DR GenomeRNAi; 10908; -.
DR NextBio; 35535401; -.
DR PRO; PR:Q8IY17; -.
DR ArrayExpress; Q8IY17; -.
DR Bgee; Q8IY17; -.
DR CleanEx; HS_PNPLA6; -.
DR Genevestigator; Q8IY17; -.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral to membrane; IEA:UniProtKB-KW.
DR GO; GO:0004622; F:lysophospholipase activity; IEA:UniProtKB-EC.
DR GO; GO:0001525; P:angiogenesis; IEA:Ensembl.
DR GO; GO:0008219; P:cell death; IEA:UniProtKB-KW.
DR GO; GO:0016042; P:lipid catabolic process; IEA:UniProtKB-KW.
DR GO; GO:0009887; P:organ morphogenesis; IEA:Ensembl.
DR GO; GO:0046470; P:phosphatidylcholine metabolic process; IEA:InterPro.
DR Gene3D; 2.60.120.10; -; 3.
DR InterPro; IPR016035; Acyl_Trfase/lysoPLipase.
DR InterPro; IPR018490; cNMP-bd-like.
DR InterPro; IPR000595; cNMP-bd_dom.
DR InterPro; IPR001423; LysoPLipase_patatin_CS.
DR InterPro; IPR002641; Patatin/PLipase_A2-rel.
DR InterPro; IPR014710; RmlC-like_jellyroll.
DR Pfam; PF00027; cNMP_binding; 3.
DR Pfam; PF01734; Patatin; 1.
DR SMART; SM00100; cNMP; 3.
DR SUPFAM; SSF51206; SSF51206; 3.
DR SUPFAM; SSF52151; SSF52151; 1.
DR PROSITE; PS00888; CNMP_BINDING_1; FALSE_NEG.
DR PROSITE; PS00889; CNMP_BINDING_2; FALSE_NEG.
DR PROSITE; PS50042; CNMP_BINDING_3; 3.
DR PROSITE; PS01237; UPF0028; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Complete proteome; Disease mutation;
KW Endoplasmic reticulum; Glycoprotein; Hereditary spastic paraplegia;
KW Hydrolase; Lipid degradation; Lipid metabolism; Membrane;
KW Neurodegeneration; Phosphoprotein; Polymorphism; Reference proteome;
KW Repeat; Transmembrane; Transmembrane helix.
FT CHAIN 1 1366 Neuropathy target esterase.
FT /FTId=PRO_0000292199.
FT TOPO_DOM 1 50 Lumenal (Potential).
FT TRANSMEM 51 71 Helical; (Potential).
FT TOPO_DOM 72 1366 Cytoplasmic (Potential).
FT DOMAIN 972 1138 Patatin.
FT NP_BIND 186 313 cNMP 1.
FT NP_BIND 502 624 cNMP 2.
FT NP_BIND 620 740 cNMP 3.
FT MOTIF 1003 1007 GXSXG.
FT ACT_SITE 1005 1005 By similarity.
FT MOD_RES 345 345 Phosphoserine.
FT MOD_RES 352 352 Phosphothreonine.
FT MOD_RES 353 353 Phosphoserine.
FT CARBOHYD 11 11 N-linked (GlcNAc...) (Potential).
FT VAR_SEQ 1 48 MGTSSHGLATNSSGAKVAERDGFQDVLAPGEGSAGRICGAQ
FT PVPFVPQ -> MEAPLQTGM (in isoform 2 and
FT isoform 5).
FT /FTId=VSP_026388.
FT VAR_SEQ 1 1 M -> MEAPLQTGMM (in isoform 4).
FT /FTId=VSP_046064.
FT VAR_SEQ 511 536 Missing (in isoform 5).
FT /FTId=VSP_046975.
FT VAR_SEQ 754 754 Missing (in isoform 3 and isoform 5).
FT /FTId=VSP_026389.
FT VARIANT 403 403 A -> P (in dbSNP:rs17854645).
FT /FTId=VAR_032949.
FT VARIANT 929 929 R -> H (in SPG39).
FT /FTId=VAR_044409.
FT VARIANT 1024 1024 K -> R (in dbSNP:rs17854647).
FT /FTId=VAR_032950.
FT VARIANT 1051 1051 M -> V (in SPG39).
FT /FTId=VAR_044410.
FT CONFLICT 34 37 AGRI -> TRPV (in Ref. 5; AAH38229).
FT CONFLICT 639 639 T -> A (in Ref. 2; BAG57380).
FT CONFLICT 705 705 A -> T (in Ref. 5; AAH38229).
FT CONFLICT 985 985 I -> W (in Ref. 6; CAB43674).
FT CONFLICT 1169 1169 W -> V (in Ref. 6; CAB43674).
FT CONFLICT 1287 1287 E -> G (in Ref. 6; CAB43674).
FT CONFLICT 1293 1293 E -> K (in Ref. 3; BAH13718).
SQ SEQUENCE 1366 AA; 149995 MW; 705E9A4E2195C887 CRC64;
MGTSSHGLAT NSSGAKVAER DGFQDVLAPG EGSAGRICGA QPVPFVPQVL GVMIGAGVAV
VVTAVLILLV VRRLRVPKTP APDGPRYRFR KRDKVLFYGR KIMRKVSQST SSLVDTSVSA
TSRPRMRKKL KMLNIAKKIL RIQKETPTLQ RKEPPPAVLE ADLTEGDLAN SHLPSEVLYM
LKNVRVLGHF EKPLFLELCR HMVFQRLGQG DYVFRPGQPD ASIYVVQDGL LELCLPGPDG
KECVVKEVVP GDSVNSLLSI LDVITGHQHP QRTVSARAAR DSTVLRLPVE AFSAVFTKYP
ESLVRVVQII MVRLQRVTFL ALHNYLGLTN ELFSHEIQPL RLFPSPGLPT RTSPVRGSKR
MVSTSATDEP RETPGRPPDP TGAPLPGPTG DPVKPTSLET PSAPLLSRCV SMPGDISGLQ
GGPRSDFDMA YERGRISVSL QEEASGGSLA APARTPTQEP REQPAGACEY SYCEDESATG
GCPFGPYQGR QTSSIFEAAK QELAKLMRIE DPSLLNSRVL LHHAKAGTII ARQGDQDVSL
HFVLWGCLHV YQRMIDKAED VCLFVAQPGE LVGQLAVLTG EPLIFTLRAQ RDCTFLRISK
SDFYEIMRAQ PSVVLSAAHT VAARMSPFVR QMDFAIDWTA VEAGRALYRQ GDRSDCTYIV
LNGRLRSVIQ RGSGKKELVG EYGRGDLIGV VEALTRQPRA TTVHAVRDTE LAKLPEGTLG
HIKRRYPQVV TRLIHLLSQK ILGNLQQLQG PFPAGSGLGV PPHSELTNPA SNLATVAILP
VCAEVPMVAF TLELQHALQA IGPTLLLNSD IIRARLGASA LDSIQEFRLS GWLAQQEDAH
RIVLYQTDAS LTPWTVRCLR QADCILIVGL GDQEPTLGQL EQMLENTAVR ALKQLVLLHR
EEGAGPTRTV EWLNMRSWCS GHLHLRCPRR LFSRRSPAKL HELYEKVFSR RADRHSDFSR
LARVLTGNTI ALVLGGGGAR GCSHIGVLKA LEEAGVPVDL VGGTSIGSFI GALYAEERSA
SRTKQRAREW AKSMTSVLEP VLDLTYPVTS MFTGSAFNRS IHRVFQDKQI EDLWLPYFNV
TTDITASAMR VHKDGSLWRY VRASMTLSGY LPPLCDPKDG HLLMDGGYIN NLPADIARSM
GAKTVIAIDV GSQDETDLST YGDSLSGWWL LWKRLNPWAD KVKVPDMAEI QSRLAYVSCV
RQLEVVKSSS YCEYLRPPID CFKTMDFGKF DQIYDVGYQY GKAVFGGWSR GNVIEKMLTD
RRSTDLNESR RADVLAFPSS GFTDLAEIVS RIEPPTSYVS DGCADGEESD CLTEYEEDAG
PDCSRDEGGS PEGASPSTAS EMEEEKSILR QRRCLPQEPP GSATDA
//
ID PLPL6_HUMAN Reviewed; 1366 AA.
AC Q8IY17; A6NGQ0; B4DFB9; B7Z7T2; F5H5K9; J3KQS3; O60859; Q86W58;
read moreAC Q9UG58;
DT 26-JUN-2007, integrated into UniProtKB/Swiss-Prot.
DT 26-JUN-2007, sequence version 2.
DT 22-JAN-2014, entry version 86.
DE RecName: Full=Neuropathy target esterase;
DE EC=3.1.1.5;
DE AltName: Full=Patatin-like phospholipase domain-containing protein 6;
GN Name=PNPLA6; Synonyms=NTE;
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), GLYCOSYLATION, AND TISSUE
RP SPECIFICITY.
RC TISSUE=Fetal brain;
RX PubMed=9576844;
RA Lush M.J., Li Y., Read D.J., Willis A.C., Glynn P.;
RT "Neuropathy target esterase and a homologous Drosophila
RT neurodegeneration-associated mutant protein contain a novel domain
RT conserved from bacteria to man.";
RL Biochem. J. 332:1-4(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 4 AND 5), AND VARIANT
RP PRO-403.
RC TISSUE=Cerebellum;
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 [3]
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 [4]
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 [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), NUCLEOTIDE
RP SEQUENCE [LARGE SCALE MRNA] OF 34-1366 (ISOFORM 3), AND VARIANTS
RP PRO-403 AND ARG-1024.
RC TISSUE=Brain, Duodenum, and Testis;
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 NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 985-1366 (ISOFORMS 1/2).
RC TISSUE=Brain;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [7]
RP FUNCTION.
RX PubMed=1666291;
RA Lotti M.;
RT "The pathogenesis of organophosphate polyneuropathy.";
RL Crit. Rev. Toxicol. 21:465-487(1991).
RN [8]
RP FUNCTION, ENZYME REGULATION, AND SUBCELLULAR LOCATION.
RX PubMed=15044461; DOI=10.1074/jbc.M400830200;
RA Zaccheo O., Dinsdale D., Meacock P.A., Glynn P.;
RT "Neuropathy target esterase and its yeast homologue degrade
RT phosphatidylcholine to glycerophosphocholine in living cells.";
RL J. Biol. Chem. 279:24024-24033(2004).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-345, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-345; THR-352 AND
RP SER-353, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-345, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [12]
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 [13]
RP VARIANTS SPG39 HIS-929 AND VAL-1051.
RX PubMed=18313024; DOI=10.1016/j.ajhg.2007.12.018;
RA Rainier S., Bui M., Mark E., Thomas D., Tokarz D., Ming L.,
RA Delaney C., Richardson R.J., Albers J.W., Matsunami N., Stevens J.,
RA Coon H., Leppert M., Fink J.K.;
RT "Neuropathy target esterase gene mutations cause motor neuron
RT disease.";
RL Am. J. Hum. Genet. 82:780-785(2008).
CC -!- FUNCTION: Phospholipase B that deacylates intracellular
CC phosphatidylcholine (PtdCho), generating glycerophosphocholine
CC (GroPtdCho). This deacylation occurs at both sn-2 and sn-1
CC positions of PtdCho. Its specific chemical modification by certain
CC organophosphorus (OP) compounds leads to distal axonopathy.
CC -!- CATALYTIC ACTIVITY: 2-lysophosphatidylcholine + H(2)O =
CC glycerophosphocholine + a carboxylate.
CC -!- ENZYME REGULATION: Inhibited by a series a OPs such as mipafox
CC (MPX), phenyl saligenin phosphate (PSP), phenyl dipentyl
CC phosphinate (PDPP), diisopropyl fluorophosphate and paraoxon.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane; Single-pass
CC type I membrane protein; Cytoplasmic side. Note=Anchored to the
CC cytoplasmic face of the endoplasmic reticulum by its amino-
CC terminal transmembrane segment.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=5;
CC Name=1;
CC IsoId=Q8IY17-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q8IY17-2; Sequence=VSP_026388;
CC Name=3;
CC IsoId=Q8IY17-3; Sequence=VSP_026389;
CC Note=No experimental confirmation available;
CC Name=4;
CC IsoId=Q8IY17-4; Sequence=VSP_046064;
CC Note=No experimental confirmation available;
CC Name=5;
CC IsoId=Q8IY17-5; Sequence=VSP_026388, VSP_046975, VSP_026389;
CC -!- TISSUE SPECIFICITY: Expressed in brain, placenta, kidney, neuron
CC and skeletal muscle.
CC -!- PTM: Glycosylated.
CC -!- DISEASE: Spastic paraplegia 39, autosomal recessive (SPG39)
CC [MIM:612020]: A form of spastic paraplegia, a neurodegenerative
CC disorder characterized by a slow, gradual, progressive weakness
CC and spasticity of the lower limbs. Rate of progression and the
CC severity of symptoms are quite variable. Initial symptoms may
CC include difficulty with balance, weakness and stiffness in the
CC legs, muscle spasms, and dragging the toes when walking. In some
CC forms of the disorder, bladder symptoms (such as incontinence) may
CC appear, or the weakness and stiffness may spread to other parts of
CC the body. SPG39 is associated with a motor axonopathy affecting
CC upper and lower limbs and resulting in progressive wasting of
CC distal upper and lower extremity muscles. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the NTE family.
CC -!- SIMILARITY: Contains 3 cyclic nucleotide-binding domains.
CC -!- SIMILARITY: Contains 1 patatin domain.
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DR EMBL; AJ004832; CAA06164.1; -; mRNA.
DR EMBL; AK294021; BAG57380.1; -; mRNA.
DR EMBL; AK302462; BAH13718.1; -; mRNA.
DR EMBL; AC008878; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC009003; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471139; EAW69029.1; -; Genomic_DNA.
DR EMBL; BC038229; AAH38229.1; -; mRNA.
DR EMBL; BC050553; AAH50553.1; -; mRNA.
DR EMBL; BC051768; AAH51768.1; -; mRNA.
DR EMBL; AL050362; CAB43674.1; -; mRNA.
DR RefSeq; NP_001159583.1; NM_001166111.1.
DR RefSeq; NP_001159584.1; NM_001166112.1.
DR RefSeq; NP_001159585.1; NM_001166113.1.
DR RefSeq; NP_001159586.1; NM_001166114.1.
DR RefSeq; NP_006693.3; NM_006702.4.
DR RefSeq; XP_005272512.1; XM_005272455.1.
DR RefSeq; XP_005272514.1; XM_005272457.1.
DR UniGene; Hs.631863; -.
DR ProteinModelPortal; Q8IY17; -.
DR SMR; Q8IY17; 527-714.
DR STRING; 9606.ENSP00000221249; -.
DR ChEMBL; CHEMBL2189129; -.
DR PhosphoSite; Q8IY17; -.
DR DMDM; 150403921; -.
DR PaxDb; Q8IY17; -.
DR PRIDE; Q8IY17; -.
DR Ensembl; ENST00000221249; ENSP00000221249; ENSG00000032444.
DR Ensembl; ENST00000414982; ENSP00000407509; ENSG00000032444.
DR Ensembl; ENST00000450331; ENSP00000394348; ENSG00000032444.
DR Ensembl; ENST00000545201; ENSP00000443323; ENSG00000032444.
DR Ensembl; ENST00000600737; ENSP00000473211; ENSG00000032444.
DR GeneID; 10908; -.
DR KEGG; hsa:10908; -.
DR UCSC; uc010xjq.2; human.
DR CTD; 10908; -.
DR GeneCards; GC19P007598; -.
DR HGNC; HGNC:16268; PNPLA6.
DR HPA; HPA007522; -.
DR MIM; 603197; gene.
DR MIM; 612020; phenotype.
DR neXtProt; NX_Q8IY17; -.
DR Orphanet; 139480; Autosomal recessive spastic paraplegia type 39.
DR PharmGKB; PA145148268; -.
DR eggNOG; COG0664; -.
DR HOVERGEN; HBG053067; -.
DR InParanoid; Q8IY17; -.
DR KO; K14676; -.
DR OMA; KQRAREW; -.
DR OrthoDB; EOG7QRQT1; -.
DR GeneWiki; Neuropathy_target_esterase; -.
DR GenomeRNAi; 10908; -.
DR NextBio; 35535401; -.
DR PRO; PR:Q8IY17; -.
DR ArrayExpress; Q8IY17; -.
DR Bgee; Q8IY17; -.
DR CleanEx; HS_PNPLA6; -.
DR Genevestigator; Q8IY17; -.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral to membrane; IEA:UniProtKB-KW.
DR GO; GO:0004622; F:lysophospholipase activity; IEA:UniProtKB-EC.
DR GO; GO:0001525; P:angiogenesis; IEA:Ensembl.
DR GO; GO:0008219; P:cell death; IEA:UniProtKB-KW.
DR GO; GO:0016042; P:lipid catabolic process; IEA:UniProtKB-KW.
DR GO; GO:0009887; P:organ morphogenesis; IEA:Ensembl.
DR GO; GO:0046470; P:phosphatidylcholine metabolic process; IEA:InterPro.
DR Gene3D; 2.60.120.10; -; 3.
DR InterPro; IPR016035; Acyl_Trfase/lysoPLipase.
DR InterPro; IPR018490; cNMP-bd-like.
DR InterPro; IPR000595; cNMP-bd_dom.
DR InterPro; IPR001423; LysoPLipase_patatin_CS.
DR InterPro; IPR002641; Patatin/PLipase_A2-rel.
DR InterPro; IPR014710; RmlC-like_jellyroll.
DR Pfam; PF00027; cNMP_binding; 3.
DR Pfam; PF01734; Patatin; 1.
DR SMART; SM00100; cNMP; 3.
DR SUPFAM; SSF51206; SSF51206; 3.
DR SUPFAM; SSF52151; SSF52151; 1.
DR PROSITE; PS00888; CNMP_BINDING_1; FALSE_NEG.
DR PROSITE; PS00889; CNMP_BINDING_2; FALSE_NEG.
DR PROSITE; PS50042; CNMP_BINDING_3; 3.
DR PROSITE; PS01237; UPF0028; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Complete proteome; Disease mutation;
KW Endoplasmic reticulum; Glycoprotein; Hereditary spastic paraplegia;
KW Hydrolase; Lipid degradation; Lipid metabolism; Membrane;
KW Neurodegeneration; Phosphoprotein; Polymorphism; Reference proteome;
KW Repeat; Transmembrane; Transmembrane helix.
FT CHAIN 1 1366 Neuropathy target esterase.
FT /FTId=PRO_0000292199.
FT TOPO_DOM 1 50 Lumenal (Potential).
FT TRANSMEM 51 71 Helical; (Potential).
FT TOPO_DOM 72 1366 Cytoplasmic (Potential).
FT DOMAIN 972 1138 Patatin.
FT NP_BIND 186 313 cNMP 1.
FT NP_BIND 502 624 cNMP 2.
FT NP_BIND 620 740 cNMP 3.
FT MOTIF 1003 1007 GXSXG.
FT ACT_SITE 1005 1005 By similarity.
FT MOD_RES 345 345 Phosphoserine.
FT MOD_RES 352 352 Phosphothreonine.
FT MOD_RES 353 353 Phosphoserine.
FT CARBOHYD 11 11 N-linked (GlcNAc...) (Potential).
FT VAR_SEQ 1 48 MGTSSHGLATNSSGAKVAERDGFQDVLAPGEGSAGRICGAQ
FT PVPFVPQ -> MEAPLQTGM (in isoform 2 and
FT isoform 5).
FT /FTId=VSP_026388.
FT VAR_SEQ 1 1 M -> MEAPLQTGMM (in isoform 4).
FT /FTId=VSP_046064.
FT VAR_SEQ 511 536 Missing (in isoform 5).
FT /FTId=VSP_046975.
FT VAR_SEQ 754 754 Missing (in isoform 3 and isoform 5).
FT /FTId=VSP_026389.
FT VARIANT 403 403 A -> P (in dbSNP:rs17854645).
FT /FTId=VAR_032949.
FT VARIANT 929 929 R -> H (in SPG39).
FT /FTId=VAR_044409.
FT VARIANT 1024 1024 K -> R (in dbSNP:rs17854647).
FT /FTId=VAR_032950.
FT VARIANT 1051 1051 M -> V (in SPG39).
FT /FTId=VAR_044410.
FT CONFLICT 34 37 AGRI -> TRPV (in Ref. 5; AAH38229).
FT CONFLICT 639 639 T -> A (in Ref. 2; BAG57380).
FT CONFLICT 705 705 A -> T (in Ref. 5; AAH38229).
FT CONFLICT 985 985 I -> W (in Ref. 6; CAB43674).
FT CONFLICT 1169 1169 W -> V (in Ref. 6; CAB43674).
FT CONFLICT 1287 1287 E -> G (in Ref. 6; CAB43674).
FT CONFLICT 1293 1293 E -> K (in Ref. 3; BAH13718).
SQ SEQUENCE 1366 AA; 149995 MW; 705E9A4E2195C887 CRC64;
MGTSSHGLAT NSSGAKVAER DGFQDVLAPG EGSAGRICGA QPVPFVPQVL GVMIGAGVAV
VVTAVLILLV VRRLRVPKTP APDGPRYRFR KRDKVLFYGR KIMRKVSQST SSLVDTSVSA
TSRPRMRKKL KMLNIAKKIL RIQKETPTLQ RKEPPPAVLE ADLTEGDLAN SHLPSEVLYM
LKNVRVLGHF EKPLFLELCR HMVFQRLGQG DYVFRPGQPD ASIYVVQDGL LELCLPGPDG
KECVVKEVVP GDSVNSLLSI LDVITGHQHP QRTVSARAAR DSTVLRLPVE AFSAVFTKYP
ESLVRVVQII MVRLQRVTFL ALHNYLGLTN ELFSHEIQPL RLFPSPGLPT RTSPVRGSKR
MVSTSATDEP RETPGRPPDP TGAPLPGPTG DPVKPTSLET PSAPLLSRCV SMPGDISGLQ
GGPRSDFDMA YERGRISVSL QEEASGGSLA APARTPTQEP REQPAGACEY SYCEDESATG
GCPFGPYQGR QTSSIFEAAK QELAKLMRIE DPSLLNSRVL LHHAKAGTII ARQGDQDVSL
HFVLWGCLHV YQRMIDKAED VCLFVAQPGE LVGQLAVLTG EPLIFTLRAQ RDCTFLRISK
SDFYEIMRAQ PSVVLSAAHT VAARMSPFVR QMDFAIDWTA VEAGRALYRQ GDRSDCTYIV
LNGRLRSVIQ RGSGKKELVG EYGRGDLIGV VEALTRQPRA TTVHAVRDTE LAKLPEGTLG
HIKRRYPQVV TRLIHLLSQK ILGNLQQLQG PFPAGSGLGV PPHSELTNPA SNLATVAILP
VCAEVPMVAF TLELQHALQA IGPTLLLNSD IIRARLGASA LDSIQEFRLS GWLAQQEDAH
RIVLYQTDAS LTPWTVRCLR QADCILIVGL GDQEPTLGQL EQMLENTAVR ALKQLVLLHR
EEGAGPTRTV EWLNMRSWCS GHLHLRCPRR LFSRRSPAKL HELYEKVFSR RADRHSDFSR
LARVLTGNTI ALVLGGGGAR GCSHIGVLKA LEEAGVPVDL VGGTSIGSFI GALYAEERSA
SRTKQRAREW AKSMTSVLEP VLDLTYPVTS MFTGSAFNRS IHRVFQDKQI EDLWLPYFNV
TTDITASAMR VHKDGSLWRY VRASMTLSGY LPPLCDPKDG HLLMDGGYIN NLPADIARSM
GAKTVIAIDV GSQDETDLST YGDSLSGWWL LWKRLNPWAD KVKVPDMAEI QSRLAYVSCV
RQLEVVKSSS YCEYLRPPID CFKTMDFGKF DQIYDVGYQY GKAVFGGWSR GNVIEKMLTD
RRSTDLNESR RADVLAFPSS GFTDLAEIVS RIEPPTSYVS DGCADGEESD CLTEYEEDAG
PDCSRDEGGS PEGASPSTAS EMEEEKSILR QRRCLPQEPP GSATDA
//
MIM
603197
*RECORD*
*FIELD* NO
603197
*FIELD* TI
*603197 PATATIN-LIKE PHOSPHOLIPASE DOMAIN-CONTAINING PROTEIN 6; PNPLA6
;;NEUROPATHY TARGET ESTERASE; NTE;;
read moreNEUROTOXIC ESTERASE
*FIELD* TX
CLONING
Covalent modification of neuropathy target esterase (NTE) by certain
organophosphorus esters (OPs) leads, after a delay of several days, to a
degeneration of long axons in the spinal cord and peripheral nerves.
Lush et al. (1998) determined a partial protein sequence of pig NTE.
They searched an EST database and identified a human cDNA that encodes a
polypeptide showing homology to 1 of the pig NTE peptides. Using this
cDNA as a probe, the authors screened a human fetal brain cDNA library
and isolated a cDNA containing the entire NTE coding sequence. The
deduced 1,327-amino acid protein contains 4 predicted transmembrane
domains and multiple potential sites for N- and O-linked glycosylation.
SDS-PAGE and biochemical analyses showed that human NTE is a
glycoprotein with an apparent molecular mass of 155 kD. NTE shares 41%
amino acid sequence identity with the Drosophila 'Swiss Cheese' (Sws)
protein, which is involved in the regulation of interactions between
neurons and glia in the developing fly brain.
MAPPING
In the positional cloning of the mucolipidosis IV gene (MCOLN1; 605248),
which maps to 19p13.3-p13.2, Bargal et al. (2000) found that the NTE
gene is located in this region. They analyzed all 33 coding exons of
this gene in 6 mucolipidosis IV patients and identified no mutations.
By FISH, Winrow et al. (2003) demonstrated that the Nte locus maps to
mouse chromosome 8A1.1 and the human NTE gene maps to 19p13.3.
MOLECULAR GENETICS
The pathogenesis of organophosphorous (OP) compound-induced delayed
neuropathy (OPIDN) involves neuropathy target esterase (NTE), a neuronal
membrane protein, either through direct OP-induced inhibition of NTE or
through generation of OP-NTE neurotoxic complexes ('aged NTE'). Rainier
et al. (2008) described 2 families, one consanguineous, in which
affected subjects exhibited progressive spastic paraplegia and distal
muscle wasting (SPG39; 612020). Affected subjects resembled those with
OPIDN and those with Troyer syndrome (275900) due to SPG20 (607111) gene
mutation. The latter possibility was excluded by genetic linkage and
sequence analysis of the SPG20 gene. Genomewide analysis suggested
linkage to a 22-cM homozygous locus on 19p13 to which NTE had been
mapped. NTE was a candidate because of its role in OPIDN and the
similarity of the patients to those with OPIDN. Affected subjects in the
consanguineous kindred were homozygous for a disease-specific NTE
mutation, 3034A-G, that disrupted an interspecies-conserved residue in
NTE's catalytic domain (M1012V; 603197.0001). Affected subjects in the
nonconsanguineous family were compound heterozygotes: 1 allele carried a
2669G-A mutation that disrupted an interspecies-conserved residue in
NTE's catalytic domain (R890H; 603197.0002), and the other allele had an
insertion that caused frameshift and protein truncation (603197.0003).
Disease-specific, nonconserved NTE mutations in unrelated patients with
motor neuron disease (MND) indicated the importance of NTE in
maintaining axonal integrity, raised the possibility that NTE pathway
disturbances contribute to other MNDs including amyotrophic lateral
sclerosis (ALS; see 105400), and supported the role of NTE abnormalities
in axonopathy produced by neuropathic OP compounds.
ANIMAL MODEL
NTE is involved in neuronal development and is the target for
neurodegeneration induced by selected organophosphorus pesticides and
chemical warfare agents. Winrow et al. (2003) generated mice with
disruption in Nte. Nte -/- mice died after embryonic day 8, and
heterozygous Nte +/- mice had lower activity of Nte in the brain and
higher mortality when exposed to an Nte-inhibiting compound (EOPF) than
did wildtype mice. Nte +/- and wildtype mice treated with 1 mg per kg of
body weight of EOPF had elevated motor activity, showing that even minor
reduction of Nte activity leads to hyperactivity. Studies showed that
genetic or chemical reduction of Nte activity results in a neurologic
phenotype of hyperactivity in mammals and indicated that EOPF toxicity
occurs directly through inhibition of Nte without the requirement for
Nte gain of function or aging.
O'Callaghan (2003) interpreted the significance of the studies of Winrow
et al. (2003) in relation to the toxicity of organophosphates, which
have long been used as pesticides and which are a concern because of
their potential use as chemical warfare agents. As a class of compounds,
organophosphate esters inhibit serine-containing esterases owing to
phosphorylation of serine residues at the active site of these enzymes,
the most notable of which is acetylcholinesterase (100740). Most
features of the acute toxicity of these compounds relate to their
inhibition of this enzyme. A less well known feature of some
organophosphates is their propensity to cause a delayed neuropathy that
has been termed organophosphate-induced delayed neurotoxicity (OPIDN).
This is a progressive neurologic condition characterized by weakness,
ataxia, and subsequent paralysis of the limbs. The major neuropathologic
hallmarks of OPIDN are degeneration of the long exons of the spinal cord
and peripheral neurons. The proposed target for initiation of OPIDN has
been NTE. The mechanistic basis for initiation of OPIDN through NTE was
thought to involve the generation of an 'aged' form of the enzyme. The
work of Winrow et al. (2003) provided evidence against the aging concept
without ruling out involvement of NTE itself. Mice deficient in the
enzyme should be less susceptible to toxicity, but the opposite turned
out to be the case.
Moser et al. (2004) observed lethality in Nte-null mouse embryos after
gastrulation at embryonic day 9 postcoitum. As early as embryonic day
7.5, mutant embryos showed growth retardation which did not reflect
impaired cell proliferation but resulted from failed placental
development; as a consequence, massive apoptosis within the developing
embryo preceded its resorption. Histologic analysis indicated that NTE
is essential for the formation of the labyrinth layer and the survival
and differentiation of secondary giant cells. Impaired vasculogenesis in
the yolk sacs and embryos of null mutant conceptuses suggested that NTE
is also required for normal blood vessel development.
*FIELD* AV
.0001
SPASTIC PARAPLEGIA 39, AUTOSOMAL RECESSIVE
PNPLA6, MET1012VAL
In a consanguineous family of Ashkenazi Jewish ancestry, Rainier et al.
(2008) demonstrated an association between motor neuron disease (SPG39;
612020) and homozygosity for a missense mutation in the NTE gene:
3034A-G, met1012 to val (M1012V).
.0002
SPASTIC PARAPLEGIA 39, AUTOSOMAL RECESSIVE
NTE, ARG890HIS
In a nonconsanguineous family, Rainier et al. (2008) found that motor
neuron disease (SPG39; 612020) was associated with compound
heterozygosity for 2 mutations in the NTE gene. On 1 allele the 2
affected individuals carried a G-to-A transition at cDNA position 2669
that resulted in substitution of histidine for arginine at codon 890
(R890H); the other allele carried a 4-bp insertion (603197.0003). The
affected individuals were brother and sister, and inherited the missense
mutation from the father and the insertion from the mother.
.0003
SPASTIC PARAPLEGIA 39, AUTOSOMAL RECESSIVE
NTE, 4-BP INS, 2946CAGC
The 2 affected individuals with motor neuron disease (SPG39; 612020) in
the nonconsanguineous family described by Rainier et al. (2008) carried
a 4-bp insertion on the maternal allele, 2946_2947insCAGC, that caused
frameshift and protein truncation (S982fs1019). The paternal allele
carried a missense mutation (603197.0002).
*FIELD* RF
1. Bargal, R.; Avidan, N.; Ben-Asher, E.; Olender, Z.; Zeigler, M.;
Frumkin, A.; Raas-Rothschild, A.; Glusman, G.; Lancet, D.; Bach, G.
: Identification of the gene causing mucolipidosis type IV. Nature
Genet. 26: 120-123, 2000.
2. Lush, M. J.; Li, Y.; Read, D. J.; Willis, A. C.; Glynn, P.: Neuropathy
target esterase and a homologous Drosophila neurodegeneration-associated
mutant protein contain a novel domain conserved from bacteria to man. Biochem.
J. 332: 1-4, 1998.
3. Moser, M.; Li, Y.; Vaupel, K.; Kretzschmar, D.; Kluge, R.; Glynn,
P.; Buettner, R.: Placental failure and impaired vasculogenesis result
in embryonic lethality for neuropathy target esterase-deficient mice. Molec.
Cell. Biol. 24: 1667-1679, 2004.
4. O'Callaghan, J. P.: Neurotoxic esterase: not so toxic? Nature
Genet. 33: 437-438, 2003.
5. Rainier, S.; Bui, M.; Mark, E.; Thomas, D.; Tokarz, D.; Ming, L.;
Delaney, C.; Richardson, R. J.; Albers, J. W.; Matsunami, N.; Stevens,
J.; Coon, H.; Leppert, M.; Fink, J. K.: Neuropathy target esterase
gene mutations cause motor neuron disease. Am. J. Hum. Genet. 82:
780-785, 2008.
6. Winrow, C. J.; Hemming, M. L.; Allen, D. M.; Quistad, G. B.; Casida,
J. E.; Barlow, C.: Loss of neuropathy target esterase in mice links
organophosphate exposure to hyperactivity. Nature Genet. 33: 477-486,
2003.
*FIELD* CN
Victor A. McKusick - updated: 4/14/2008
Patricia A. Hartz - updated: 2/17/2004
Victor A. McKusick - updated: 3/18/2003
Victor A. McKusick - updated: 8/30/2000
*FIELD* CD
Rebekah S. Rasooly: 10/23/1998
*FIELD* ED
alopez: 05/05/2008
terry: 4/14/2008
wwang: 11/7/2007
cwells: 2/24/2004
terry: 2/17/2004
carol: 5/30/2003
alopez: 5/28/2003
alopez: 4/1/2003
alopez: 3/18/2003
terry: 3/18/2003
alopez: 8/31/2000
terry: 8/30/2000
psherman: 10/23/1998
*RECORD*
*FIELD* NO
603197
*FIELD* TI
*603197 PATATIN-LIKE PHOSPHOLIPASE DOMAIN-CONTAINING PROTEIN 6; PNPLA6
;;NEUROPATHY TARGET ESTERASE; NTE;;
read moreNEUROTOXIC ESTERASE
*FIELD* TX
CLONING
Covalent modification of neuropathy target esterase (NTE) by certain
organophosphorus esters (OPs) leads, after a delay of several days, to a
degeneration of long axons in the spinal cord and peripheral nerves.
Lush et al. (1998) determined a partial protein sequence of pig NTE.
They searched an EST database and identified a human cDNA that encodes a
polypeptide showing homology to 1 of the pig NTE peptides. Using this
cDNA as a probe, the authors screened a human fetal brain cDNA library
and isolated a cDNA containing the entire NTE coding sequence. The
deduced 1,327-amino acid protein contains 4 predicted transmembrane
domains and multiple potential sites for N- and O-linked glycosylation.
SDS-PAGE and biochemical analyses showed that human NTE is a
glycoprotein with an apparent molecular mass of 155 kD. NTE shares 41%
amino acid sequence identity with the Drosophila 'Swiss Cheese' (Sws)
protein, which is involved in the regulation of interactions between
neurons and glia in the developing fly brain.
MAPPING
In the positional cloning of the mucolipidosis IV gene (MCOLN1; 605248),
which maps to 19p13.3-p13.2, Bargal et al. (2000) found that the NTE
gene is located in this region. They analyzed all 33 coding exons of
this gene in 6 mucolipidosis IV patients and identified no mutations.
By FISH, Winrow et al. (2003) demonstrated that the Nte locus maps to
mouse chromosome 8A1.1 and the human NTE gene maps to 19p13.3.
MOLECULAR GENETICS
The pathogenesis of organophosphorous (OP) compound-induced delayed
neuropathy (OPIDN) involves neuropathy target esterase (NTE), a neuronal
membrane protein, either through direct OP-induced inhibition of NTE or
through generation of OP-NTE neurotoxic complexes ('aged NTE'). Rainier
et al. (2008) described 2 families, one consanguineous, in which
affected subjects exhibited progressive spastic paraplegia and distal
muscle wasting (SPG39; 612020). Affected subjects resembled those with
OPIDN and those with Troyer syndrome (275900) due to SPG20 (607111) gene
mutation. The latter possibility was excluded by genetic linkage and
sequence analysis of the SPG20 gene. Genomewide analysis suggested
linkage to a 22-cM homozygous locus on 19p13 to which NTE had been
mapped. NTE was a candidate because of its role in OPIDN and the
similarity of the patients to those with OPIDN. Affected subjects in the
consanguineous kindred were homozygous for a disease-specific NTE
mutation, 3034A-G, that disrupted an interspecies-conserved residue in
NTE's catalytic domain (M1012V; 603197.0001). Affected subjects in the
nonconsanguineous family were compound heterozygotes: 1 allele carried a
2669G-A mutation that disrupted an interspecies-conserved residue in
NTE's catalytic domain (R890H; 603197.0002), and the other allele had an
insertion that caused frameshift and protein truncation (603197.0003).
Disease-specific, nonconserved NTE mutations in unrelated patients with
motor neuron disease (MND) indicated the importance of NTE in
maintaining axonal integrity, raised the possibility that NTE pathway
disturbances contribute to other MNDs including amyotrophic lateral
sclerosis (ALS; see 105400), and supported the role of NTE abnormalities
in axonopathy produced by neuropathic OP compounds.
ANIMAL MODEL
NTE is involved in neuronal development and is the target for
neurodegeneration induced by selected organophosphorus pesticides and
chemical warfare agents. Winrow et al. (2003) generated mice with
disruption in Nte. Nte -/- mice died after embryonic day 8, and
heterozygous Nte +/- mice had lower activity of Nte in the brain and
higher mortality when exposed to an Nte-inhibiting compound (EOPF) than
did wildtype mice. Nte +/- and wildtype mice treated with 1 mg per kg of
body weight of EOPF had elevated motor activity, showing that even minor
reduction of Nte activity leads to hyperactivity. Studies showed that
genetic or chemical reduction of Nte activity results in a neurologic
phenotype of hyperactivity in mammals and indicated that EOPF toxicity
occurs directly through inhibition of Nte without the requirement for
Nte gain of function or aging.
O'Callaghan (2003) interpreted the significance of the studies of Winrow
et al. (2003) in relation to the toxicity of organophosphates, which
have long been used as pesticides and which are a concern because of
their potential use as chemical warfare agents. As a class of compounds,
organophosphate esters inhibit serine-containing esterases owing to
phosphorylation of serine residues at the active site of these enzymes,
the most notable of which is acetylcholinesterase (100740). Most
features of the acute toxicity of these compounds relate to their
inhibition of this enzyme. A less well known feature of some
organophosphates is their propensity to cause a delayed neuropathy that
has been termed organophosphate-induced delayed neurotoxicity (OPIDN).
This is a progressive neurologic condition characterized by weakness,
ataxia, and subsequent paralysis of the limbs. The major neuropathologic
hallmarks of OPIDN are degeneration of the long exons of the spinal cord
and peripheral neurons. The proposed target for initiation of OPIDN has
been NTE. The mechanistic basis for initiation of OPIDN through NTE was
thought to involve the generation of an 'aged' form of the enzyme. The
work of Winrow et al. (2003) provided evidence against the aging concept
without ruling out involvement of NTE itself. Mice deficient in the
enzyme should be less susceptible to toxicity, but the opposite turned
out to be the case.
Moser et al. (2004) observed lethality in Nte-null mouse embryos after
gastrulation at embryonic day 9 postcoitum. As early as embryonic day
7.5, mutant embryos showed growth retardation which did not reflect
impaired cell proliferation but resulted from failed placental
development; as a consequence, massive apoptosis within the developing
embryo preceded its resorption. Histologic analysis indicated that NTE
is essential for the formation of the labyrinth layer and the survival
and differentiation of secondary giant cells. Impaired vasculogenesis in
the yolk sacs and embryos of null mutant conceptuses suggested that NTE
is also required for normal blood vessel development.
*FIELD* AV
.0001
SPASTIC PARAPLEGIA 39, AUTOSOMAL RECESSIVE
PNPLA6, MET1012VAL
In a consanguineous family of Ashkenazi Jewish ancestry, Rainier et al.
(2008) demonstrated an association between motor neuron disease (SPG39;
612020) and homozygosity for a missense mutation in the NTE gene:
3034A-G, met1012 to val (M1012V).
.0002
SPASTIC PARAPLEGIA 39, AUTOSOMAL RECESSIVE
NTE, ARG890HIS
In a nonconsanguineous family, Rainier et al. (2008) found that motor
neuron disease (SPG39; 612020) was associated with compound
heterozygosity for 2 mutations in the NTE gene. On 1 allele the 2
affected individuals carried a G-to-A transition at cDNA position 2669
that resulted in substitution of histidine for arginine at codon 890
(R890H); the other allele carried a 4-bp insertion (603197.0003). The
affected individuals were brother and sister, and inherited the missense
mutation from the father and the insertion from the mother.
.0003
SPASTIC PARAPLEGIA 39, AUTOSOMAL RECESSIVE
NTE, 4-BP INS, 2946CAGC
The 2 affected individuals with motor neuron disease (SPG39; 612020) in
the nonconsanguineous family described by Rainier et al. (2008) carried
a 4-bp insertion on the maternal allele, 2946_2947insCAGC, that caused
frameshift and protein truncation (S982fs1019). The paternal allele
carried a missense mutation (603197.0002).
*FIELD* RF
1. Bargal, R.; Avidan, N.; Ben-Asher, E.; Olender, Z.; Zeigler, M.;
Frumkin, A.; Raas-Rothschild, A.; Glusman, G.; Lancet, D.; Bach, G.
: Identification of the gene causing mucolipidosis type IV. Nature
Genet. 26: 120-123, 2000.
2. Lush, M. J.; Li, Y.; Read, D. J.; Willis, A. C.; Glynn, P.: Neuropathy
target esterase and a homologous Drosophila neurodegeneration-associated
mutant protein contain a novel domain conserved from bacteria to man. Biochem.
J. 332: 1-4, 1998.
3. Moser, M.; Li, Y.; Vaupel, K.; Kretzschmar, D.; Kluge, R.; Glynn,
P.; Buettner, R.: Placental failure and impaired vasculogenesis result
in embryonic lethality for neuropathy target esterase-deficient mice. Molec.
Cell. Biol. 24: 1667-1679, 2004.
4. O'Callaghan, J. P.: Neurotoxic esterase: not so toxic? Nature
Genet. 33: 437-438, 2003.
5. Rainier, S.; Bui, M.; Mark, E.; Thomas, D.; Tokarz, D.; Ming, L.;
Delaney, C.; Richardson, R. J.; Albers, J. W.; Matsunami, N.; Stevens,
J.; Coon, H.; Leppert, M.; Fink, J. K.: Neuropathy target esterase
gene mutations cause motor neuron disease. Am. J. Hum. Genet. 82:
780-785, 2008.
6. Winrow, C. J.; Hemming, M. L.; Allen, D. M.; Quistad, G. B.; Casida,
J. E.; Barlow, C.: Loss of neuropathy target esterase in mice links
organophosphate exposure to hyperactivity. Nature Genet. 33: 477-486,
2003.
*FIELD* CN
Victor A. McKusick - updated: 4/14/2008
Patricia A. Hartz - updated: 2/17/2004
Victor A. McKusick - updated: 3/18/2003
Victor A. McKusick - updated: 8/30/2000
*FIELD* CD
Rebekah S. Rasooly: 10/23/1998
*FIELD* ED
alopez: 05/05/2008
terry: 4/14/2008
wwang: 11/7/2007
cwells: 2/24/2004
terry: 2/17/2004
carol: 5/30/2003
alopez: 5/28/2003
alopez: 4/1/2003
alopez: 3/18/2003
terry: 3/18/2003
alopez: 8/31/2000
terry: 8/30/2000
psherman: 10/23/1998
MIM
612020
*RECORD*
*FIELD* NO
612020
*FIELD* TI
#612020 SPASTIC PARAPLEGIA 39, AUTOSOMAL RECESSIVE; SPG39
;;NTE-RELATED MOTOR NEURON DISORDER; NTEMND
read more*FIELD* TX
A number sign (#) is used with this entry because spastic paraplegia-39
is caused by mutation in the PNPLA6 gene (603197), encoding neuropathy
target esterase (NTE).
DESCRIPTION
The form of motor neuron disease designated spastic paraplegia-39
(SPG39) by Rainier et al. (2008) is an autosomal recessive progressive
spastic paraplegia associated with distal upper and lower extremity
wasting.
CLINICAL FEATURES
Rainier et al. (2008) reported a consanguineous family of Ashkenazi
Jewish ancestry and an unrelated nonconsanguineous family of northern
European ancestry in which affected subjects developed childhood onset
of insidiously progressive lower extremity spastic weakness and
progressive wasting of distal upper and lower extremity muscles.
Electrophysiologic studies were consistent with a motor axonopathy
affecting upper and lower limbs. Magnetic resonance imaging demonstrated
spinal cord atrophy, particularly in the thoracic region. The affected
phenotype in each family conformed both to organophosphorous (OP)
compound-induced delayed neuropathy (OPIDN) and to Troyer syndrome
(275900), an autosomal recessive hereditary spastic paraplegia
associated with distal muscle wasting. Additional neurologic and
systemic abnormalities including delayed milestone acquisition, skeletal
abnormalities, and cerebellar, extrapyramidal, and cognitive impairments
seen in Troyer syndrome were not observed.
MAPPING
Rainier et al. (2008) performed genomewide linkage analysis in a large
consanguineous Ashkenazi family and in a second nonconsanguineous
family. An extended linkage haplotype that spanned 22 cM between D19S565
and D19S884 on chromosome 19p13 was defined in the consanguineous
family; in the nonconsanguineous family the same markers also resulted
in haplotype sharing in affected subjects, consistent with genetic
linkage of the region.
MOLECULAR GENETICS
In affected members of 2 families with motor neuron disease, Rainier et
al. (2008) detected homozygosity or compound heterozygosity for
mutations in the NTE gene. Affected subjects in the consanguineous
kindred were homozygous for a disease-specific NTE mutation, 3034A-G,
that disrupted an interspecies-conserved residue in NTE's catalytic
domain (M1012V; 603197.0001). Affected subjects in the nonconsanguineous
family were compound heterozygotes: 1 allele carried a 2669G-A mutation
that disrupted an interspecies-conserved residue in NTE's catalytic
domain (R890H; 603197.0002), and the other allele had an insertion that
caused frameshift and protein truncation (603197.0003).
*FIELD* RF
1. Rainier, S.; Bui, M.; Mark, E.; Thomas, D.; Tokarz, D.; Ming, L.;
Delaney, C.; Richardson, R. J.; Albers, J. W.; Matsunami, N.; Stevens,
J.; Coon, H.; Leppert, M.; Fink, J. K.: Neuropathy target esterase
gene mutations cause motor neuron disease. Am. J. Hum. Genet. 82:
780-785, 2008.
*FIELD* CD
Victor A. McKusick: 5/5/2008
*FIELD* ED
alopez: 05/05/2008
*RECORD*
*FIELD* NO
612020
*FIELD* TI
#612020 SPASTIC PARAPLEGIA 39, AUTOSOMAL RECESSIVE; SPG39
;;NTE-RELATED MOTOR NEURON DISORDER; NTEMND
read more*FIELD* TX
A number sign (#) is used with this entry because spastic paraplegia-39
is caused by mutation in the PNPLA6 gene (603197), encoding neuropathy
target esterase (NTE).
DESCRIPTION
The form of motor neuron disease designated spastic paraplegia-39
(SPG39) by Rainier et al. (2008) is an autosomal recessive progressive
spastic paraplegia associated with distal upper and lower extremity
wasting.
CLINICAL FEATURES
Rainier et al. (2008) reported a consanguineous family of Ashkenazi
Jewish ancestry and an unrelated nonconsanguineous family of northern
European ancestry in which affected subjects developed childhood onset
of insidiously progressive lower extremity spastic weakness and
progressive wasting of distal upper and lower extremity muscles.
Electrophysiologic studies were consistent with a motor axonopathy
affecting upper and lower limbs. Magnetic resonance imaging demonstrated
spinal cord atrophy, particularly in the thoracic region. The affected
phenotype in each family conformed both to organophosphorous (OP)
compound-induced delayed neuropathy (OPIDN) and to Troyer syndrome
(275900), an autosomal recessive hereditary spastic paraplegia
associated with distal muscle wasting. Additional neurologic and
systemic abnormalities including delayed milestone acquisition, skeletal
abnormalities, and cerebellar, extrapyramidal, and cognitive impairments
seen in Troyer syndrome were not observed.
MAPPING
Rainier et al. (2008) performed genomewide linkage analysis in a large
consanguineous Ashkenazi family and in a second nonconsanguineous
family. An extended linkage haplotype that spanned 22 cM between D19S565
and D19S884 on chromosome 19p13 was defined in the consanguineous
family; in the nonconsanguineous family the same markers also resulted
in haplotype sharing in affected subjects, consistent with genetic
linkage of the region.
MOLECULAR GENETICS
In affected members of 2 families with motor neuron disease, Rainier et
al. (2008) detected homozygosity or compound heterozygosity for
mutations in the NTE gene. Affected subjects in the consanguineous
kindred were homozygous for a disease-specific NTE mutation, 3034A-G,
that disrupted an interspecies-conserved residue in NTE's catalytic
domain (M1012V; 603197.0001). Affected subjects in the nonconsanguineous
family were compound heterozygotes: 1 allele carried a 2669G-A mutation
that disrupted an interspecies-conserved residue in NTE's catalytic
domain (R890H; 603197.0002), and the other allele had an insertion that
caused frameshift and protein truncation (603197.0003).
*FIELD* RF
1. Rainier, S.; Bui, M.; Mark, E.; Thomas, D.; Tokarz, D.; Ming, L.;
Delaney, C.; Richardson, R. J.; Albers, J. W.; Matsunami, N.; Stevens,
J.; Coon, H.; Leppert, M.; Fink, J. K.: Neuropathy target esterase
gene mutations cause motor neuron disease. Am. J. Hum. Genet. 82:
780-785, 2008.
*FIELD* CD
Victor A. McKusick: 5/5/2008
*FIELD* ED
alopez: 05/05/2008