Full text data of ERLIN2
ERLIN2
(C8orf2, SPFH2)
[Confidence: high (present in two of the MS resources)]
Erlin-2 (Endoplasmic reticulum lipid raft-associated protein 2; Stomatin-prohibitin-flotillin-HflC/K domain-containing protein 2; SPFH domain-containing protein 2)
Erlin-2 (Endoplasmic reticulum lipid raft-associated protein 2; Stomatin-prohibitin-flotillin-HflC/K domain-containing protein 2; SPFH domain-containing protein 2)
UniProt
O94905
ID ERLN2_HUMAN Reviewed; 339 AA.
AC O94905; A0JLQ1; A8K5S9; B4DM38; D3DSW0; Q6NW21; Q86VS6; Q86W49;
read moreDT 31-OCT-2003, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-1999, sequence version 1.
DT 22-JAN-2014, entry version 104.
DE RecName: Full=Erlin-2;
DE AltName: Full=Endoplasmic reticulum lipid raft-associated protein 2;
DE AltName: Full=Stomatin-prohibitin-flotillin-HflC/K domain-containing protein 2;
DE Short=SPFH domain-containing protein 2;
GN Name=ERLIN2; Synonyms=C8orf2, SPFH2; ORFNames=UNQ2441/PRO5003/PRO9924;
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 [GENOMIC DNA], ALTERNATIVE SPLICING, AND TISSUE
RP SPECIFICITY.
RX PubMed=10449903;
RA Ikegawa S., Isomura M., Koshizuka Y., Nakamura Y.;
RT "Cloning and characterization of a novel gene (C8orf2), a human
RT representative of a novel gene family with homology to C. elegans
RT C42.C1.9.";
RL Cytogenet. Cell Genet. 85:227-231(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Lymph node;
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 [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RX PubMed=12975309; DOI=10.1101/gr.1293003;
RA Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J.,
RA Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P.,
RA Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E., Heldens S.,
RA Huang A., Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J.,
RA Lewis L., Liao D., Mark M.R., Robbie E., Sanchez C., Schoenfeld J.,
RA Seshagiri S., Simmons L., Singh J., Smith V., Stinson J., Vagts A.,
RA Vandlen R.L., Watanabe C., Wieand D., Woods K., Xie M.-H.,
RA Yansura D.G., Yi S., Yu G., Yuan J., Zhang M., Zhang Z., Goddard A.D.,
RA Wood W.I., Godowski P.J., Gray A.M.;
RT "The secreted protein discovery initiative (SPDI), a large-scale
RT effort to identify novel human secreted and transmembrane proteins: a
RT bioinformatics assessment.";
RL Genome Res. 13:2265-2270(2003).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 3).
RC TISSUE=Brain, and Fetal brain;
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].
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 [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2 AND 3), AND
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-338 (ISOFORM 1).
RC TISSUE=Duodenum, Prostate, 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 [7]
RP PROTEIN SEQUENCE, FUNCTION, SUBUNIT, SUBCELLULAR LOCATION,
RP GLYCOSYLATION, AND INTERACTION WITH ERLIN1.
RX PubMed=19240031; DOI=10.1074/jbc.M809801200;
RA Pearce M.M.P., Wormer D.B., Wilkens S., Wojcikiewicz R.J.H.;
RT "An endoplasmic reticulum (ER) membrane complex composed of SPFH1 and
RT SPFH2 mediates the ER-associated degradation of inositol 1,4,5-
RT trisphosphate receptors.";
RL J. Biol. Chem. 284:10433-10445(2009).
RN [8]
RP SUBCELLULAR LOCATION.
RX PubMed=16835267; DOI=10.1242/jcs.03060;
RA Browman D.T., Resek M.E., Zajchowski L.D., Robbins S.M.;
RT "Erlin-1 and erlin-2 are novel members of the prohibitin family of
RT proteins that define lipid-raft-like domains of the ER.";
RL J. Cell Sci. 119:3149-3160(2006).
RN [9]
RP FUNCTION, SUBCELLULAR LOCATION, GLYCOSYLATION AT ASN-106, AND
RP MUTAGENESIS OF ASN-106.
RX PubMed=17502376; DOI=10.1074/jbc.M701862200;
RA Pearce M.M., Wang Y., Kelley G.G., Wojcikiewicz R.J.H.;
RT "SPFH2 mediates the endoplasmic reticulum-associated degradation of
RT inositol 1,4,5-trisphosphate receptors and other substrates in
RT mammalian cells.";
RL J. Biol. Chem. 282:20104-20115(2007).
RN [10]
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 [11]
RP INVOLVEMENT IN SPG18.
RX PubMed=21330303; DOI=10.1093/hmg/ddr070;
RA Yildirim Y., Orhan E.K., Iseri S.A., Serdaroglu-Oflazer P., Kara B.,
RA Solakoglu S., Tolun A.;
RT "A frameshift mutation of ERLIN2 in recessive intellectual disability,
RT motor dysfunction and multiple joint contractures.";
RL Hum. Mol. Genet. 20:1886-1892(2011).
RN [12]
RP INTERACTION WITH RNF170.
RX PubMed=21610068; DOI=10.1074/jbc.M111.251983;
RA Lu J.P., Wang Y., Sliter D.A., Pearce M.M., Wojcikiewicz R.J.;
RT "RNF170 protein, an endoplasmic reticulum membrane ubiquitin ligase,
RT mediates inositol 1,4,5-trisphosphate receptor ubiquitination and
RT degradation.";
RL J. Biol. Chem. 286:24426-24433(2011).
CC -!- FUNCTION: Component of the ERLIN1/ERLIN2 complex which mediates
CC the endoplasmic reticulum-associated degradation (ERAD) of
CC inositol 1,4,5-trisphosphate receptors (IP3Rs). Also involved in
CC ITPR1 degradation by the ERAD pathway.
CC -!- SUBUNIT: Interacts with activated ITPR1, independently of the
CC degree of ITPR1 polyubiquitination (By similarity). Forms a
CC heteromeric complex with ERLIN1. In complex with ERLIN1, interacts
CC with RNF170.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane; Single-pass
CC type II membrane protein. Note=Associated with lipid raft-like
CC domains of the endoplasmic reticulum membrane.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=O94905-1; Sequence=Displayed;
CC Name=2;
CC IsoId=O94905-2; Sequence=VSP_008713, VSP_008714;
CC Name=3;
CC IsoId=O94905-3; Sequence=VSP_013940, VSP_013941;
CC -!- TISSUE SPECIFICITY: Ubiquitous.
CC -!- DISEASE: Spastic paraplegia 18, autosomal recessive (SPG18)
CC [MIM:611225]: 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. SPG18 is a severe form with onset in early childhood.
CC Most affected individuals have severe psychomotor retardation.
CC Some may develop significant joint contractures. Note=The disease
CC is caused by mutations affecting the gene represented in this
CC entry.
CC -!- SIMILARITY: Belongs to the band 7/mec-2 family.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH50611.1; Type=Erroneous initiation;
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DR EMBL; AB018790; BAA36845.1; -; Genomic_DNA.
DR EMBL; AL442077; CAC09443.1; -; mRNA.
DR EMBL; AY358108; AAQ88475.1; -; mRNA.
DR EMBL; AY358851; AAQ89210.1; -; mRNA.
DR EMBL; AK291394; BAF84083.1; -; mRNA.
DR EMBL; AK297279; BAG59750.1; -; mRNA.
DR EMBL; CH471080; EAW63365.1; -; Genomic_DNA.
DR EMBL; CH471080; EAW63366.1; -; Genomic_DNA.
DR EMBL; BC005950; AAH05950.1; ALT_TERM; mRNA.
DR EMBL; BC048308; AAH48308.1; -; mRNA.
DR EMBL; BC050611; AAH50611.1; ALT_INIT; mRNA.
DR EMBL; BC067765; AAH67765.1; -; mRNA.
DR RefSeq; NP_001003790.1; NM_001003790.3.
DR RefSeq; NP_001003791.1; NM_001003791.2.
DR RefSeq; NP_009106.1; NM_007175.6.
DR RefSeq; XP_005273449.1; XM_005273392.1.
DR UniGene; Hs.705490; -.
DR ProteinModelPortal; O94905; -.
DR IntAct; O94905; 6.
DR MINT; MINT-3035811; -.
DR STRING; 9606.ENSP00000276461; -.
DR PhosphoSite; O94905; -.
DR PaxDb; O94905; -.
DR PRIDE; O94905; -.
DR DNASU; 11160; -.
DR Ensembl; ENST00000276461; ENSP00000276461; ENSG00000147475.
DR Ensembl; ENST00000335171; ENSP00000335220; ENSG00000147475.
DR Ensembl; ENST00000397228; ENSP00000380405; ENSG00000147475.
DR Ensembl; ENST00000518586; ENSP00000427847; ENSG00000147475.
DR Ensembl; ENST00000519638; ENSP00000428112; ENSG00000147475.
DR Ensembl; ENST00000523107; ENSP00000473292; ENSG00000147475.
DR Ensembl; ENST00000523887; ENSP00000429903; ENSG00000147475.
DR GeneID; 11160; -.
DR KEGG; hsa:11160; -.
DR UCSC; uc003xke.4; human.
DR CTD; 11160; -.
DR GeneCards; GC08P037594; -.
DR HGNC; HGNC:1356; ERLIN2.
DR HPA; CAB014894; -.
DR HPA; HPA002025; -.
DR MIM; 611225; phenotype.
DR MIM; 611605; gene.
DR neXtProt; NX_O94905; -.
DR Orphanet; 209951; Autosomal recessive spastic paraplegia type 18.
DR Orphanet; 247604; Juvenile primary lateral sclerosis.
DR Orphanet; 280384; Recessive intellectual disability - motor dysfunction - multiple joint contractures.
DR PharmGKB; PA25961; -.
DR eggNOG; NOG307809; -.
DR HOVERGEN; HBG050934; -.
DR InParanoid; O94905; -.
DR OMA; NMFVDSA; -.
DR OrthoDB; EOG7Z69D1; -.
DR PhylomeDB; O94905; -.
DR GeneWiki; ERLIN2; -.
DR GenomeRNAi; 11160; -.
DR NextBio; 42451; -.
DR PRO; PR:O94905; -.
DR ArrayExpress; O94905; -.
DR Bgee; O94905; -.
DR CleanEx; HS_ERLIN2; -.
DR Genevestigator; O94905; -.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IDA:UniProtKB.
DR GO; GO:0016021; C:integral to membrane; IEA:UniProtKB-KW.
DR GO; GO:0005886; C:plasma membrane; IDA:HPA.
DR GO; GO:0043234; C:protein complex; IDA:MGI.
DR GO; GO:0008219; P:cell death; IEA:UniProtKB-KW.
DR GO; GO:0030433; P:ER-associated ubiquitin-dependent protein catabolic process; IDA:UniProtKB.
DR InterPro; IPR001107; Band_7.
DR Pfam; PF01145; Band_7; 1.
DR SMART; SM00244; PHB; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Complete proteome; Direct protein sequencing;
KW Endoplasmic reticulum; Glycoprotein; Hereditary spastic paraplegia;
KW Membrane; Neurodegeneration; Polymorphism; Reference proteome;
KW Signal-anchor; Transmembrane; Transmembrane helix.
FT CHAIN 1 339 Erlin-2.
FT /FTId=PRO_0000002787.
FT TOPO_DOM 1 3 Cytoplasmic (Potential).
FT TRANSMEM 4 24 Helical; (Potential).
FT TOPO_DOM 25 339 Lumenal (Potential).
FT REGION 177 309 Interaction with ERLIN1.
FT CARBOHYD 106 106 N-linked (GlcNAc...).
FT VAR_SEQ 142 206 DQIDENLKLALQQDLTSMAPGLVIQAVRVTKPNIPEAIRRN
FT YELMESEKTKLLIAAQKQKVVEKE -> GKKVSPEHAVLKQ
FT GSWNPASLHCLKPGCLQGVMVTYGQEMLKNLVLRSWSQRSS
FT WRMLIAMQQDP (in isoform 3).
FT /FTId=VSP_013940.
FT VAR_SEQ 142 152 DQIDENLKLAL -> GLENDFSQESS (in isoform
FT 2).
FT /FTId=VSP_008713.
FT VAR_SEQ 153 339 Missing (in isoform 2).
FT /FTId=VSP_008714.
FT VAR_SEQ 207 339 Missing (in isoform 3).
FT /FTId=VSP_013941.
FT VARIANT 71 71 V -> A (in dbSNP:rs2032066).
FT /FTId=VAR_059140.
FT MUTAGEN 106 106 N->Q: Loss of glycosylation.
FT CONFLICT 61 61 S -> P (in Ref. 6; AAH05950).
SQ SEQUENCE 339 AA; 37840 MW; 3CF322548FD58DB0 CRC64;
MAQLGAVVAV ASSFFCASLF SAVHKIEEGH IGVYYRGGAL LTSTSGPGFH LMLPFITSYK
SVQTTLQTDE VKNVPCGTSG GVMIYFDRIE VVNFLVPNAV YDIVKNYTAD YDKALIFNKI
HHELNQFCSV HTLQEVYIEL FDQIDENLKL ALQQDLTSMA PGLVIQAVRV TKPNIPEAIR
RNYELMESEK TKLLIAAQKQ KVVEKEAETE RKKALIEAEK VAQVAEITYG QKVMEKETEK
KISEIEDAAF LAREKAKADA ECYTAMKIAE ANKLKLTPEY LQLMKYKAIA SNSKIYFGKD
IPNMFMDSAG SVSKQFEGLA DKLSFGLEDE PLETATKEN
//
ID ERLN2_HUMAN Reviewed; 339 AA.
AC O94905; A0JLQ1; A8K5S9; B4DM38; D3DSW0; Q6NW21; Q86VS6; Q86W49;
read moreDT 31-OCT-2003, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-1999, sequence version 1.
DT 22-JAN-2014, entry version 104.
DE RecName: Full=Erlin-2;
DE AltName: Full=Endoplasmic reticulum lipid raft-associated protein 2;
DE AltName: Full=Stomatin-prohibitin-flotillin-HflC/K domain-containing protein 2;
DE Short=SPFH domain-containing protein 2;
GN Name=ERLIN2; Synonyms=C8orf2, SPFH2; ORFNames=UNQ2441/PRO5003/PRO9924;
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 [GENOMIC DNA], ALTERNATIVE SPLICING, AND TISSUE
RP SPECIFICITY.
RX PubMed=10449903;
RA Ikegawa S., Isomura M., Koshizuka Y., Nakamura Y.;
RT "Cloning and characterization of a novel gene (C8orf2), a human
RT representative of a novel gene family with homology to C. elegans
RT C42.C1.9.";
RL Cytogenet. Cell Genet. 85:227-231(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Lymph node;
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 [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RX PubMed=12975309; DOI=10.1101/gr.1293003;
RA Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J.,
RA Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P.,
RA Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E., Heldens S.,
RA Huang A., Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J.,
RA Lewis L., Liao D., Mark M.R., Robbie E., Sanchez C., Schoenfeld J.,
RA Seshagiri S., Simmons L., Singh J., Smith V., Stinson J., Vagts A.,
RA Vandlen R.L., Watanabe C., Wieand D., Woods K., Xie M.-H.,
RA Yansura D.G., Yi S., Yu G., Yuan J., Zhang M., Zhang Z., Goddard A.D.,
RA Wood W.I., Godowski P.J., Gray A.M.;
RT "The secreted protein discovery initiative (SPDI), a large-scale
RT effort to identify novel human secreted and transmembrane proteins: a
RT bioinformatics assessment.";
RL Genome Res. 13:2265-2270(2003).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 3).
RC TISSUE=Brain, and Fetal brain;
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].
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 [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2 AND 3), AND
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-338 (ISOFORM 1).
RC TISSUE=Duodenum, Prostate, 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 [7]
RP PROTEIN SEQUENCE, FUNCTION, SUBUNIT, SUBCELLULAR LOCATION,
RP GLYCOSYLATION, AND INTERACTION WITH ERLIN1.
RX PubMed=19240031; DOI=10.1074/jbc.M809801200;
RA Pearce M.M.P., Wormer D.B., Wilkens S., Wojcikiewicz R.J.H.;
RT "An endoplasmic reticulum (ER) membrane complex composed of SPFH1 and
RT SPFH2 mediates the ER-associated degradation of inositol 1,4,5-
RT trisphosphate receptors.";
RL J. Biol. Chem. 284:10433-10445(2009).
RN [8]
RP SUBCELLULAR LOCATION.
RX PubMed=16835267; DOI=10.1242/jcs.03060;
RA Browman D.T., Resek M.E., Zajchowski L.D., Robbins S.M.;
RT "Erlin-1 and erlin-2 are novel members of the prohibitin family of
RT proteins that define lipid-raft-like domains of the ER.";
RL J. Cell Sci. 119:3149-3160(2006).
RN [9]
RP FUNCTION, SUBCELLULAR LOCATION, GLYCOSYLATION AT ASN-106, AND
RP MUTAGENESIS OF ASN-106.
RX PubMed=17502376; DOI=10.1074/jbc.M701862200;
RA Pearce M.M., Wang Y., Kelley G.G., Wojcikiewicz R.J.H.;
RT "SPFH2 mediates the endoplasmic reticulum-associated degradation of
RT inositol 1,4,5-trisphosphate receptors and other substrates in
RT mammalian cells.";
RL J. Biol. Chem. 282:20104-20115(2007).
RN [10]
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 [11]
RP INVOLVEMENT IN SPG18.
RX PubMed=21330303; DOI=10.1093/hmg/ddr070;
RA Yildirim Y., Orhan E.K., Iseri S.A., Serdaroglu-Oflazer P., Kara B.,
RA Solakoglu S., Tolun A.;
RT "A frameshift mutation of ERLIN2 in recessive intellectual disability,
RT motor dysfunction and multiple joint contractures.";
RL Hum. Mol. Genet. 20:1886-1892(2011).
RN [12]
RP INTERACTION WITH RNF170.
RX PubMed=21610068; DOI=10.1074/jbc.M111.251983;
RA Lu J.P., Wang Y., Sliter D.A., Pearce M.M., Wojcikiewicz R.J.;
RT "RNF170 protein, an endoplasmic reticulum membrane ubiquitin ligase,
RT mediates inositol 1,4,5-trisphosphate receptor ubiquitination and
RT degradation.";
RL J. Biol. Chem. 286:24426-24433(2011).
CC -!- FUNCTION: Component of the ERLIN1/ERLIN2 complex which mediates
CC the endoplasmic reticulum-associated degradation (ERAD) of
CC inositol 1,4,5-trisphosphate receptors (IP3Rs). Also involved in
CC ITPR1 degradation by the ERAD pathway.
CC -!- SUBUNIT: Interacts with activated ITPR1, independently of the
CC degree of ITPR1 polyubiquitination (By similarity). Forms a
CC heteromeric complex with ERLIN1. In complex with ERLIN1, interacts
CC with RNF170.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane; Single-pass
CC type II membrane protein. Note=Associated with lipid raft-like
CC domains of the endoplasmic reticulum membrane.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=O94905-1; Sequence=Displayed;
CC Name=2;
CC IsoId=O94905-2; Sequence=VSP_008713, VSP_008714;
CC Name=3;
CC IsoId=O94905-3; Sequence=VSP_013940, VSP_013941;
CC -!- TISSUE SPECIFICITY: Ubiquitous.
CC -!- DISEASE: Spastic paraplegia 18, autosomal recessive (SPG18)
CC [MIM:611225]: 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. SPG18 is a severe form with onset in early childhood.
CC Most affected individuals have severe psychomotor retardation.
CC Some may develop significant joint contractures. Note=The disease
CC is caused by mutations affecting the gene represented in this
CC entry.
CC -!- SIMILARITY: Belongs to the band 7/mec-2 family.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH50611.1; Type=Erroneous initiation;
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; AB018790; BAA36845.1; -; Genomic_DNA.
DR EMBL; AL442077; CAC09443.1; -; mRNA.
DR EMBL; AY358108; AAQ88475.1; -; mRNA.
DR EMBL; AY358851; AAQ89210.1; -; mRNA.
DR EMBL; AK291394; BAF84083.1; -; mRNA.
DR EMBL; AK297279; BAG59750.1; -; mRNA.
DR EMBL; CH471080; EAW63365.1; -; Genomic_DNA.
DR EMBL; CH471080; EAW63366.1; -; Genomic_DNA.
DR EMBL; BC005950; AAH05950.1; ALT_TERM; mRNA.
DR EMBL; BC048308; AAH48308.1; -; mRNA.
DR EMBL; BC050611; AAH50611.1; ALT_INIT; mRNA.
DR EMBL; BC067765; AAH67765.1; -; mRNA.
DR RefSeq; NP_001003790.1; NM_001003790.3.
DR RefSeq; NP_001003791.1; NM_001003791.2.
DR RefSeq; NP_009106.1; NM_007175.6.
DR RefSeq; XP_005273449.1; XM_005273392.1.
DR UniGene; Hs.705490; -.
DR ProteinModelPortal; O94905; -.
DR IntAct; O94905; 6.
DR MINT; MINT-3035811; -.
DR STRING; 9606.ENSP00000276461; -.
DR PhosphoSite; O94905; -.
DR PaxDb; O94905; -.
DR PRIDE; O94905; -.
DR DNASU; 11160; -.
DR Ensembl; ENST00000276461; ENSP00000276461; ENSG00000147475.
DR Ensembl; ENST00000335171; ENSP00000335220; ENSG00000147475.
DR Ensembl; ENST00000397228; ENSP00000380405; ENSG00000147475.
DR Ensembl; ENST00000518586; ENSP00000427847; ENSG00000147475.
DR Ensembl; ENST00000519638; ENSP00000428112; ENSG00000147475.
DR Ensembl; ENST00000523107; ENSP00000473292; ENSG00000147475.
DR Ensembl; ENST00000523887; ENSP00000429903; ENSG00000147475.
DR GeneID; 11160; -.
DR KEGG; hsa:11160; -.
DR UCSC; uc003xke.4; human.
DR CTD; 11160; -.
DR GeneCards; GC08P037594; -.
DR HGNC; HGNC:1356; ERLIN2.
DR HPA; CAB014894; -.
DR HPA; HPA002025; -.
DR MIM; 611225; phenotype.
DR MIM; 611605; gene.
DR neXtProt; NX_O94905; -.
DR Orphanet; 209951; Autosomal recessive spastic paraplegia type 18.
DR Orphanet; 247604; Juvenile primary lateral sclerosis.
DR Orphanet; 280384; Recessive intellectual disability - motor dysfunction - multiple joint contractures.
DR PharmGKB; PA25961; -.
DR eggNOG; NOG307809; -.
DR HOVERGEN; HBG050934; -.
DR InParanoid; O94905; -.
DR OMA; NMFVDSA; -.
DR OrthoDB; EOG7Z69D1; -.
DR PhylomeDB; O94905; -.
DR GeneWiki; ERLIN2; -.
DR GenomeRNAi; 11160; -.
DR NextBio; 42451; -.
DR PRO; PR:O94905; -.
DR ArrayExpress; O94905; -.
DR Bgee; O94905; -.
DR CleanEx; HS_ERLIN2; -.
DR Genevestigator; O94905; -.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IDA:UniProtKB.
DR GO; GO:0016021; C:integral to membrane; IEA:UniProtKB-KW.
DR GO; GO:0005886; C:plasma membrane; IDA:HPA.
DR GO; GO:0043234; C:protein complex; IDA:MGI.
DR GO; GO:0008219; P:cell death; IEA:UniProtKB-KW.
DR GO; GO:0030433; P:ER-associated ubiquitin-dependent protein catabolic process; IDA:UniProtKB.
DR InterPro; IPR001107; Band_7.
DR Pfam; PF01145; Band_7; 1.
DR SMART; SM00244; PHB; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Complete proteome; Direct protein sequencing;
KW Endoplasmic reticulum; Glycoprotein; Hereditary spastic paraplegia;
KW Membrane; Neurodegeneration; Polymorphism; Reference proteome;
KW Signal-anchor; Transmembrane; Transmembrane helix.
FT CHAIN 1 339 Erlin-2.
FT /FTId=PRO_0000002787.
FT TOPO_DOM 1 3 Cytoplasmic (Potential).
FT TRANSMEM 4 24 Helical; (Potential).
FT TOPO_DOM 25 339 Lumenal (Potential).
FT REGION 177 309 Interaction with ERLIN1.
FT CARBOHYD 106 106 N-linked (GlcNAc...).
FT VAR_SEQ 142 206 DQIDENLKLALQQDLTSMAPGLVIQAVRVTKPNIPEAIRRN
FT YELMESEKTKLLIAAQKQKVVEKE -> GKKVSPEHAVLKQ
FT GSWNPASLHCLKPGCLQGVMVTYGQEMLKNLVLRSWSQRSS
FT WRMLIAMQQDP (in isoform 3).
FT /FTId=VSP_013940.
FT VAR_SEQ 142 152 DQIDENLKLAL -> GLENDFSQESS (in isoform
FT 2).
FT /FTId=VSP_008713.
FT VAR_SEQ 153 339 Missing (in isoform 2).
FT /FTId=VSP_008714.
FT VAR_SEQ 207 339 Missing (in isoform 3).
FT /FTId=VSP_013941.
FT VARIANT 71 71 V -> A (in dbSNP:rs2032066).
FT /FTId=VAR_059140.
FT MUTAGEN 106 106 N->Q: Loss of glycosylation.
FT CONFLICT 61 61 S -> P (in Ref. 6; AAH05950).
SQ SEQUENCE 339 AA; 37840 MW; 3CF322548FD58DB0 CRC64;
MAQLGAVVAV ASSFFCASLF SAVHKIEEGH IGVYYRGGAL LTSTSGPGFH LMLPFITSYK
SVQTTLQTDE VKNVPCGTSG GVMIYFDRIE VVNFLVPNAV YDIVKNYTAD YDKALIFNKI
HHELNQFCSV HTLQEVYIEL FDQIDENLKL ALQQDLTSMA PGLVIQAVRV TKPNIPEAIR
RNYELMESEK TKLLIAAQKQ KVVEKEAETE RKKALIEAEK VAQVAEITYG QKVMEKETEK
KISEIEDAAF LAREKAKADA ECYTAMKIAE ANKLKLTPEY LQLMKYKAIA SNSKIYFGKD
IPNMFMDSAG SVSKQFEGLA DKLSFGLEDE PLETATKEN
//
MIM
611225
*RECORD*
*FIELD* NO
611225
*FIELD* TI
#611225 SPASTIC PARAPLEGIA 18, AUTOSOMAL RECESSIVE; SPG18
;;INTELLECTUAL DISABILITY, MOTOR DYSFUNCTION, AND JOINT CONTRACTURES;
read moreIDMDC
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
autosomal recessive spastic paraplegia-18 (SPG18) is caused by
homozygous mutation in the ERLIN2 gene (611605) on chromosome 8p11.
DESCRIPTION
Spastic paraplegia-18 is a severe autosomal recessive neurologic
disorder characterized by onset in early childhood of progressive
spastic paraplegia resulting in motor disability. Most affected
individuals have severe psychomotor retardation. Some may develop
significant joint contractures (summary by Alazami et al., 2011 and
Yildirim et al., 2011).
CLINICAL FEATURES
Al-Yahyaee et al. (2006) reported 2 unrelated consanguineous Omani
families with autosomal recessive complicated SPG. In 1 family (family
B), 3 affected individuals presented with walking difficulties between
ages 4 and 6 years. Physical examination showed lower limb spasticity
primarily affecting the hamstring and posterior tibial muscles. Two of
the children also had epilepsy; all had normal brain CT scans and normal
mental development. Affected individuals from the second family (family
A) had early-onset spasticity, mental retardation, and thin corpus
callosum on brain MRI. Family A was later found by Schuurs-Hoeijmakers
et al. (2012) to have SPG54 (615033), caused by mutation in the DDHD2
gene (615003) on chromosome 8p11.
Alazami et al. (2011) reported a consanguineous Saudi family with a
complicated form of SPG. One of 2 affected sibs was described in detail.
At age 30 months, he developed progressive tightening of the lower
extremities with later involvement of the upper extremities, rendering
him wheelchair-bound at age 4 years. He had a history of delayed early
motor development and intellectual disability, and failed to acquire
language. He also developed seizures at age 7 years, and EEG was
severely abnormal, with generalized slowing of background and
generalized slow spike and wave activities compatible with atypical
absence epilepsy. Brain MRI was normal. His younger sister had a similar
disease course, except without seizures. Three maternal uncles, who were
not examined, reportedly had severe intellectual disability, aphasia,
and marked hypertonia, all without seizures.
Yildirim et al. (2011) reported a very large, highly consanguineous
family from eastern Turkey with a neurologic disorder that the authors
termed 'intellectual disability, motor dysfunction, and joint
contractures' (IDMDC). Affected individuals presented between ages 6
months and 2 years with an arrest and regression of motor function. Nine
patients had infantile febrile seizures. Distal limb deformities became
evident after the age of 1 or 2 years and progressed very slowly, but
each child finally assumed a specific fixed position. Contractures
seemed to begin from the feet and spread in an ascending manner,
involving the ankles, knees, and elbows, and finally involving the spine
and the neck. Examination of 11 patients between ages 4 and 22 years
revealed that none of the patients could walk or crawl; only 2 were
still able to sit. All had severe intellectual disability, and none
could speak, read, or write. Features suggestive of spasticity included
hyperactive reflexes, ankle clonus, and extensor plantar responses, but
the neurologic examination was difficult to perform in most. Muscle
biopsy of 2 patients, EMG of 4 patients, and brain imaging of 3 patients
were all normal. Electron microscopy of white blood cells from 2
affected sibs showed large membrane-bound vacuoles containing flocculent
material in 7 to 10% of cells, and these vacuoles appeared to be
associated with the endoplasmic reticulum.
Al-Saif et al. (2012) reported 4 sibs, born of consanguineous Turkish
parents, with a clinical diagnosis of severe juvenile primary lateral
sclerosis. The patients showed difficulty in crawling and limb
spasticity around 8 months of age. The motor problems were progressive:
patients had delayed motor development, required crutches and walkers at
age 5 to 6 years, were wheelchair-bound at age 11 to 12 years, and were
bedridden by age 15. Speech and articulation regressed after age 2
years, and the patients were unable to communicate verbally. Cognition
was difficult to assess, but was apparently delayed. Other features
included kyphosis, scoliosis, high-arched palate, abnormal smooth
pursuit, and pseudobulbar palsy as manifest by increased jaw and
glabellar reflexes and weak cough. There was distal muscle weakness,
overall decreased muscle bulk, and increased muscle tone with
hyperreflexia and extensor plantar responses. Seizures were not
reported, and brain MRI showed no significant abnormalities.
INHERITANCE
The transmission pattern of the neurologic disease in the families
reported by Yildirim et al. (2011) and Al-Saif et al. (2012) was
consistent with autosomal recessive inheritance.
MAPPING
By genomewide linkage analysis in 2 unrelated Omani families with SPG,
Al-Yahyaee et al. (2006) identified a candidate disease locus, referred
to here as SPG18, on chromosome 8p12-p11.21 (2-point maximum lod score
of 5.91 at D8S1820; combined multipoint lod score of 7.08 at D8S505).
Haplotype analysis of both families delineated a 9-cM candidate region
between D8S1820 and D8S532. The locus did not overlap with SPG5A
(270800). One of the families (family A) was later found to have SPG54,
which also maps to 8p11 (Schuurs-Hoeijmakers et al., 2012).
By autozygosity mapping of a consanguineous Saudi family with
complicated SPG, Alazami et al. (2011) found linkage to an 18.2-Mb
interval on chromosome 8p12-q11.22 (maximum lod score of 4.205), which
overlapped with the SPG18 locus delineated by Al-Yahyaee et al. (2006).
CYTOGENETICS
By autozygosity mapping followed by candidate gene sequencing in a
consanguineous Saudi family with complicated SPG, Alazami et al. (2011)
identified a homozygous 20-kb deletion on chromosome 8, with the distal
breakpoint near physical position 37,694,857 (NCBI36) and the proximal
breakpoint near 37,714,575 immediately upstream of exon 2 of the ERLIN2
gene (611605). This 20-kb interval spans 2 protein-coding genes, ERLIN2
and FLJ34378. RT-PCR analysis of patient lymphoblasts showed loss of
ERLIN2 transcription, consistent with a null allele. Alazami et al.
(2011) noted that ERLIN2 is involved in the endoplasmic reticulum
degradation (ERAD) pathway, and postulated that loss of ERLIN2 may
result in persistent activation of IP3 signaling and neuronal channel
activity since ERAD normally degrades IP3 receptors (see, e.g., ITPR1,
147265). Alazami et al. (2011) also concluded that ERLIN2 depletion
caused the phenotype, although they could not exclude a role for
FLJ34378.
MOLECULAR GENETICS
In affected members of a consanguineous Turkish family with autosomal
recessive intellectual disability, motor dysfunction, and contractures,
Yildirim et al. (2011) identified a homozygous truncation mutation in
the ERLIN2 gene (611605.0001). The mutation was found by linkage
analysis followed by candidate gene sequencing.
In 4 sibs, born of consanguineous Turkish parents, with a clinical
diagnosis of juvenile primary lateral sclerosis, Al-Saif et al. (2012)
identified a homozygous splice site mutation in the ERLIN2 gene
(611605.0002). The mutation was found by homozygosity mapping followed
by candidate gene sequencing and segregated with the disorder in the
family. Analysis of patient cells demonstrated that the mutation caused
premature termination and a decrease in levels of ERLIN2 mRNA (about 15%
of controls), and that the mutant transcript underwent nonsense-mediated
mRNA decay, resulting in a loss of function. Knockdown of ERLIN2 in
mouse neuronal cells resulted in decreased cellular growth compared to
controls, supporting a deleterious effect of loss of Erlin2 in patient
neurons.
*FIELD* RF
1. Al-Saif, A.; Bohlega, S.; Al-Mohanna, F.: Loss of ERLIN2 function
leads to juvenile primary lateral sclerosis. Ann. Neurol. 72: 510-516,
2012.
2. Al-Yahyaee, S.; Al-Gazali, L. I.; De Jonghe, P.; Al-Barwany, H.;
Al-Kindi, M.; De Vriendt, E.; Chand, P.; Koul, R.; Jacob, P. C.; Gururaj,
A.; Sztriha, L.; Parrado, A.; Van Broeckhoven, C.; Bayoumi, R. A.
: A novel locus for hereditary spastic paraplegia with thin corpus
callosum and epilepsy. Neurology 66: 1230-1234, 2006.
3. Alazami, A. M.; Adly, N.; Al Dhalaan, H.; Alkuraya, F. S.: A nullimorphic
ERLIN2 mutation defines a complicated hereditary spastic paraplegia
locus (SPG18). Neurogenetics 12: 333-336, 2011.
4. Schuurs-Hoeijmakers, J. H. M.; Geraghty, M. T.; Kamsteeg, E.-J.;
Ben-Salem, S.; de Bot, S. T.; Nijhof, B.; van de Vondervoort, I. I.
G. M.; van der Graaf, M.; Nobau, A. C.; Otte-Holler, I.; Vermeer,
S.; Smith, A. C.; and 29 others: Mutations in DDHD2, encoding an
intracellular phospholipase A(1), cause a recessive form of complex
hereditary spastic paraplegia. Am. J. Hum. Genet. 91: 1073-1081,
2012.
5. Yildirim, Y.; Orhan, E. K.; Iseri, S. A. U.; Serdaroglu-Oflazer,
P.; Kara, B.; Solakoglu, S.; Tolun, A.: A frameshift mutation of
ERLIN2 in recessive intellectual disability, motor dysfunction and
multiple joint contractures. Hum. Molec. Genet. 20: 1886-1892, 2011.
*FIELD* CS
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Eyes];
Squint
SKELETAL:
Contractures, progressive, severe;
[Feet];
Pes cavus
MUSCLE, SOFT TISSUE:
Lower limb muscle weakness
NEUROLOGIC:
[Central nervous system];
Delayed walking;
Abnormal gait;
Lower limb spasticity;
Upper limb spasticity, mild;
Extensor plantar responses;
Hyperreflexia;
Mental retardation (in most patients);
Seizures (in most patients)
MISCELLANEOUS:
Onset in infancy or childhood (range 1 to 6 years);
Slowly progressive;
Results in severe motor disability
MOLECULAR BASIS:
Caused by mutation in the endoplasmic reticulum lipid raft-associated
protein 2 gene (ERLIN2, 611605.0001)
*FIELD* CN
Cassandra L. Kniffin - updated: 1/24/2013
Cassandra L. Kniffin - updated: 1/3/2012
*FIELD* CD
Cassandra L. Kniffin: 7/19/2007
*FIELD* ED
joanna: 06/04/2013
ckniffin: 1/24/2013
joanna: 1/10/2012
ckniffin: 1/3/2012
ckniffin: 6/9/2009
*FIELD* CN
Cassandra L. Kniffin - updated: 1/6/2014
Cassandra L. Kniffin - updated: 1/24/2013
Cassandra L. Kniffin - updated: 1/3/2012
*FIELD* CD
Cassandra L. Kniffin: 7/19/2007
*FIELD* ED
carol: 01/06/2014
ckniffin: 1/6/2014
carol: 1/25/2013
ckniffin: 1/24/2013
joanna: 3/14/2012
carol: 1/3/2012
ckniffin: 1/3/2012
wwang: 6/9/2009
ckniffin: 6/9/2009
*RECORD*
*FIELD* NO
611225
*FIELD* TI
#611225 SPASTIC PARAPLEGIA 18, AUTOSOMAL RECESSIVE; SPG18
;;INTELLECTUAL DISABILITY, MOTOR DYSFUNCTION, AND JOINT CONTRACTURES;
read moreIDMDC
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
autosomal recessive spastic paraplegia-18 (SPG18) is caused by
homozygous mutation in the ERLIN2 gene (611605) on chromosome 8p11.
DESCRIPTION
Spastic paraplegia-18 is a severe autosomal recessive neurologic
disorder characterized by onset in early childhood of progressive
spastic paraplegia resulting in motor disability. Most affected
individuals have severe psychomotor retardation. Some may develop
significant joint contractures (summary by Alazami et al., 2011 and
Yildirim et al., 2011).
CLINICAL FEATURES
Al-Yahyaee et al. (2006) reported 2 unrelated consanguineous Omani
families with autosomal recessive complicated SPG. In 1 family (family
B), 3 affected individuals presented with walking difficulties between
ages 4 and 6 years. Physical examination showed lower limb spasticity
primarily affecting the hamstring and posterior tibial muscles. Two of
the children also had epilepsy; all had normal brain CT scans and normal
mental development. Affected individuals from the second family (family
A) had early-onset spasticity, mental retardation, and thin corpus
callosum on brain MRI. Family A was later found by Schuurs-Hoeijmakers
et al. (2012) to have SPG54 (615033), caused by mutation in the DDHD2
gene (615003) on chromosome 8p11.
Alazami et al. (2011) reported a consanguineous Saudi family with a
complicated form of SPG. One of 2 affected sibs was described in detail.
At age 30 months, he developed progressive tightening of the lower
extremities with later involvement of the upper extremities, rendering
him wheelchair-bound at age 4 years. He had a history of delayed early
motor development and intellectual disability, and failed to acquire
language. He also developed seizures at age 7 years, and EEG was
severely abnormal, with generalized slowing of background and
generalized slow spike and wave activities compatible with atypical
absence epilepsy. Brain MRI was normal. His younger sister had a similar
disease course, except without seizures. Three maternal uncles, who were
not examined, reportedly had severe intellectual disability, aphasia,
and marked hypertonia, all without seizures.
Yildirim et al. (2011) reported a very large, highly consanguineous
family from eastern Turkey with a neurologic disorder that the authors
termed 'intellectual disability, motor dysfunction, and joint
contractures' (IDMDC). Affected individuals presented between ages 6
months and 2 years with an arrest and regression of motor function. Nine
patients had infantile febrile seizures. Distal limb deformities became
evident after the age of 1 or 2 years and progressed very slowly, but
each child finally assumed a specific fixed position. Contractures
seemed to begin from the feet and spread in an ascending manner,
involving the ankles, knees, and elbows, and finally involving the spine
and the neck. Examination of 11 patients between ages 4 and 22 years
revealed that none of the patients could walk or crawl; only 2 were
still able to sit. All had severe intellectual disability, and none
could speak, read, or write. Features suggestive of spasticity included
hyperactive reflexes, ankle clonus, and extensor plantar responses, but
the neurologic examination was difficult to perform in most. Muscle
biopsy of 2 patients, EMG of 4 patients, and brain imaging of 3 patients
were all normal. Electron microscopy of white blood cells from 2
affected sibs showed large membrane-bound vacuoles containing flocculent
material in 7 to 10% of cells, and these vacuoles appeared to be
associated with the endoplasmic reticulum.
Al-Saif et al. (2012) reported 4 sibs, born of consanguineous Turkish
parents, with a clinical diagnosis of severe juvenile primary lateral
sclerosis. The patients showed difficulty in crawling and limb
spasticity around 8 months of age. The motor problems were progressive:
patients had delayed motor development, required crutches and walkers at
age 5 to 6 years, were wheelchair-bound at age 11 to 12 years, and were
bedridden by age 15. Speech and articulation regressed after age 2
years, and the patients were unable to communicate verbally. Cognition
was difficult to assess, but was apparently delayed. Other features
included kyphosis, scoliosis, high-arched palate, abnormal smooth
pursuit, and pseudobulbar palsy as manifest by increased jaw and
glabellar reflexes and weak cough. There was distal muscle weakness,
overall decreased muscle bulk, and increased muscle tone with
hyperreflexia and extensor plantar responses. Seizures were not
reported, and brain MRI showed no significant abnormalities.
INHERITANCE
The transmission pattern of the neurologic disease in the families
reported by Yildirim et al. (2011) and Al-Saif et al. (2012) was
consistent with autosomal recessive inheritance.
MAPPING
By genomewide linkage analysis in 2 unrelated Omani families with SPG,
Al-Yahyaee et al. (2006) identified a candidate disease locus, referred
to here as SPG18, on chromosome 8p12-p11.21 (2-point maximum lod score
of 5.91 at D8S1820; combined multipoint lod score of 7.08 at D8S505).
Haplotype analysis of both families delineated a 9-cM candidate region
between D8S1820 and D8S532. The locus did not overlap with SPG5A
(270800). One of the families (family A) was later found to have SPG54,
which also maps to 8p11 (Schuurs-Hoeijmakers et al., 2012).
By autozygosity mapping of a consanguineous Saudi family with
complicated SPG, Alazami et al. (2011) found linkage to an 18.2-Mb
interval on chromosome 8p12-q11.22 (maximum lod score of 4.205), which
overlapped with the SPG18 locus delineated by Al-Yahyaee et al. (2006).
CYTOGENETICS
By autozygosity mapping followed by candidate gene sequencing in a
consanguineous Saudi family with complicated SPG, Alazami et al. (2011)
identified a homozygous 20-kb deletion on chromosome 8, with the distal
breakpoint near physical position 37,694,857 (NCBI36) and the proximal
breakpoint near 37,714,575 immediately upstream of exon 2 of the ERLIN2
gene (611605). This 20-kb interval spans 2 protein-coding genes, ERLIN2
and FLJ34378. RT-PCR analysis of patient lymphoblasts showed loss of
ERLIN2 transcription, consistent with a null allele. Alazami et al.
(2011) noted that ERLIN2 is involved in the endoplasmic reticulum
degradation (ERAD) pathway, and postulated that loss of ERLIN2 may
result in persistent activation of IP3 signaling and neuronal channel
activity since ERAD normally degrades IP3 receptors (see, e.g., ITPR1,
147265). Alazami et al. (2011) also concluded that ERLIN2 depletion
caused the phenotype, although they could not exclude a role for
FLJ34378.
MOLECULAR GENETICS
In affected members of a consanguineous Turkish family with autosomal
recessive intellectual disability, motor dysfunction, and contractures,
Yildirim et al. (2011) identified a homozygous truncation mutation in
the ERLIN2 gene (611605.0001). The mutation was found by linkage
analysis followed by candidate gene sequencing.
In 4 sibs, born of consanguineous Turkish parents, with a clinical
diagnosis of juvenile primary lateral sclerosis, Al-Saif et al. (2012)
identified a homozygous splice site mutation in the ERLIN2 gene
(611605.0002). The mutation was found by homozygosity mapping followed
by candidate gene sequencing and segregated with the disorder in the
family. Analysis of patient cells demonstrated that the mutation caused
premature termination and a decrease in levels of ERLIN2 mRNA (about 15%
of controls), and that the mutant transcript underwent nonsense-mediated
mRNA decay, resulting in a loss of function. Knockdown of ERLIN2 in
mouse neuronal cells resulted in decreased cellular growth compared to
controls, supporting a deleterious effect of loss of Erlin2 in patient
neurons.
*FIELD* RF
1. Al-Saif, A.; Bohlega, S.; Al-Mohanna, F.: Loss of ERLIN2 function
leads to juvenile primary lateral sclerosis. Ann. Neurol. 72: 510-516,
2012.
2. Al-Yahyaee, S.; Al-Gazali, L. I.; De Jonghe, P.; Al-Barwany, H.;
Al-Kindi, M.; De Vriendt, E.; Chand, P.; Koul, R.; Jacob, P. C.; Gururaj,
A.; Sztriha, L.; Parrado, A.; Van Broeckhoven, C.; Bayoumi, R. A.
: A novel locus for hereditary spastic paraplegia with thin corpus
callosum and epilepsy. Neurology 66: 1230-1234, 2006.
3. Alazami, A. M.; Adly, N.; Al Dhalaan, H.; Alkuraya, F. S.: A nullimorphic
ERLIN2 mutation defines a complicated hereditary spastic paraplegia
locus (SPG18). Neurogenetics 12: 333-336, 2011.
4. Schuurs-Hoeijmakers, J. H. M.; Geraghty, M. T.; Kamsteeg, E.-J.;
Ben-Salem, S.; de Bot, S. T.; Nijhof, B.; van de Vondervoort, I. I.
G. M.; van der Graaf, M.; Nobau, A. C.; Otte-Holler, I.; Vermeer,
S.; Smith, A. C.; and 29 others: Mutations in DDHD2, encoding an
intracellular phospholipase A(1), cause a recessive form of complex
hereditary spastic paraplegia. Am. J. Hum. Genet. 91: 1073-1081,
2012.
5. Yildirim, Y.; Orhan, E. K.; Iseri, S. A. U.; Serdaroglu-Oflazer,
P.; Kara, B.; Solakoglu, S.; Tolun, A.: A frameshift mutation of
ERLIN2 in recessive intellectual disability, motor dysfunction and
multiple joint contractures. Hum. Molec. Genet. 20: 1886-1892, 2011.
*FIELD* CS
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Eyes];
Squint
SKELETAL:
Contractures, progressive, severe;
[Feet];
Pes cavus
MUSCLE, SOFT TISSUE:
Lower limb muscle weakness
NEUROLOGIC:
[Central nervous system];
Delayed walking;
Abnormal gait;
Lower limb spasticity;
Upper limb spasticity, mild;
Extensor plantar responses;
Hyperreflexia;
Mental retardation (in most patients);
Seizures (in most patients)
MISCELLANEOUS:
Onset in infancy or childhood (range 1 to 6 years);
Slowly progressive;
Results in severe motor disability
MOLECULAR BASIS:
Caused by mutation in the endoplasmic reticulum lipid raft-associated
protein 2 gene (ERLIN2, 611605.0001)
*FIELD* CN
Cassandra L. Kniffin - updated: 1/24/2013
Cassandra L. Kniffin - updated: 1/3/2012
*FIELD* CD
Cassandra L. Kniffin: 7/19/2007
*FIELD* ED
joanna: 06/04/2013
ckniffin: 1/24/2013
joanna: 1/10/2012
ckniffin: 1/3/2012
ckniffin: 6/9/2009
*FIELD* CN
Cassandra L. Kniffin - updated: 1/6/2014
Cassandra L. Kniffin - updated: 1/24/2013
Cassandra L. Kniffin - updated: 1/3/2012
*FIELD* CD
Cassandra L. Kniffin: 7/19/2007
*FIELD* ED
carol: 01/06/2014
ckniffin: 1/6/2014
carol: 1/25/2013
ckniffin: 1/24/2013
joanna: 3/14/2012
carol: 1/3/2012
ckniffin: 1/3/2012
wwang: 6/9/2009
ckniffin: 6/9/2009
MIM
611605
*RECORD*
*FIELD* NO
611605
*FIELD* TI
*611605 ENDOPLASMIC RETICULUM LIPID RAFT-ASSOCIATED PROTEIN 2; ERLIN2
;;SPFH DOMAIN-CONTAINING PROTEIN 2; SPFH2;;
read moreCHROMOSOME 8 OPEN READING FRAME 2; C8ORF2
*FIELD* TX
CLONING
By genomic sequence analysis, followed by PCR and RACE of adult and
fetal cDNA libraries, Ikegawa et al. (1999) cloned 2 splice variants of
ERLIN2, which they designated C8ORF2. The deduced 339- and 152-amino
acid proteins share the first 141 N-terminal amino acids, then diverge.
Both proteins have an N-glycosylation site and type-2 membrane topology,
and the longer protein has a lysine- and glutamic acid-rich region.
Northern blot analysis detected ubiquitous expression of 1.6- and 2.5-kb
transcripts; a minor 4.4-kb transcript was also observed.
Using monoclonal antibodies to human lipid raft proteins, Browman et al.
(2006) identified ERLIN1 (611604) and ERLIN2 as components of lipid
rafts. Immunohistochemical analysis of endogenous and
fluorescence-tagged proteins revealed that ERLIN1 and ERLIN2 localized
specifically to the endoplasmic reticulum (ER) and nuclear envelope. The
2 proteins share 83% identity, and both contain a conserved prohibitin
(PHB; 176705) homology domain of about 160 amino acids.
GENE FUNCTION
The ER-associated degradation (ERAD) pathway removes aberrant proteins
and metabolically regulated native proteins from the ER. Pearce et al.
(2007) found that SPFH2 associated rapidly with activated IP3 receptors
(see IP3R1; 147265), which are substrates for the ERAD pathway, in
various mammalian cell lines. A proportion of SPFH2 associated with
several components of the ERAD pathway, and RNA interference-mediated
depletion of SPFH2 inhibited polyubiquitination and degradation of IP3R1
and turnover of model ERAD substrates. Pearce et al. (2007) concluded
that SPFH2 is a key ERAD pathway component that may act as a substrate
recognition factor.
GENE STRUCTURE
Ikegawa et al. (1999) determined that the ERLIN2 gene contains 16 exons
and spans more than 16.5 kb. The first 4 exons encode alternative
5-prime UTRs, exon 5 contains the initiating methionine, and exons 10
and 16 encode alternative 3-prime UTRs.
MAPPING
By genomic sequence analysis, Ikegawa et al. (1999) mapped the ERLIN2
gene to chromosome 8p11.2.
CYTOGENETICS
By autozygosity mapping followed by candidate gene sequencing in a
consanguineous Saudi family with complicated SPG18 (611225), Alazami et
al. (2011) identified a homozygous 20-kb deletion on chromosome 8, with
the distal breakpoint near physical position 37,694,857 (NCBI36) and the
proximal breakpoint near 37,714,575 immediately upstream of exon 2 of
the ERLIN2 gene. This 20-kb interval spans 2 protein-coding genes,
ERLIN2 and FLJ34378. RT-PCR analysis of patient lymphoblasts showed loss
of ERLIN2 transcription, consistent with a null allele. Alazami et al.
(2011) noted that ERLIN2 is involved in the endoplasmic
reticulum-associated degradation (ERAD) pathway, and postulated that
loss of ERLIN2 may result in persistent activation of IP3 signaling and
neuronal channel activity since ERAD normally degrades IP3 receptors.
Alazami et al. (2011) concluded that ERLIN2 depletion caused the
phenotype, although they could not exclude a role for FLJ34378.
MOLECULAR GENETICS
In affected members of a consanguineous Turkish family with autosomal
recessive spastic paraplegia-18 (SPG18; 611225), Yildirim et al. (2011)
identified a truncation mutation in the ERLIN2 gene (611605.0001) by
linkage analysis followed by candidate gene sequencing. The authors
termed the disorder 'intellectual disability, motor dysfunction, and
contractures (IDMDC).' Affected individuals presented between ages 6
months and 2 years with an arrest and regression of motor function. They
developed progressive severe contractures of all joints, resulting in
severe motor disability and a fixed position. All had severe
intellectual disability, and none could speak, read, or write. Features
suggestive of spasticity included hyperactive reflexes, ankle clonus,
and extensor plantar responses, but the neurologic examination was
difficult to perform in most. Electron microscopy of white blood cells
from 2 affected sibs showed large membrane-bound vacuoles containing
flocculent material in 7 to 10% of cells, and these vacuoles appeared to
be associated with the endoplasmic reticulum.
In 4 sibs, born of consanguineous Turkish parents, with a clinical
diagnosis of juvenile primary lateral sclerosis and features of
spasticity, Al-Saif et al. (2012) identified a homozygous splice site
mutation in the ERLIN2 gene (611605.0002). The mutation was found by
homozygosity mapping followed by candidate gene sequencing and
segregated with the disorder in the family. Analysis of patient cells
demonstrated that the mutation caused premature termination, decreased
levels of ERLIN2 mRNA (about 15% of controls), and that the mutant
transcript underwent nonsense-mediated mRNA decay, resulting in a loss
of function. Knockdown of ERLIN2 in mouse neuronal cells resulted in
decreased cellular growth compared to controls, supporting a deleterious
effect of loss of Erlin2 in patient neurons. The patients showed
difficulty in crawling and limb spasticity around 8 months of age. The
motor problems were progressive, and all patients were bedridden by age
15. Speech and articulation regressed after age 2 years, and the
patients were unable to communicate verbally. Other features included
kyphosis, scoliosis, joint contractures, and pseudobulbar palsy.
Features of spasticity included increased muscle tone with hyperreflexia
and extensor plantar responses. Seizures were not reported, and brain
MRI showed no significant abnormalities. The phenotype was similar to
that reported by Yildirim et al. (2011).
*FIELD* AV
.0001
SPASTIC PARAPLEGIA 18, AUTOSOMAL RECESSIVE
ERLIN2, 2-BP INS, 812AC
In affected members of a consanguineous Turkish family with autosomal
recessive intellectual disability, motor dysfunction, and contractures,
or spastic paraplegia-18 (SPG18; 611225), Yildirim et al. (2011)
identified a 2-bp insertion (812insAC) in exon 11 of the ERLIN2 gene,
resulting in a frameshift and premature termination in the
oligomerization domain. The protein was predicted to be truncated by
20%, but the mutant transcript did not appear to undergo
nonsense-mediated decay. The mutation was not found in 109 control
individuals.
.0002
SPASTIC PARAPLEGIA 18, AUTOSOMAL RECESSIVE
ERLIN2, IVS7AS, G-T, -1
In 4 sibs, born of consanguineous Turkish parents, with SPG18 (611225),
Al-Saif et al. (2012) identified a homozygous G-to-T transversion
(c.499-1G-T) in intron 7 of the ERLIN2 gene. The mutation was found by
homozygosity mapping followed by candidate gene sequencing and
segregated with the disorder in the family. It was found in 1 of 570
population-matched control alleles, consistent with a founder effect.
Analysis of patient cells demonstrated that the mutation caused
premature termination and a decrease in levels of ERLIN2 mRNA (about 15%
of controls), and that the mutant transcript underwent nonsense-mediated
mRNA decay, resulting in a loss of function. Knockdown of ERLIN2 in
mouse neuronal cells resulted in decreased cellular growth compared to
controls, supporting a deleterious effect of loss of Erlin2 in patient
neurons.
*FIELD* RF
1. Al-Saif, A.; Bohlega, S.; Al-Mohanna, F.: Loss of ERLIN2 function
leads to juvenile primary lateral sclerosis. Ann. Neurol. 72: 510-516,
2012.
2. Alazami, A. M.; Adly, N.; Al Dhalaan, H.; Alkuraya, F. S.: A nullimorphic
ERLIN2 mutation defines a complicated hereditary spastic paraplegia
locus (SPG18). Neurogenetics 12: 333-336, 2011.
3. Browman, D. T.; Resek, M. E.; Zajchowski, L. D.; Robbins, S. M.
: Erlin-1 and erlin-2 are novel members of the prohibitin family of
proteins that define lipid-raft-like domains of the ER. J. Cell Sci. 119:
3149-3160, 2006.
4. Ikegawa, S.; Isomura, M.; Koshizuka, Y.; Nakamura, Y.: Cloning
and characterization of a novel gene (C8orf2), a human representative
of a novel gene family with homology to C. elegans C42.C1.9. Cytogenet.
Cell Genet. 85: 227-231, 1999.
5. Pearce, M. M. P.; Wang, Y.; Kelley, G. G.; Wojcikiewicz, R. J.
H.: SPFH2 mediates the endoplasmic reticulum-associated degradation
of inositol 1,4,5-trisphosphate receptors and other substrates in
mammalian cells. J. Biol. Chem. 282: 20104-20115, 2007.
6. Yildirim, Y.; Orhan, E. K.; Iseri, S. A. U.; Serdaroglu-Oflazer,
P.; Kara, B.; Solakoglu, S.; Tolun, A.: A frameshift mutation of
ERLIN2 in recessive intellectual disability, motor dysfunction and
multiple joint contractures. Hum. Molec. Genet. 20: 1886-1892, 2011.
*FIELD* CN
Cassandra L. Kniffin - updated: 1/6/2014
Cassandra L. Kniffin - updated: 1/3/2012
*FIELD* CD
Patricia A. Hartz: 11/20/2007
*FIELD* ED
carol: 01/06/2014
ckniffin: 1/6/2014
carol: 9/12/2013
carol: 1/3/2012
ckniffin: 1/3/2012
mgross: 11/20/2007
*RECORD*
*FIELD* NO
611605
*FIELD* TI
*611605 ENDOPLASMIC RETICULUM LIPID RAFT-ASSOCIATED PROTEIN 2; ERLIN2
;;SPFH DOMAIN-CONTAINING PROTEIN 2; SPFH2;;
read moreCHROMOSOME 8 OPEN READING FRAME 2; C8ORF2
*FIELD* TX
CLONING
By genomic sequence analysis, followed by PCR and RACE of adult and
fetal cDNA libraries, Ikegawa et al. (1999) cloned 2 splice variants of
ERLIN2, which they designated C8ORF2. The deduced 339- and 152-amino
acid proteins share the first 141 N-terminal amino acids, then diverge.
Both proteins have an N-glycosylation site and type-2 membrane topology,
and the longer protein has a lysine- and glutamic acid-rich region.
Northern blot analysis detected ubiquitous expression of 1.6- and 2.5-kb
transcripts; a minor 4.4-kb transcript was also observed.
Using monoclonal antibodies to human lipid raft proteins, Browman et al.
(2006) identified ERLIN1 (611604) and ERLIN2 as components of lipid
rafts. Immunohistochemical analysis of endogenous and
fluorescence-tagged proteins revealed that ERLIN1 and ERLIN2 localized
specifically to the endoplasmic reticulum (ER) and nuclear envelope. The
2 proteins share 83% identity, and both contain a conserved prohibitin
(PHB; 176705) homology domain of about 160 amino acids.
GENE FUNCTION
The ER-associated degradation (ERAD) pathway removes aberrant proteins
and metabolically regulated native proteins from the ER. Pearce et al.
(2007) found that SPFH2 associated rapidly with activated IP3 receptors
(see IP3R1; 147265), which are substrates for the ERAD pathway, in
various mammalian cell lines. A proportion of SPFH2 associated with
several components of the ERAD pathway, and RNA interference-mediated
depletion of SPFH2 inhibited polyubiquitination and degradation of IP3R1
and turnover of model ERAD substrates. Pearce et al. (2007) concluded
that SPFH2 is a key ERAD pathway component that may act as a substrate
recognition factor.
GENE STRUCTURE
Ikegawa et al. (1999) determined that the ERLIN2 gene contains 16 exons
and spans more than 16.5 kb. The first 4 exons encode alternative
5-prime UTRs, exon 5 contains the initiating methionine, and exons 10
and 16 encode alternative 3-prime UTRs.
MAPPING
By genomic sequence analysis, Ikegawa et al. (1999) mapped the ERLIN2
gene to chromosome 8p11.2.
CYTOGENETICS
By autozygosity mapping followed by candidate gene sequencing in a
consanguineous Saudi family with complicated SPG18 (611225), Alazami et
al. (2011) identified a homozygous 20-kb deletion on chromosome 8, with
the distal breakpoint near physical position 37,694,857 (NCBI36) and the
proximal breakpoint near 37,714,575 immediately upstream of exon 2 of
the ERLIN2 gene. This 20-kb interval spans 2 protein-coding genes,
ERLIN2 and FLJ34378. RT-PCR analysis of patient lymphoblasts showed loss
of ERLIN2 transcription, consistent with a null allele. Alazami et al.
(2011) noted that ERLIN2 is involved in the endoplasmic
reticulum-associated degradation (ERAD) pathway, and postulated that
loss of ERLIN2 may result in persistent activation of IP3 signaling and
neuronal channel activity since ERAD normally degrades IP3 receptors.
Alazami et al. (2011) concluded that ERLIN2 depletion caused the
phenotype, although they could not exclude a role for FLJ34378.
MOLECULAR GENETICS
In affected members of a consanguineous Turkish family with autosomal
recessive spastic paraplegia-18 (SPG18; 611225), Yildirim et al. (2011)
identified a truncation mutation in the ERLIN2 gene (611605.0001) by
linkage analysis followed by candidate gene sequencing. The authors
termed the disorder 'intellectual disability, motor dysfunction, and
contractures (IDMDC).' Affected individuals presented between ages 6
months and 2 years with an arrest and regression of motor function. They
developed progressive severe contractures of all joints, resulting in
severe motor disability and a fixed position. All had severe
intellectual disability, and none could speak, read, or write. Features
suggestive of spasticity included hyperactive reflexes, ankle clonus,
and extensor plantar responses, but the neurologic examination was
difficult to perform in most. Electron microscopy of white blood cells
from 2 affected sibs showed large membrane-bound vacuoles containing
flocculent material in 7 to 10% of cells, and these vacuoles appeared to
be associated with the endoplasmic reticulum.
In 4 sibs, born of consanguineous Turkish parents, with a clinical
diagnosis of juvenile primary lateral sclerosis and features of
spasticity, Al-Saif et al. (2012) identified a homozygous splice site
mutation in the ERLIN2 gene (611605.0002). The mutation was found by
homozygosity mapping followed by candidate gene sequencing and
segregated with the disorder in the family. Analysis of patient cells
demonstrated that the mutation caused premature termination, decreased
levels of ERLIN2 mRNA (about 15% of controls), and that the mutant
transcript underwent nonsense-mediated mRNA decay, resulting in a loss
of function. Knockdown of ERLIN2 in mouse neuronal cells resulted in
decreased cellular growth compared to controls, supporting a deleterious
effect of loss of Erlin2 in patient neurons. The patients showed
difficulty in crawling and limb spasticity around 8 months of age. The
motor problems were progressive, and all patients were bedridden by age
15. Speech and articulation regressed after age 2 years, and the
patients were unable to communicate verbally. Other features included
kyphosis, scoliosis, joint contractures, and pseudobulbar palsy.
Features of spasticity included increased muscle tone with hyperreflexia
and extensor plantar responses. Seizures were not reported, and brain
MRI showed no significant abnormalities. The phenotype was similar to
that reported by Yildirim et al. (2011).
*FIELD* AV
.0001
SPASTIC PARAPLEGIA 18, AUTOSOMAL RECESSIVE
ERLIN2, 2-BP INS, 812AC
In affected members of a consanguineous Turkish family with autosomal
recessive intellectual disability, motor dysfunction, and contractures,
or spastic paraplegia-18 (SPG18; 611225), Yildirim et al. (2011)
identified a 2-bp insertion (812insAC) in exon 11 of the ERLIN2 gene,
resulting in a frameshift and premature termination in the
oligomerization domain. The protein was predicted to be truncated by
20%, but the mutant transcript did not appear to undergo
nonsense-mediated decay. The mutation was not found in 109 control
individuals.
.0002
SPASTIC PARAPLEGIA 18, AUTOSOMAL RECESSIVE
ERLIN2, IVS7AS, G-T, -1
In 4 sibs, born of consanguineous Turkish parents, with SPG18 (611225),
Al-Saif et al. (2012) identified a homozygous G-to-T transversion
(c.499-1G-T) in intron 7 of the ERLIN2 gene. The mutation was found by
homozygosity mapping followed by candidate gene sequencing and
segregated with the disorder in the family. It was found in 1 of 570
population-matched control alleles, consistent with a founder effect.
Analysis of patient cells demonstrated that the mutation caused
premature termination and a decrease in levels of ERLIN2 mRNA (about 15%
of controls), and that the mutant transcript underwent nonsense-mediated
mRNA decay, resulting in a loss of function. Knockdown of ERLIN2 in
mouse neuronal cells resulted in decreased cellular growth compared to
controls, supporting a deleterious effect of loss of Erlin2 in patient
neurons.
*FIELD* RF
1. Al-Saif, A.; Bohlega, S.; Al-Mohanna, F.: Loss of ERLIN2 function
leads to juvenile primary lateral sclerosis. Ann. Neurol. 72: 510-516,
2012.
2. Alazami, A. M.; Adly, N.; Al Dhalaan, H.; Alkuraya, F. S.: A nullimorphic
ERLIN2 mutation defines a complicated hereditary spastic paraplegia
locus (SPG18). Neurogenetics 12: 333-336, 2011.
3. Browman, D. T.; Resek, M. E.; Zajchowski, L. D.; Robbins, S. M.
: Erlin-1 and erlin-2 are novel members of the prohibitin family of
proteins that define lipid-raft-like domains of the ER. J. Cell Sci. 119:
3149-3160, 2006.
4. Ikegawa, S.; Isomura, M.; Koshizuka, Y.; Nakamura, Y.: Cloning
and characterization of a novel gene (C8orf2), a human representative
of a novel gene family with homology to C. elegans C42.C1.9. Cytogenet.
Cell Genet. 85: 227-231, 1999.
5. Pearce, M. M. P.; Wang, Y.; Kelley, G. G.; Wojcikiewicz, R. J.
H.: SPFH2 mediates the endoplasmic reticulum-associated degradation
of inositol 1,4,5-trisphosphate receptors and other substrates in
mammalian cells. J. Biol. Chem. 282: 20104-20115, 2007.
6. Yildirim, Y.; Orhan, E. K.; Iseri, S. A. U.; Serdaroglu-Oflazer,
P.; Kara, B.; Solakoglu, S.; Tolun, A.: A frameshift mutation of
ERLIN2 in recessive intellectual disability, motor dysfunction and
multiple joint contractures. Hum. Molec. Genet. 20: 1886-1892, 2011.
*FIELD* CN
Cassandra L. Kniffin - updated: 1/6/2014
Cassandra L. Kniffin - updated: 1/3/2012
*FIELD* CD
Patricia A. Hartz: 11/20/2007
*FIELD* ED
carol: 01/06/2014
ckniffin: 1/6/2014
carol: 9/12/2013
carol: 1/3/2012
ckniffin: 1/3/2012
mgross: 11/20/2007