RBCC Red Blood Cell Collection

EIF2B4 (EIF2BD) [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Translation initiation factor eIF-2B subunit delta (eIF-2B GDP-GTP exchange factor subunit delta)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt Q9UI10
ID EI2BD_HUMAN Reviewed; 523 AA.
AC Q9UI10; Q53RY7; Q5BJF4; Q9BUV9; Q9UBG4; Q9UIQ9; Q9UJ95;
DT 01-DEC-2000, integrated into UniProtKB/Swiss-Prot.
read moreDT 12-FEB-2003, sequence version 2.
DT 22-JAN-2014, entry version 119.
DE RecName: Full=Translation initiation factor eIF-2B subunit delta;
DE AltName: Full=eIF-2B GDP-GTP exchange factor subunit delta;
GN Name=EIF2B4; Synonyms=EIF2BD;
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 [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Adrenal gland;
RX PubMed=10931946; DOI=10.1073/pnas.160270997;
RA Hu R.-M., Han Z.-G., Song H.-D., Peng Y.-D., Huang Q.-H., Ren S.-X.,
RA Gu Y.-J., Huang C.-H., Li Y.-B., Jiang C.-L., Fu G., Zhang Q.-H.,
RA Gu B.-W., Dai M., Mao Y.-F., Gao G.-F., Rong R., Ye M., Zhou J.,
RA Xu S.-H., Gu J., Shi J.-X., Jin W.-R., Zhang C.-K., Wu T.-M.,
RA Huang G.-Y., Chen Z., Chen M.-D., Chen J.-L.;
RT "Gene expression profiling in the human hypothalamus-pituitary-adrenal
RT axis and full-length cDNA cloning.";
RL Proc. Natl. Acad. Sci. U.S.A. 97:9543-9548(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORMS 1; 2 AND 3).
RA Wightman P.J., Bonthron D.T.;
RT "cDNA cloning, genomic organization and chromosomal localization of
RT the human eIF2B delta subunit.";
RL Submitted (SEP-1998) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H.,
RA Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M.,
RA Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E.,
RA Kremitzki C., Oddy L., Du H., Sun H., Bradshaw-Cordum H., Ali J.,
RA Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C.,
RA Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J.,
RA Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A.,
RA Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K.,
RA Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M.,
RA Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N.,
RA Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M.,
RA Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E.,
RA Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P.,
RA Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A.,
RA Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A.,
RA Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T.,
RA Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D.,
RA Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X.,
RA McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D.,
RA Waterston R.H., Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2
RT and 4.";
RL Nature 434:724-731(2005).
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 1).
RC TISSUE=Lung, 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 IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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 [7]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-86, AND MASS
RP 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 [8]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-86, AND MASS
RP SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-86, 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 [11]
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 [12]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [13]
RP VARIANTS VWM VAL-228; GLN-357 AND CYS-374, AND VARIANT GLY-306.
RX PubMed=11835386; DOI=10.1002/ana.10112;
RA van der Knaap M.S., Leegwater P.A.J., Koenst A.A.M., Visser A.,
RA Naidu S., Oudejans C.B.M., Schutgens R.B.H., Pronk J.C.;
RT "Mutations in each of the five subunits of translation initiation
RT factor eIF2B can cause leukoencephalopathy with vanishing white
RT matter.";
RL Ann. Neurol. 51:264-270(2002).
RN [14]
RP VARIANTS VWM ARG-465 AND HIS-489.
RX PubMed=12707859; DOI=10.1086/375404;
RA Fogli A., Rodriguez D., Eymard-Pierre E., Bouhour F., Labauge P.,
RA Meaney B.F., Zeesman S., Kaneski C.R., Schiffmann R.,
RA Boespflug-Tanguy O.;
RT "Ovarian failure related to eukaryotic initiation factor 2B
RT mutations.";
RL Am. J. Hum. Genet. 72:1544-1550(2003).
RN [15]
RP VARIANTS VWM GLN-209; ARG-269 AND CYS-374.
RX PubMed=15776425; DOI=10.1002/humu.9325;
RA Ohlenbusch A., Henneke M., Brockmann K., Goerg M., Hanefeld F.,
RA Kohlschutter A., Gartner J.;
RT "Identification of ten novel mutations in patients with eIF2B-related
RT disorders.";
RL Hum. Mutat. 25:411-411(2005).
CC -!- FUNCTION: Catalyzes the exchange of eukaryotic initiation factor
CC 2-bound GDP for GTP.
CC -!- SUBUNIT: Complex of five different subunits; alpha, beta, gamma,
CC delta and epsilon.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=Q9UI10-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9UI10-2; Sequence=VSP_001433, VSP_040130;
CC Name=3;
CC IsoId=Q9UI10-3; Sequence=VSP_040130;
CC -!- DISEASE: Leukodystrophy with vanishing white matter (VWM)
CC [MIM:603896]: A leukodystrophy that occurs mainly in children.
CC Neurological signs include progressive cerebellar ataxia,
CC spasticity, inconstant optic atrophy and relatively preserved
CC mental abilities. The disease is chronic-progressive with, in most
CC individuals, additional episodes of rapid deterioration following
CC febrile infections or minor head trauma. While childhood onset is
CC the most common form of the disorder, some severe forms are
CC apparent at birth. A severe, early-onset form seen among the Cree
CC and Chippewayan populations of Quebec and Manitoba is called Cree
CC leukoencephalopathy. Milder forms may not become evident until
CC adolescence or adulthood. Some females with milder forms of the
CC disease who survive to adolescence exhibit ovarian dysfunction.
CC This variant of the disorder is called ovarioleukodystrophy.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- SIMILARITY: Belongs to the eIF-2B alpha/beta/delta subunits
CC family.
CC -!- SEQUENCE CAUTION:
CC Sequence=CAB57305.1; Type=Erroneous gene model prediction;
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/EIF2B4";
CC -!- WEB RESOURCE: Name=Mendelian genes eukaryotic translation
CC initiation factor 2B, subunit 4 delta, 67kDa (EIF2B4); Note=Leiden
CC Open Variation Database (LOVD);
CC URL="http://www.lovd.nl/EIF2B4";
CC -----------------------------------------------------------------------
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DR EMBL; AF112207; AAF17195.1; -; mRNA.
DR EMBL; AJ011305; CAB57260.1; -; mRNA.
DR EMBL; AJ011306; CAB57261.1; -; mRNA.
DR EMBL; AJ011307; CAB57304.1; -; Genomic_DNA.
DR EMBL; AJ011308; CAB57304.1; JOINED; Genomic_DNA.
DR EMBL; AJ011307; CAB57305.1; ALT_SEQ; Genomic_DNA.
DR EMBL; AJ011308; CAB57305.1; JOINED; Genomic_DNA.
DR EMBL; AC074117; AAY14843.1; -; Genomic_DNA.
DR EMBL; CH471053; EAX00591.1; -; Genomic_DNA.
DR EMBL; BC001870; AAH01870.1; -; mRNA.
DR EMBL; BC091502; AAH91502.1; -; mRNA.
DR RefSeq; NP_001029288.1; NM_001034116.1.
DR RefSeq; NP_056451.3; NM_015636.3.
DR RefSeq; NP_751945.2; NM_172195.3.
DR UniGene; Hs.169474; -.
DR ProteinModelPortal; Q9UI10; -.
DR SMR; Q9UI10; 219-517.
DR IntAct; Q9UI10; 6.
DR MINT; MINT-4990902; -.
DR STRING; 9606.ENSP00000394869; -.
DR PhosphoSite; Q9UI10; -.
DR DMDM; 28381357; -.
DR PaxDb; Q9UI10; -.
DR PRIDE; Q9UI10; -.
DR Ensembl; ENST00000347454; ENSP00000233552; ENSG00000115211.
DR Ensembl; ENST00000445933; ENSP00000394397; ENSG00000115211.
DR Ensembl; ENST00000451130; ENSP00000394869; ENSG00000115211.
DR GeneID; 8890; -.
DR KEGG; hsa:8890; -.
DR UCSC; uc002rka.3; human.
DR CTD; 8890; -.
DR GeneCards; GC02M027587; -.
DR HGNC; HGNC:3260; EIF2B4.
DR HPA; CAB032234; -.
DR MIM; 603896; phenotype.
DR MIM; 606687; gene.
DR neXtProt; NX_Q9UI10; -.
DR Orphanet; 99854; Cree leukoencephalopathy.
DR Orphanet; 157716; Late infantile CACH syndrome.
DR Orphanet; 99853; Ovarioleukodystrophy.
DR PharmGKB; PA27691; -.
DR eggNOG; COG1184; -.
DR HOGENOM; HOG000176924; -.
DR HOVERGEN; HBG051459; -.
DR InParanoid; Q9UI10; -.
DR KO; K03680; -.
DR OrthoDB; EOG7XSTF0; -.
DR Reactome; REACT_17015; Metabolism of proteins.
DR Reactome; REACT_71; Gene Expression.
DR GeneWiki; EIF2B4; -.
DR GenomeRNAi; 8890; -.
DR NextBio; 33383; -.
DR PRO; PR:Q9UI10; -.
DR ArrayExpress; Q9UI10; -.
DR Bgee; Q9UI10; -.
DR CleanEx; HS_EIF2B4; -.
DR Genevestigator; Q9UI10; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005851; C:eukaryotic translation initiation factor 2B complex; IDA:UniProtKB.
DR GO; GO:0003743; F:translation initiation factor activity; IEA:UniProtKB-KW.
DR GO; GO:0031369; F:translation initiation factor binding; ISS:UniProtKB.
DR GO; GO:0042552; P:myelination; IMP:UniProtKB.
DR GO; GO:0032057; P:negative regulation of translational initiation in response to stress; ISS:UniProtKB.
DR GO; GO:0014003; P:oligodendrocyte development; IMP:UniProtKB.
DR GO; GO:0001541; P:ovarian follicle development; IMP:UniProtKB.
DR GO; GO:0009749; P:response to glucose stimulus; ISS:UniProtKB.
DR GO; GO:0009408; P:response to heat; ISS:UniProtKB.
DR GO; GO:0043434; P:response to peptide hormone stimulus; ISS:UniProtKB.
DR GO; GO:0006413; P:translational initiation; IDA:UniProtKB.
DR InterPro; IPR000649; IF-2B-related.
DR Pfam; PF01008; IF-2B; 1.
PE 1: Evidence at protein level;
KW Acetylation; Alternative splicing; Complete proteome;
KW Disease mutation; Initiation factor; Leukodystrophy; Phosphoprotein;
KW Polymorphism; Protein biosynthesis; Reference proteome.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 523 Translation initiation factor eIF-2B
FT subunit delta.
FT /FTId=PRO_0000156067.
FT MOD_RES 2 2 N-acetylalanine.
FT MOD_RES 86 86 Phosphothreonine.
FT VAR_SEQ 1 10 MAAVAVAVRE -> MPTQQPAAPSTRAPKPSRSLSGSLCAL
FT FSDA (in isoform 2).
FT /FTId=VSP_001433.
FT VAR_SEQ 71 71 Missing (in isoform 2 and isoform 3).
FT /FTId=VSP_040130.
FT VARIANT 93 93 A -> V (in dbSNP:rs34155621).
FT /FTId=VAR_048918.
FT VARIANT 209 209 R -> Q (in VWM).
FT /FTId=VAR_068455.
FT VARIANT 228 228 A -> V (in VWM).
FT /FTId=VAR_015405.
FT VARIANT 269 269 L -> R (in VWM).
FT /FTId=VAR_068456.
FT VARIANT 306 306 R -> G (in dbSNP:rs78599355).
FT /FTId=VAR_015406.
FT VARIANT 357 357 R -> Q (in VWM).
FT /FTId=VAR_015407.
FT VARIANT 374 374 R -> C (in VWM).
FT /FTId=VAR_015408.
FT VARIANT 465 465 C -> R (in VWM; with ovarian failure).
FT /FTId=VAR_016843.
FT VARIANT 489 489 Y -> H (in VWM; with ovarian failure).
FT /FTId=VAR_016844.
FT CONFLICT 197 197 S -> T (in Ref. 2; CAB57260/CAB57261/
FT CAB57304/CAB57305).
FT CONFLICT 323 323 A -> S (in Ref. 1; AAF17195).
FT CONFLICT 481 481 S -> L (in Ref. 1; AAF17195).
SQ SEQUENCE 523 AA; 57557 MW; 5F38CF10CAD5A45E CRC64;
MAAVAVAVRE DSGSGMKAEL PPGPGAVGRE MTKEEKLQLR KEKKQQKKKR KEEKGAEPET
GSAVSAAQCQ VGPTRELPES GIQLGTPREK VPAGRSKAEL RAERRAKQEA ERALKQARKG
EQGGPPPKAS PSTAGETPSG VKRLPEYPQV DDLLLRRLVK KPERQQVPTR KDYGSKVSLF
SHLPQYSRQN SLTQFMSIPS SVIHPAMVRL GLQYSQGLVS GSNARCIALL RALQQVIQDY
TTPPNEELSR DLVNKLKPYM SFLTQCRPLS ASMHNAIKFL NKEITSVGSS KREEEAKSEL
RAAIDRYVQE KIVLAAQAIS RFAYQKISNG DVILVYGCSS LVSRILQEAW TEGRRFRVVV
VDSRPWLEGR HTLRSLVHAG VPASYLLIPA ASYVLPEVSK VLLGAHALLA NGSVMSRVGT
AQLALVARAH NVPVLVCCET YKFCERVQTD AFVSNELDDP DDLQCKRGEH VALANWQNHA
SLRLLNLVYD VTPPELVDLV ITELGMIPCS SVPVVLRVKS SDQ
//

MIM 603896
*RECORD*
*FIELD* NO
603896
*FIELD* TI
#603896 LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER; VWM
;;CHILDHOOD ATAXIA WITH CENTRAL NERVOUS SYSTEM HYPOMYELINIZATION; CACH;;
read moreVANISHING WHITE MATTER LEUKODYSTROPHY;;
CREE LEUKOENCEPHALOPATHY; CLE
VANISHING WHITE MATTER LEUKODYSTROPHY WITH OVARIAN FAILURE, INCLUDED;;
OVARIOLEUKODYSTROPHY, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because leukoencephalopathy
with vanishing white matter (VWM) can be caused by homozygous or
compound heterozygous mutation in any of the 5 genes encoding subunits
of the translation initiation factor EIF2B: EIF2B1 (606686) on
chromosome 12q24, EIF2B2 (606454) on chromosome 14q24, EIF2B3 (606273)
on chromosome 1p34, EIF2B4 (606687) on chromosome 2p23, or EIF2B5
(603945) on chromosome 3q27.

DESCRIPTION

Vanishing white matter leukodystrophy is an autosomal recessive
neurologic disorder characterized by variable neurologic features,
including progressive cerebellar ataxia, spasticity, and cognitive
impairment associated with white matter lesions on brain imaging. The
age at onset can range from early infancy to adulthood. Rapid neurologic
deterioration can occur following minor head trauma. Female mutation
carriers may develop ovarian failure, manifest as primary amenorrhea or
as secondary amenorrhea lasting more than 6 months, associated with
elevated gonadotropin levels at age less than 40 years (summary by Van
der Knaap et al., 1998 and Schiffmann et al., 1997).

CLINICAL FEATURES

Van der Knaap et al. (1997) identified 9 children with a 'new'
leukoencephalopathy with vanishing white matter. The 9 patients included
3 affected sib pairs; the age range was 3 to 19 years. The onset of the
disease was in childhood and the course was chronic, progressive, and
episodic. Episodes of deterioration followed infections and minor head
traumas, and these could result in unexplained coma. In 8 patients with
advanced disease, magnetic resonance imaging (MRI) revealed a diffuse
cerebral hemispheric leukoencephalopathy in which increasing areas of
the abnormal white matter had a signal intensity close to that of CSF on
all pulse sequences. In 1 patient in the early stages of disease,
initial MRI showed diffusely abnormal cerebral white matter which only
reached the signal characteristics of CSF at a later stage. In the
patients in whom the disease was advanced, magnetic resonance
spectroscopy (MRS) of the white matter showed an almost complete
disappearance of all normal signals and the presence of glucose and
lactate compatible with the presence of mainly CSF and little brain
tissue. Autopsy in 1 patient confirmed the presence of extensive cystic
degeneration of the cerebral white matter with reactive change and a
preserved cortex. The disease has an autosomal recessive mode of
inheritance. One of the 9 patients who was not part of an affected sib
pair had consanguineous parents.

Van der Knaap et al. (1998) reported on phenotypic variation in
leukoencephalopathy with vanishing white matter in 5 additional patients
who met the diagnostic criteria for the disorder except for the age at
onset. Four of the patients had onset in late childhood or adolescence,
and one was presymptomatic in his early twenties. The course of the
disease tended to be milder than in the patients with early childhood
onset. Van der Knaap et al. (1998) concluded that later onset does occur
in the disease of vanishing white matter and that both MRS and
histopathology are compatible with a primary axonopathy rather than
primary demyelination. Extensive metabolic investigation in these 5
patients and the 9 previously reported patients failed to determine an
underlying cause.

Schiffmann et al. (1994) described 4 unrelated girls with progressive
ataxic diplegia who had normal development until the ages of 1.5 to 5
years. A diffuse confluent abnormality of the white matter of the
central nervous system was present on computed tomography and magnetic
resonance scans obtained early in the course of the illness. Light and
electron microscopy of open-brain biopsy specimens from 2 girls showed
selective white matter abnormalities including hypomyelination,
demyelination, and gliosis. Myelin-specific proteins in the subcortical
white matter were of normal molecular size but were markedly reduced in
quantity in both patients compared to control subjects. Lipid analysis
revealed decreased levels of characteristic myelin lipids. When examined
by magnetic resonance spectroscopic imaging, all patients showed a
marked decrease of N-acetylaspartic acid, choline, and creatine in white
matter only. The authors concluded that the magnetic resonance
spectroscopic imaging profile was a unique diagnostic feature of this
group of patients.

Rodriguez et al. (1999) reported neuropathologic, biochemical, and
molecular studies of 2 patients, ages 6 and 10 years, who had died of
complications of childhood ataxia with diffuse central nervous system
hypomyelination. At autopsy, both had severe cavitating orthochromatic
leukodystrophy without atrophy, predominating in hemispheric white
matter. The severity of white matter lesions contrasted with the paucity
of myelin breakdown products and astroglial and microglial reactions.
Within the white matter, there was an increase in oligodendrocytes.
Myelin protein and lipid content were reduced. In 1 case, there was a
decreased amount of proteolipid protein (PLP1; 300401) demonstrated by
Western blot, but Southern blot analysis of the PLP1 gene, as well as
sequencing of the coding region of the PLP1 gene, were unremarkable.

Cree leukoencephalopathy, or CLE, is a rapidly fatal leukodystrophy
described first by Black et al. (1988) in the native Cree and
Chippewayan indigenous population of northern Quebec and Manitoba. The
onset of CLE is between 3 and 9 months of age, with death in 100% by 21
months of age. Hypotonia often is noted in early infancy followed by
relatively sudden onset of seizures, spasticity, hyperventilation,
vomiting, and diarrhea, often in a setting of a febrile illness. Onset
is followed by developmental regression, lethargy, blindness, and
cessation of head growth seen as flattening of the head circumference
curve. Computerized tomography of the head shows symmetrically hypodense
white matter. Gross neuropathologic examination has shown that white
matter is grayish white with translucent zones and subcortical
cavitation. Microscopic examination has shown diffuse white matter
vacuolation in some cases and astrogliosis with presence of
oligodendrocytes and cells described as lipid-laden macrophages
(Alorainy et al., 1999). Parents of affected children are normal, and
because of a high level of consanguinity in this population, CLE is
considered autosomal recessive. Fogli et al. (2002) investigated
microscopically 3 brains of CLE patients and found the same typical
foamy oligodendrocytes observed in patients with childhood ataxia with
diffuse central hypomyelination (CACH), also called myelinopathia
centralis diffusa or vanishing white matter disease (VWM).

Black et al. (1988) described an early-onset, progressive encephalopathy
in an inbred Canadian Aboriginal community. They termed this disorder
Cree encephalitis (225750) and distinguished it clinically from Cree
leukoencephalopathy.

Vermeulen et al. (2005) reported 2 unrelated patients with VWM disease,
confirmed by genetic analysis, who experienced episodes of rapid
neurologic decline after being frightened. At age 4 years, the first
patient witnessed his mother falling down the stairs. He lost
consciousness immediately after that and remained in a coma for 10 days.
He showed partial recovery afterwards, but permanently lost the ability
to walk. At age 18 years, he was severely handicapped, wheelchair-bound,
and unable to speak. The second patient was frightened by a dog at age 4
years. He had instantaneous neurologic decline with stupor and spastic
hemiparesis. Vermeulen et al. (2005) emphasized the rapid onset of
neurologic deterioration in these 2 cases compared to the neurologic
decline after infection, which usually occurs over the course of a few
days.

Federico et al. (2006) reported a Romanian boy who developed VWM disease
at age 3 years. He had spasticity, hypotonia, and distal muscle
weakness. In addition, he had a peripheral demyelinating neuropathy with
decreased sensory and motor nerve conduction velocities. Sural nerve
biopsy showed a moderate decrease in the myelinated fibers.

Passemard et al. (2007) reported 4 patients from 2 unrelated families
with early-onset VWM disease due to compound heterozygous mutations in
the EIF2B5 gene (603945.0009-603945.0011). In the first family, 2 sibs
had acute neurologic deterioration in infancy following viral
infections. Brain MRIs showed severe white matter abnormalities and
complete disappearance of hemispheric white matter, respectively. Both
developed progressive severe macrocephaly after age 3 years. In the
second family, 1 of 2 sisters who survived beyond age 3 years developed
macrocephaly. Passemard et al. (2007) suggested that altered brain water
balance may result in swelling of the diseased white matter and
macrocephaly in some patients with VWM disease.

- Adult-Onset

Biancheri et al. (2003) reported adult onset of VWM in a 27-year-old
woman, confirmed by mutation in the EIF2B5 gene (603945.0004). At the
age of 25 years, an MRI study was performed to evaluate the pituitary
gland because of elevated prolactin levels. A diffuse
leukoencephalopathy was depicted in the absence of any clinical
neurologic signs. Two years later, she developed progressive gait
abnormalities consistent with spastic paraparesis and speech
difficulties. A second MRI showed worsening of the white matter
abnormalities with some cystic degeneration. Biancheri et al. (2003)
emphasized the clinical variability of the disorder and the importance
of a high level of suspicion for VWM even in cases of adult onset.

Ohtake et al. (2004) reported a Japanese woman, born of consanguineous
parents, with adult-onset VWM caused by a homozygous mutation in the
EIF2B5 gene (603945.0008). The patient had been well until a traffic
accident at age 40 years, after which she became progressively
disorganized, forgetful, delusional, and emotionally unstable. By age 52
years, she had developed spastic gait, hyperreflexia, and frank dementia
with defective planning and confabulation. T2-weighted MRI showed
diffuse hyperintense lesions in the cerebral white matter, most
prominent in the frontal lobe. Other findings indicated focal
rarefaction and cystic degeneration of the white matter, consistent with
VWM. Ohtake et al. (2004) suggested that patients with adult-onset VWM
may present with presenile dementia or psychiatric symptoms.

Labauge et al. (2009) reviewed the phenotypes of 16 patients from 14
families with adult-onset VWM, defined as onset after age 16 years. The
mean age of onset was 31.1 years (range, 16 to 62 years), and there was
a decreased male:female ratio (3:13). Initial symptoms were neurologic
in 11 patients, psychiatric in 2, and ovarian failure in 2, and 1
patient was initially asymptomatic but diagnosed on brain MRI. Onset of
the symptoms was linked to a precipitating factor in 13% of cases,
including minor head trauma and delivery. Two (12.5%) patients died
during a mean follow-up period of 11.2 years after a stress-induced
deterioration. Of the 14 survivors, 62% showed a decline in their
cognitive functions, and 79% were severely handicapped or bedridden. One
individual remained asymptomatic. Stress worsened clinical symptoms in
38% of the patients. MRI findings included cerebral atrophy (75%),
extensive cystic cavitating leukoencephalopathy (81%), corpus callosum
(69%) and cerebellar (38%) T2-weighted hyperintensities. Thirteen of the
families had mutations in the EIF2B5 gene, including the common R113H
mutation (603945.0004), which was found in 11 (79%) of the 14 families.
The last family had a mutation in the EIF2B2 gene (E213G; 606454.0001).
Labauge et al. (2009) concluded that VWM may be underestimated as an
adult-onset inherited leukoencephalopathy.

- Ovarioleukodystrophy

Ovarian failure can be expressed as primary amenorrhea or as secondary
amenorrhea lasting more than 6 months, associated with elevated
gonadotropin levels at age less than 40 years. Schiffmann et al. (1997)
described 4 patients with the unusual association of ovarian failure
with white matter abnormalities observed on cerebral magnetic resonance
imaging (MRI), a condition they termed ovarioleukodystrophy.

Fogli et al. (2003) reported 8 patients from 7 families with
ovarioleukodystrophy. The cerebral abnormalities in patients with
ovarioleukodystrophy were similar to those in patients with vanishing
white matter leukodystrophy. The diagnosis of ovarian failure was
confirmed by findings of high basal gonadotropin levels and low estrogen
and progesterone levels. All the patients had a normal karyotype, and
only 1 patient had consanguineous parents. In 3 patients with primary
amenorrhea, school difficulties, together with poor fine motor
performance, were present prior to the development of a slowly
progressive neurologic disease in adolescence. Only 1 patient presented
with rapid cognitive decline, including a frontal lobe syndrome. The age
at menarche was normal in the 5 patients with secondary amenorrhea. The
age at onset of neurologic deterioration correlated positively with the
severity of ovarian dysfunction. In at least 1 case ovarian failure
preceded neurologic decline.

Fogli et al. (2003) noted that 2 indigenous North American populations,
the Cree and the Chippewa, have a particularly severe form of
leukodystrophy and are homozygous for an arg195-to-his (R195H;
603945.0005) mutation in the EIF2B5 gene. Patients with this severe
EIF2B mutation, as well as patients with the classical form of VWM, do
not survive to puberty and therefore do not express ovarian failure.
However, Fogli et al. (2003) pointed out that several reports had
suggested that ovarian dysgenesis may be present in these patients. Two
children with neuropathologic abnormalities suggestive of VWM were also
found at autopsy to have 'ovarian dysgenesis' (Boltshauser et al., 2002)
or 'bilateral streak ovaries' (van der Knaap et al., 1997). Furthermore,
Verghese et al. (2002) reported 2 sisters who presented with primary
amenorrhea and behavior problems at ages greater than 30 years, with
subsequent neurologic deterioration, white matter abnormalities detected
during cerebral MRI, and pigmentary orthochromatic leukodystrophy
observed at autopsy.

PATHOGENESIS

Tedeschi et al. (1995) studied a group of 6 patients (4 unrelated girls
and 2 brothers from 5 families) with CACH by proton magnetic resonance
spectroscopic imaging. Relative to controls, there was a decrease in the
signal intensity of N-acetylaspartate, choline, and creatine throughout
the white matter in all 6 patients. Tedeschi et al. (1995) identified
lactate signals in white matter in 3 of the children with advanced
disease. The degree of white matter involvement was not homogeneous over
the entire patient group, but did correlate with clinical presentation.
No abnormalities were detected in the gray matter. Tedeschi et al.
(1995) concluded that this syndrome is secondary to a metabolic defect
causing hypomyelination, axonal degeneration, and, in the most
compromised cases, accumulation of lactate.

Fogli et al. (2004) measured the guanine nucleotide exchange factor
(GEF) activity of EIF2B in transformed lymphocytes from 30 patients with
leukoencephalopathies with homozygous or compound heterozygous mutations
in EIF2B2, EIF2B3, EIF2B4, and EIF2B5 compared to 10 unaffected
heterozygotes and 22 controls with no EIF2B mutation. A significant
decrease of 20 to 70% in GEF activity was observed in all mutated cells,
and the extent of the decrease correlated with age at onset of disease.
Fogli et al. (2004) suggested that a deficiency in GEF activity
underlies the encephalopathy in EIF2B-related disease.

In cell cultures from the brain of an individual with VWM who had
compound heterozygosity for mutations in EIF2B5 (T91A, 603945.0001 and
W628R, 603945.0002), Dietrich et al. (2005) observed prompt development
of normal-appearing oligodendrocytes despite the extensive demyelination
seen in the patient. However, few glial fibrillary acidic protein (GFAP;
137780)-expressing astrocytes were present in primary cultures,
induction of astrocytes was severely compromised, and the few astrocytes
generated showed abnormal morphologies and antigenic phenotypes. Lesions
in vivo also lacked GFAP-expressing astrocytes, and RNA-interference
targeting of EIF2B5 severely compromised the induction of
GFAP-expressing cells from normal human glial progenitors. Dietrich et
al. (2005) suggested that a deficiency in astrocyte function may
contribute to the loss of white matter in VWM leukodystrophy.

DIAGNOSIS

Van der Knaap et al. (1998) proposed the following diagnostic criteria
for vanishing white matter: (1) initial motor and mental development is
normal or mildly delayed; (2) neurologic deterioration has a chronic
progressive and episodic course, and episodes of deterioration may
follow minor infection and minor head trauma and may lead to lethargy or
coma; (3) neurologic signs consist mainly of cerebellar ataxia and
spasticity; optic atrophy may develop, but is not obligatory; epilepsy
may occur, but is not the predominant sign of the disease; mental
abilities may also be affected, but not to the same degree as the motor
functions; and (4) MRI may indicate symmetric involvement of the
cerebral hemispheric white matter, and part or all of the white matter
has a signal intensity close to or the same as CSF on proton-density,
T2-weighted, T1-weighted, and FLAIR images, and cerebellar atrophy
varies from mild to severe and primarily involves the vermis. Magnetic
resonance spectroscopy can be used to obtain additional evidence for the
diagnosis. White matter spectra show a serious decrease or almost
complete disappearance of all normal signals and presence of some
lactate and glucose. The initial report of vanishing white matter
leukoencephalopathy was a report by Hanefeld et al. (1993) of 3 cases
with unique features on MRI and proton MRS.

MAPPING

Family data indicate that leukoencephalopathy with vanishing white
matter has an autosomal recessive inheritance with age-dependent
penetrance. Leegwater et al. (1999) performed a genomewide linkage
screening in 19 families with different ethnic origins. Significant
linkage to 3q27 was observed in a 7-cM interval between markers D3S3730
and D3S3592, with a maximum multipoint lod score of 5.1 calculated from
the entire data set. Genealogic studies had suggested that 7 parents in
4 Dutch families with VWM had inherited an allele for the disease from a
common ancestor who lived at least 8 generations ago. Analysis of these
families provided further evidence for the localization of the gene for
VWM to 3q27. The patients shared a haplotype spanning 5 cM between
markers D3S1618 and D3S3592. In 1 family of a different ethnic
background, the patient had, in the same region, homozygosity for 13
consecutive markers spanning at least 12 cM, suggesting consanguinity
between the parents. A healthy sib of this patient had the same
homozygous haplotype which suggested that the healthy sib was
presymptomatic for the disease. Because of ethical considerations,
Leegwater et al. (1999) could not evaluate the apparently healthy sib by
MRI and MRS. Both the patient and the asymptomatic sib were adults. Van
der Knaap et al. (1998) had described similar phenotypic variation in an
affected individual and in the individual's presymptomatic adult sib who
had MRI findings typical for VWM.

MOLECULAR GENETICS

By a genealogic study and haplotyping, Leegwater et al. (2001) showed
that single founder was involved for 12 people with VWM in 9 families.
This permitted narrowing of the location of the gene to a critical
region containing a total of 25 genes and STSs. One of these genes,
EIF2B5 (603945), contained 16 different mutations in 29 patients from 23
families. In addition, they found 2 distantly related individuals who
were homozygous for a missense mutation in EIF2B2 (606454), affecting a
conserved amino acid. Three other patients also had mutations in EIF2B2.
As eIF2B has an essential role in the regulation of translation under
different conditions, including stress, this may explain the rapid
deterioration in persons with VWM under stress. Mutant translation
initiation factors had not theretofore been implicated in disease.

Leegwater et al. (2001) and van der Knaap et al. (2002) showed that
leukoencephalopathy with vanishing white matter may be caused by
mutation in any of the 5 subunits of translation initiation factor
eIF2B.

Fogli et al. (2002) identified a homozygous missense mutation in the
EIF2B5 gene (R195H; 603945.0005) in 3 patients with CLE from 2 Cree
families. They speculated on the phenotypic differences between CLE and
CACH/VWM. A long presymptomatic phase, despite the presence of severe
white matter abnormalities on MRI, has been observed in CACH/VWM, in
contrast to the early onset and death by 21 months of age in all cases
of CLE. Basal ganglia and thalamic abnormalities described in CLE have
not been observed in CACH/VWM. Fogli et al. (2002) suggested that the
indigenous population of northern Quebec may have evolved an adaptation
to an extremely cold environment, rendering them particularly
susceptible to dysregulation of protective mechanisms that respond to
temperature elevation, such as eIF2B. They concluded that CLE may
represent the most severe observed form of eIF2-related disorders,
possibly because of an exaggerated response to heat stress induced by a
common infectious illness.

van der Knaap et al. (2003) analyzed the eIF2B genes in 9 patients with
an antenatal- or early infantile-onset encephalopathy and an early
demise. Mutations were found in 8 of the patients, with a total count of
7 different mutations: 2 in EIF2B2, 2 in EIF2B4, and 3 in EIF2B5. In
addition to signs of serious encephalopathy, they found oligohydramnios,
intrauterine growth retardation, cataracts, pancreatitis,
hepatosplenomegaly, hypoplasia of the kidneys, and ovarian dysgenesis.
Three of the patients were sisters; 2 other patients were brother and
sister. The consistently severe phenotype in affected sibs and in Cree
encephalopathy patients suggested an influence of the genotype on the
phenotype.

Among 11 unrelated Chinese patients with VWM disease, Wu et al. (2009)
found that 6 had mutations in the EIF2B5 gene and 5 had mutations in the
EIF2B3 gene. Four of the patients had the same novel mutation in EIF2B3
(I346T; 606273.0004). The phenotype was similar to that reported in
other populations.

- Ovarioleukodystrophy

Because of the similarity of cerebral abnormalities in patients with
ovarioleukodystrophy to those in patients with VWM, Fogli et al. (2003)
tested 8 patients with ovarioleukodystrophy for mutations in the 5 EIF2B
genes. In 7 of the patients, they identified mutations in the EIF2B2,
EIF2B4, and EIF2B5 genes, including 5 novel mutations. The only patient
without identified EIF2B mutations had a distinctive neurologic
presentation.

GENOTYPE/PHENOTYPE CORRELATIONS

Fogli et al. (2004) found that 68 (87%) of 78 families with MRI criteria
of leukodystrophy had a mutation in 4 of the EIF2B genes. Forty-two
families (62%) had a mutation in the EIF2B5 gene, and 71% had the
arg113-to-his mutation (R113H; 603945.0004). Thirteen families (19%), 10
families (15%), and 3 families (4%) had mutations in the EIF2B2, EIF2B4,
and EIF2B3 genes, respectively. No mutations were identified in the
EIF2B1 gene. Disease onset ranged from 4 months to 30 years of age, with
a mean of 3.9 years, and disease severity ranged from no neurologic
signs in 2 to death in 24 individuals; there was no correlation between
type of mutated gene and the age at onset or disease severity. However,
the EIF2B5 R113H mutation and the EIF2B2 glu213-to-gly mutation (E213G;
606454.0001) were significantly associated with milder phenotypes.

Van der Lei et al. (2010) identified mutations in the EIF2B5 gene in 126
(68%) of 184 patients from a large database of patients with VWM
disease. A subset of these patients were chosen for study, including 23
with a homozygous R113H mutation (603945.0004), 49 who had R113H in the
compound heterozygous state, 8 with a homozygous T91A mutation
(603945.0001), 9 with R113H/R339any, and 7 with T91A/R339any. Patients
homozygous for R113H had a milder disease than patients who were
compound heterozygous for R113H and patients homozygous for T91A.
Patients with R113H/R339any had a milder phenotype than patients with
T91A/R339any. Finally, females tended to have a milder disease than
males. Van der Lei et al. (2010) concluded that the clinical phenotype
in VWM is influenced by the combination of both mutations.

Matsukawa et al. (2011) reported 3 unrelated Japanese patients, each
born of consanguineous parents, with adult-onset VWM. Each carried a
homozygous mutation in the EIF2B2 (V85E; 606454.0006), EIF2B5 (D270H;
603945.0012), or EIF2B3 (L27Q; 606273.0005) gene, respectively. The 2
affected women also had evidence of ovarian failure. In vitro functional
expression studies showed that the GDP/GTP exchange activity of eIF2B
containing the mutant subunits was significantly decreased (20-40%
decrease) compared to wildtype, although the decrease was not as much as
observed in mutations associated with childhood-onset VWM. The findings
suggested that mutations that result in residual eIF2B activity may be
associated with a later age at disease onset.

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28. Verghese, J.; Weidenheim, K.; Malik, S.; Rapin, I.: Adult onset
pigmentary orthochromatic leukodystrophy with ovarian dysgenesis. Europ.
J. Neurol. 9: 663-670, 2002.

29. Vermeulen, G.; Seidl, R.; Mercimek-Mahmutoglu, S.; Rotteveel,
J. J.; Scheper, G. C.; van der Knapp, M. S.: Fright is a provoking
factor in vanishing white matter disease. Ann. Neurol. 57: 560-563,
2005.

30. Wu, Y.; Pan, Y.; Du, L.; Wang, J.; Gu, Q.; Gao, Z.; Li, J.; Leng,
X.; Qin, J.; Wu, X.; Jiang, Y.: Identification of novel EIF2B mutations
in Chinese patients with vanishing white matter disease. J. Hum.
Genet. 54: 74-77, 2009.

*FIELD* CS
INHERITANCE:
Autosomal recessive

HEAD AND NECK:
[Head];
Cessation of head growth in affected infants;
Macrocephaly may develop in those who survive past age 2 years;
[Eyes];
Optic atrophy;
Blindness may occur in affected infants

GENITOURINARY:
[Internal genitalia, female];
Ovarian failure, in a subset of affected patients (ovarioleukodystrophy);
Primary gonadal insufficiency

NEUROLOGIC:
[Central nervous system];
Deterioration of motor development;
Unsteady gait;
Loss of coordination;
Chronic-progressive course with episodes of rapid deterioration following
fever or head trauma;
Rapid, instantaneous neurologic decline may occur after fright;
Developmental regression in affected children;
Gait difficulties;
Hypotonia;
Lethargy;
Seizures;
Spasticity;
Mild mental decline;
Memory loss;
Cognitive deficits;
Dysarthria;
Leukoencephalopathy, severe;
Cavitating leukoencephalopathy;
Cystic degeneration of cerebral white matter with preserved cortex;
Over time, white matter vanishes and is replaced by CSF;
MRI shows symmetric, diffuse lesions with CSF-like signal intensity;
Biopsy shows white matter hypomyelination, demyelination, gliosis;
Biopsy shows foamy lipid-laden macrophages;
White matter rarefaction and cystic degeneration;
Decreased amount of myelin-specific proteins;
Decreased amount of myelin-specific lipids;
Magnetic resonance spectroscopy (MRS) shows decreased N-acetylaspartic
acid in unaffected white matter;
MRS shows decreased choline in affected white matter;
MRS shows decreased creatine in white matter;
[Behavioral/psychiatric manifestations];
Personality changes;
Delusions;
Indifference;
Emotional lability;
Psychiatric manifestations more common with adult-onset of disease

ENDOCRINE FEATURES:
Subset of patients with ovarioleukodystrophy have primary amenorrhea;
Secondary amenorrhea;
Increased serum gonadotropins;
Decreased serum estrogen;
Decreased serum progesterone

MISCELLANEOUS:
Onset usually in late infancy or childhood (1 to 6 years);
Onset may also occur in early infancy, adolescence, or adulthood;
Early death occurs in affected infants (days to months after disease
onset)

MOLECULAR BASIS:
Caused by mutation in the eukaryotic translation initiation factor
2B, subunit 1 gene (EIF2B1, 606686.0001);
Caused by mutation in the eukaryotic translation initiation factor
2B, subunit 2 gene (EIF2B2, 606454.0001);
Caused by mutation in the eukaryotic translation initiation factor
2B, subunit 3 gene (EIF2B3, 606273.0001);
Caused by mutation in the eukaryotic translation initiation factor
2B, subunit 4 gene (EIF2B4, 606687.0001);
Caused by mutation in the eukaryotic translation initiation factor
2B, subunit 5 gene (EIF2B5, 603945.0001)

*FIELD* CN
Cassandra L. Kniffin - updated: 1/31/2005

*FIELD* CD
Cassandra L. Kniffin: 5/19/2004

*FIELD* ED
ckniffin: 05/08/2013
ckniffin: 2/13/2013
ckniffin: 10/13/2009
ckniffin: 12/4/2007
ckniffin: 4/28/2005
joanna: 4/20/2005
ckniffin: 1/31/2005
joanna: 9/14/2004
ckniffin: 5/19/2004

*FIELD* CN
Cassandra L. Kniffin - updated: 2/13/2013
Cassandra L. Kniffin - updated: 11/13/2012
Cassandra L. Kniffin - updated: 3/15/2010
Cassandra L. Kniffin - updated: 6/26/2009
Cassandra L. Kniffin - updated: 12/4/2007
Cassandra L. Kniffin - updated: 7/30/2007
Cassandra L. Kniffin - updated: 4/28/2005
Marla J. F. O'Neill - updated: 3/28/2005
Marla J. F. O'Neill - updated: 2/11/2005
Cassandra L. Kniffin - updated: 1/31/2005
Victor A. McKusick - updated: 3/1/2004
Cassandra L. Kniffin - updated: 2/3/2004
Victor A. McKusick - updated: 12/12/2003
Victor A. McKusick - updated: 5/28/2003
Victor A. McKusick - updated: 11/19/2002
Victor A. McKusick - updated: 11/11/2002
Victor A. McKusick - updated: 11/12/2001
Ada Hamosh - updated: 2/11/2000
George E. Tiller - updated: 10/25/1999
Victor A. McKusick - updated: 9/20/1999

*FIELD* CD
Ada Hamosh: 6/11/1999

*FIELD* ED
ckniffin: 05/08/2013
carol: 3/4/2013
ckniffin: 2/13/2013
carol: 1/8/2013
carol: 11/28/2012
alopez: 11/19/2012
terry: 11/15/2012
ckniffin: 11/13/2012
terry: 3/22/2012
terry: 1/27/2012
wwang: 3/23/2010
ckniffin: 3/15/2010
wwang: 6/26/2009
ckniffin: 6/26/2009
wwang: 10/15/2008
wwang: 12/11/2007
ckniffin: 12/4/2007
wwang: 7/31/2007
ckniffin: 7/30/2007
carol: 8/18/2006
carol: 8/16/2006
terry: 8/16/2006
terry: 8/15/2006
ckniffin: 5/3/2006
wwang: 4/19/2006
ckniffin: 4/28/2005
wwang: 3/29/2005
wwang: 3/28/2005
wwang: 2/11/2005
tkritzer: 2/4/2005
ckniffin: 1/31/2005
ckniffin: 9/30/2004
tkritzer: 3/11/2004
terry: 3/1/2004
tkritzer: 2/24/2004
ckniffin: 2/3/2004
cwells: 12/18/2003
terry: 12/12/2003
mgross: 5/28/2003
tkritzer: 12/31/2002
mgross: 11/20/2002
terry: 11/19/2002
alopez: 11/12/2002
terry: 11/11/2002
ckniffin: 8/28/2002
alopez: 11/20/2001
alopez: 11/13/2001
terry: 11/12/2001
alopez: 2/18/2000
alopez: 2/15/2000
terry: 2/11/2000
alopez: 10/25/1999
carol: 9/30/1999
jlewis: 9/30/1999
terry: 9/20/1999
carol: 6/28/1999
carol: 6/25/1999

MIM 606687
*RECORD*
*FIELD* NO
606687
*FIELD* TI
*606687 EUKARYOTIC TRANSLATION INITIATION FACTOR 2B, SUBUNIT 4; EIF2B4
;;EUKARYOTIC TRANSLATION INITIATION FACTOR 2B, DELTA;;
read moreEIF2B-DELTA
*FIELD* TX
EIF2B is a GTP exchange factor that is essential for protein synthesis.
Its substrate is EIF2 (see 603907). EIF2B consists of alpha (EIF2B1;
606686), beta (EIF2B2; 606454), gamma (EIF2B3; 606273), delta, and
epsilon (EIF2B5; 603945) subunits.

CLONING

By screening human genomic and cDNA libraries, followed by probing mouse
cDNA libraries, Henderson et al. (1994) cloned cDNAs encoding 2 isoforms
of mouse Eif2b4, one containing 544 amino acids and the other containing
524 amino acids. The isoforms differ at their N termini. Henderson et
al. (1994) stated that the shorter isoform is present in rabbit and
human cells. Northern blot analysis revealed wide expression of a 1.9-kb
Eif2b4 transcript in mouse. Western blot analysis showed expression of
an approximately 60-kD protein, close to the predicted size. Price et
al. (1996) cloned a cDNA encoding rat Eif2b4. The 525-amino acid rat
protein is 96% identical to the 524-amino acid mouse isoform.

GENE FUNCTION

Fogli et al. (2004) measured the guanine nucleotide exchange factor
(GEF) activity of EIF2B in transformed lymphocytes from 30 patients with
leukoencephalopathies (603896) with homozygous or compound heterozygous
mutations in EIF2B2, EIF2B3, EIF2B4, and EIF2B5 compared to 10
unaffected heterozygotes and 22 controls with no EIF2B mutation. A
significant decrease of 20 to 70% in GEF activity was observed in all
mutated cells, and the extent of the decrease correlated with age at
onset of disease. Fogli et al. (2004) suggested that a deficiency in GEF
activity underlies the encephalopathy in EIF2B-related disease.

MAPPING

The International Radiation Hybrid Mapping Consortium mapped the EIF2B4
gene to chromosome 2 (TMAP WI-12589).

MOLECULAR GENETICS

Leukoencephalopathy with vanishing white matter (VWM; 603896) is an
autosomal recessive disorder characterized by a chronic progressive
course with additional episodes of rapid deterioration provoked by fever
and minor head trauma. Van der Knaap et al. (2002) demonstrated that
mutations in each of the 5 subunits of translation initiation factor
eIF2B can cause this disorder, including mutations in the EIF2B4 gene.

Fogli et al. (2003) identified mutations in the EIF2B2, EIF2B4, and
EIF2B5 genes in patients with VWM with ovarian failure, which they
referred to as ovarioleukodystrophy (603896).

*FIELD* AV
.0001
LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER
EIF2B4, ARG357GLN

In a patient with leukoencephalopathy with vanishing white matter
(603896), van der Knaap et al. (2002) found compound heterozygosity for
2 mutations in the EIF2B4 gene: an arg357 to gln (R357Q) mutation and an
arg374 to cys (R374C; 606687.0002) mutation, both in exon 11.

.0002
LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER
EIF2B4, ARG374CYS

See 606687.0001 and van der Knaap et al. (2002).

.0003
LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER
EIF2B4, IVS11, G-A, +1

In a patient with leukoencephalopathy with vanishing white matter
(603896), van der Knaap et al. (2002) found compound heterozygosity for
2 mutations in the EIF2B4 gene: a splice site mutation, IVS11+1G-A,
which resulted in the insertion of 11 amino acids following glu397; and
an ala228-to-val (A228V) mutation in exon 7 (606687.0004).

.0004
LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER
EIF2B4, ALA228VAL

See 606687.0003 and van der Knaap et al. (2002).

.0005
OVARIOLEUKODYSTROPHY
EIF2B4, CYS465ARG

In 2 sisters with ovarioleukodystrophy (603896), Fogli et al. (2003)
found compound heterozygosity for a C-to-T transition at nucleotide 1393
in the EIF2B4 gene, resulting in a cys465-to-arg (C465R) mutation, and a
C-to-T transition at nucleotide 1465, resulting in a tyr489-to-his
mutation (Y489H; 606687.0006). They were examined at 23 and 24 years of
age, respectively. Both had had difficulties in school. In both there
was spasticity of gait, gait instability having begun at ages 10 and 15
years, respectively, and 1 required the use of a walker at age 16 years.
Optic atrophy was present in both. Cognitive function was mildly to
moderately reduced.

.0006
OVARIOLEUKODYSTROPHY
EIF2B4, TYR489HIS

See 606687.0005 and Fogli et al. (2003).

*FIELD* RF
1. Fogli, A.; Rodriguez, D.; Eymard-Pierre, E.; Bouhour, F.; Labauge,
P.; Meaney, B. F.; Zeesman, S.; Kaneski, C. R.; Schiffmann, R.; Boespflug-Tanguy,
O.: Ovarian failure related to eukaryotic initiation factor 2B mutations. Am.
J. Hum. Genet. 72: 1544-1550, 2003.

2. Fogli, A.; Schiffmann, R.; Hugendubler, L.; Combes, P.; Bertini,
E.; Rodriguez, D.; Kimball, S. R.; Boespflug-Tanguy, O.: Decreased
guanine nucleotide exchange factor activity in eIF2B-mutated patients. Europ.
J. Hum. Genet. 12: 561-566, 2004.

3. Henderson, R. A.; Krissansen, G. W.; Yong, R. Y. Y.; Leung, E.;
Watson, J. D.; Dholakia, J. N.: The delta-subunit of murine guanine
nucleotide exchange factor eIF-2B: characterization of cDNAs predicts
isoforms differing at the amino-terminal end. J. Biol. Chem. 269:
30517-30523, 1994.

4. Price, N. T.; Mellor, H.; Craddock, B. L.; Flowers, K. M.; Kimball,
S. R.; Wilmer, T.; Jefferson, L. S.; Proud, C. G.: eIF2B, the guanine
nucleotide-exchange factor for eukaryotic initiation factor 2: sequence
conservation between the alpha, beta and delta subunits of eIF2B from
mammals and yeast. Biochem. J. 318: 637-643, 1996.

5. van der Knaap, M. S.; Leegwater, P. A. J.; Konst, A. A. M.; Visser,
A.; Naidu, S.; Oudejans, C. B. M.; Schutgens, R. B. H.; Pronk, J.
C.: Mutations in each of the five subunits of translation initiation
factor eIF2B can cause leukoencephalopathy with vanishing white matter. Ann.
Neurol. 51: 264-270, 2002.

*FIELD* CN
Marla J. F. O'Neill - updated: 02/11/2005
Victor A. McKusick - updated: 5/23/2003
Joanna S. Amberger - updated: 2/28/2003
Victor A. McKusick - updated: 11/11/2002

*FIELD* CD
Paul J. Converse: 2/12/2002

*FIELD* ED
wwang: 02/11/2005
wwang: 2/11/2005
cwells: 11/20/2003
mgross: 5/29/2003
terry: 5/23/2003
joanna: 2/28/2003
alopez: 11/12/2002
terry: 11/11/2002
mgross: 2/12/2002