RBCC Red Blood Cell Collection

RELN [Confidence: low (only semi-automatic identification from reviews)]
Reelin; 3.4.21.-; Flags: Precursor
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P78509
ID RELN_HUMAN Reviewed; 3460 AA.
AC P78509; A4D0P9; A4D0Q0; Q86UJ0; Q86UJ8; Q8NDV0; Q9UDQ2;
DT 27-MAR-2002, integrated into UniProtKB/Swiss-Prot.
read moreDT 18-MAY-2010, sequence version 3.
DT 22-JAN-2014, entry version 136.
DE RecName: Full=Reelin;
DE EC=3.4.21.-;
DE Flags: Precursor;
GN Name=RELN;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=9049633;
RA DeSilva U., D'Arcangelo G., Braden V.V., Chen J., Miao G.G.,
RA Curran T., Green E.D.;
RT "The human reelin gene: isolation, sequencing, and mapping on
RT chromosome 7.";
RL Genome Res. 7:157-164(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12853948; DOI=10.1038/nature01782;
RA Hillier L.W., Fulton R.S., Fulton L.A., Graves T.A., Pepin K.H.,
RA Wagner-McPherson C., Layman D., Maas J., Jaeger S., Walker R.,
RA Wylie K., Sekhon M., Becker M.C., O'Laughlin M.D., Schaller M.E.,
RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Cordes M., Du H.,
RA Sun H., Edwards J., Bradshaw-Cordum H., Ali J., Andrews S., Isak A.,
RA Vanbrunt A., Nguyen C., Du F., Lamar B., Courtney L., Kalicki J.,
RA Ozersky P., Bielicki L., Scott K., Holmes A., Harkins R., Harris A.,
RA Strong C.M., Hou S., Tomlinson C., Dauphin-Kohlberg S.,
RA Kozlowicz-Reilly A., Leonard S., Rohlfing T., Rock S.M.,
RA Tin-Wollam A.-M., Abbott A., Minx P., Maupin R., Strowmatt C.,
RA Latreille P., Miller N., Johnson D., Murray J., Woessner J.P.,
RA Wendl M.C., Yang S.-P., Schultz B.R., Wallis J.W., Spieth J.,
RA Bieri T.A., Nelson J.O., Berkowicz N., Wohldmann P.E., Cook L.L.,
RA Hickenbotham M.T., Eldred J., Williams D., Bedell J.A., Mardis E.R.,
RA Clifton S.W., Chissoe S.L., Marra M.A., Raymond C., Haugen E.,
RA Gillett W., Zhou Y., James R., Phelps K., Iadanoto S., Bubb K.,
RA Simms E., Levy R., Clendenning J., Kaul R., Kent W.J., Furey T.S.,
RA Baertsch R.A., Brent M.R., Keibler E., Flicek P., Bork P., Suyama M.,
RA Bailey J.A., Portnoy M.E., Torrents D., Chinwalla A.T., Gish W.R.,
RA Eddy S.R., McPherson J.D., Olson M.V., Eichler E.E., Green E.D.,
RA Waterston R.H., Wilson R.K.;
RT "The DNA sequence of human chromosome 7.";
RL Nature 424:157-164(2003).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12690205; DOI=10.1126/science.1083423;
RA Scherer S.W., Cheung J., MacDonald J.R., Osborne L.R., Nakabayashi K.,
RA Herbrick J.-A., Carson A.R., Parker-Katiraee L., Skaug J., Khaja R.,
RA Zhang J., Hudek A.K., Li M., Haddad M., Duggan G.E., Fernandez B.A.,
RA Kanematsu E., Gentles S., Christopoulos C.C., Choufani S.,
RA Kwasnicka D., Zheng X.H., Lai Z., Nusskern D.R., Zhang Q., Gu Z.,
RA Lu F., Zeesman S., Nowaczyk M.J., Teshima I., Chitayat D., Shuman C.,
RA Weksberg R., Zackai E.H., Grebe T.A., Cox S.R., Kirkpatrick S.J.,
RA Rahman N., Friedman J.M., Heng H.H.Q., Pelicci P.G., Lo-Coco F.,
RA Belloni E., Shaffer L.G., Pober B., Morton C.C., Gusella J.F.,
RA Bruns G.A.P., Korf B.R., Quade B.J., Ligon A.H., Ferguson H.,
RA Higgins A.W., Leach N.T., Herrick S.R., Lemyre E., Farra C.G.,
RA Kim H.-G., Summers A.M., Gripp K.W., Roberts W., Szatmari P.,
RA Winsor E.J.T., Grzeschik K.-H., Teebi A., Minassian B.A., Kere J.,
RA Armengol L., Pujana M.A., Estivill X., Wilson M.D., Koop B.F.,
RA Tosi S., Moore G.E., Boright A.P., Zlotorynski E., Kerem B.,
RA Kroisel P.M., Petek E., Oscier D.G., Mould S.J., Doehner H.,
RA Doehner K., Rommens J.M., Vincent J.B., Venter J.C., Li P.W.,
RA Mural R.J., Adams M.D., Tsui L.-C.;
RT "Human chromosome 7: DNA sequence and biology.";
RL Science 300:767-772(2003).
RN [4]
RP ALTERNATIVE SPLICING.
RX PubMed=10328932; DOI=10.1006/exnr.1999.7019;
RA Lambert de Rouvroit C., Bernier B., Royaux I., de Bergeyck V.,
RA Goffinet A.M.;
RT "Evolutionarily conserved, alternative splicing of reelin during brain
RT development.";
RL Exp. Neurol. 156:229-238(1999).
RN [5]
RP TISSUE SPECIFICITY.
RX PubMed=9861036; DOI=10.1073/pnas.95.26.15718;
RA Impagnatiello F., Guidotti A.R., Pesold C., Dwivedi Y., Caruncho H.,
RA Pisu M.G., Uzunov D.P., Smalheiser N.R., Davis J.M., Pandey G.N.,
RA Pappas G.D., Tueting P., Sharma R.P., Costa E.;
RT "A decrease of reelin expression as a putative vulnerability factor in
RT schizophrenia.";
RL Proc. Natl. Acad. Sci. U.S.A. 95:15718-15723(1998).
RN [6]
RP INVOLVEMENT IN LIS2.
RX PubMed=10973257; DOI=10.1038/79246;
RA Hong S.E., Shugart Y.Y., Huang D.T., Shahwan S.A., Grant P.E.,
RA Hourihane J.O.B., Martin N.D.T., Walsh C.A.;
RT "Autosomal recessive lissencephaly with cerebellar hypoplasia is
RT associated with human RELN mutations.";
RL Nat. Genet. 26:93-96(2000).
RN [7]
RP ERRATUM.
RA Hong S.E., Shugart Y.Y., Huang D.T., Shahwan S.A., Grant P.E.,
RA Hourihane J.O.B., Martin N.D.T., Walsh C.A.;
RL Nat. Genet. 27:225-225(2001).
RN [8]
RP POLYMORPHISM.
RX PubMed=11317216; DOI=10.1038/sj.mp.4000850;
RA Persico A.M., D'Agruma L., Maiorano N., Totaro A., Militerni R.,
RA Bravaccio C., Wassink T.H., Schneider C., Melmed R., Trillo S.,
RA Montecchi F., Palermo M., Pascucci T., Puglisi-Allegra S.,
RA Reichelt K.-L., Conciatori M., Marino R., Quattrocchi C.C., Baldi A.,
RA Zelante L., Gasparini P., Keller F.;
RT "Reelin gene alleles and haplotypes as a factor predisposing to
RT autistic disorder.";
RL Mol. Psychiatry 6:150-159(2001).
RN [9]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-305; ASN-1920 AND
RP ASN-3015, AND MASS SPECTROMETRY.
RC TISSUE=Liver;
RX PubMed=19159218; DOI=10.1021/pr8008012;
RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.;
RT "Glycoproteomics analysis of human liver tissue by combination of
RT multiple enzyme digestion and hydrazide chemistry.";
RL J. Proteome Res. 8:651-661(2009).
CC -!- FUNCTION: Extracellular matrix serine protease that plays a role
CC in layering of neurons in the cerebral cortex and cerebellum.
CC Regulates microtubule function in neurons and neuronal migration.
CC Affects migration of sympathetic preganglionic neurons in the
CC spinal cord, where it seems to act as a barrier to neuronal
CC migration. Enzymatic activity is important for the modulation of
CC cell adhesion. Binding to the extracellular domains of lipoprotein
CC receptors VLDLR and LRP8/APOER2 induces tyrosine phosphorylation
CC of DAB1 and modulation of TAU phosphorylation (By similarity).
CC -!- SUBUNIT: Oligomer of disulfide-linked homodimers. Binds to the
CC ectodomains of VLDLR and LRP8/APOER2 (By similarity).
CC -!- SUBCELLULAR LOCATION: Secreted, extracellular space, extracellular
CC matrix (By similarity).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=P78509-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P78509-2; Sequence=VSP_005575;
CC Name=3;
CC IsoId=P78509-3; Sequence=VSP_005576;
CC -!- TISSUE SPECIFICITY: Abundantly produced during brain ontogenesis
CC by the Cajal-Retzius cells and other pioneer neurons located in
CC the telencephalic marginal zone and by granule cells of the
CC external granular layer of the cerebellum. In adult brain,
CC preferentially expressed in GABAergic interneurons of prefrontal
CC cortices, temporal cortex, hippocampus and glutamatergic granule
CC cells of cerebellum. Expression is reduced to about 50% in
CC patients with schizophrenia. Also expressed in fetal and adult
CC liver.
CC -!- DEVELOPMENTAL STAGE: Expressed in fetal and postnatal brain and
CC liver. Expression in postnatal human brain is high in the
CC cerebellum.
CC -!- DOMAIN: The basic C-terminal region is essential for secretion (By
CC similarity).
CC -!- POLYMORPHISM: A polymorphic GGC triplet repeat located in the 5'-
CC UTR region of RELN gene, which harbors in the normal population 8
CC to 10 repeats, is significantly increased in autistic patients to
CC carry 4 to 23 additional repeats.
CC -!- DISEASE: Lissencephaly 2 (LIS2) [MIM:257320]: A classic type
CC lissencephaly associated with ataxia, mental retardation, seizures
CC and abnormalities of the cerebellum, hippocampus and brainstem.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- SIMILARITY: Belongs to the reelin family.
CC -!- SIMILARITY: Contains 16 BNR repeats.
CC -!- SIMILARITY: Contains 8 EGF-like domains.
CC -!- SIMILARITY: Contains 1 reelin domain.
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Reelin entry;
CC URL="http://en.wikipedia.org/wiki/Reelin";
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DR EMBL; U79716; AAC51105.1; -; mRNA.
DR EMBL; AC002067; AAM49151.1; -; Genomic_DNA.
DR EMBL; AC006981; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC073208; AAP22355.1; -; Genomic_DNA.
DR EMBL; AC005101; AAP22330.1; -; Genomic_DNA.
DR EMBL; AC000121; AAB46357.2; -; Genomic_DNA.
DR EMBL; AC006316; AAD29127.1; -; Genomic_DNA.
DR EMBL; AC005064; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH236947; EAL24410.1; -; Genomic_DNA.
DR EMBL; CH236947; EAL24411.1; -; Genomic_DNA.
DR RefSeq; NP_005036.2; NM_005045.3.
DR RefSeq; NP_774959.1; NM_173054.2.
DR UniGene; Hs.655654; -.
DR ProteinModelPortal; P78509; -.
DR SMR; P78509; 1293-1596, 1955-2661.
DR MINT; MINT-155986; -.
DR STRING; 9606.ENSP00000392423; -.
DR PhosphoSite; P78509; -.
DR DMDM; 296452988; -.
DR PaxDb; P78509; -.
DR PRIDE; P78509; -.
DR Ensembl; ENST00000343529; ENSP00000345694; ENSG00000189056.
DR Ensembl; ENST00000428762; ENSP00000392423; ENSG00000189056.
DR GeneID; 5649; -.
DR KEGG; hsa:5649; -.
DR UCSC; uc022ajq.1; human.
DR CTD; 5649; -.
DR GeneCards; GC07M103112; -.
DR H-InvDB; HIX0033998; -.
DR H-InvDB; HIX0201200; -.
DR HGNC; HGNC:9957; RELN.
DR HPA; CAB004556; -.
DR MIM; 257320; phenotype.
DR MIM; 600514; gene.
DR neXtProt; NX_P78509; -.
DR Orphanet; 89844; Lissencephaly syndrome, Norman-Roberts type.
DR PharmGKB; PA34323; -.
DR eggNOG; NOG45680; -.
DR HOVERGEN; HBG023117; -.
DR InParanoid; P78509; -.
DR KO; K06249; -.
DR OMA; NWFFYPG; -.
DR OrthoDB; EOG7P2XR4; -.
DR GeneWiki; Reelin; -.
DR GenomeRNAi; 5649; -.
DR NextBio; 21946; -.
DR PRO; PR:P78509; -.
DR ArrayExpress; P78509; -.
DR Bgee; P78509; -.
DR CleanEx; HS_RELN; -.
DR Genevestigator; P78509; -.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0030425; C:dendrite; ISS:UniProtKB.
DR GO; GO:0005615; C:extracellular space; ISS:UniProtKB.
DR GO; GO:0005578; C:proteinaceous extracellular matrix; IEA:UniProtKB-SubCell.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0004712; F:protein serine/threonine/tyrosine kinase activity; ISS:UniProtKB.
DR GO; GO:0008236; F:serine-type peptidase activity; IEA:UniProtKB-KW.
DR GO; GO:0070326; F:very-low-density lipoprotein particle receptor binding; ISS:BHF-UCL.
DR GO; GO:0008306; P:associative learning; IEA:Ensembl.
DR GO; GO:0007411; P:axon guidance; ISS:UniProtKB.
DR GO; GO:0007155; P:cell adhesion; IEA:UniProtKB-KW.
DR GO; GO:0021800; P:cerebral cortex tangential migration; ISS:UniProtKB.
DR GO; GO:0016358; P:dendrite development; IEA:Ensembl.
DR GO; GO:0010001; P:glial cell differentiation; ISS:UniProtKB.
DR GO; GO:0021766; P:hippocampus development; ISS:BHF-UCL.
DR GO; GO:0007616; P:long-term memory; IEA:Ensembl.
DR GO; GO:0097114; P:N-methyl-D-aspartate receptor clustering; IEA:Ensembl.
DR GO; GO:0001764; P:neuron migration; ISS:UniProtKB.
DR GO; GO:0018108; P:peptidyl-tyrosine phosphorylation; ISS:UniProtKB.
DR GO; GO:2000969; P:positive regulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate selective glutamate receptor activity; ISS:BHF-UCL.
DR GO; GO:0032793; P:positive regulation of CREB transcription factor activity; ISS:BHF-UCL.
DR GO; GO:0061003; P:positive regulation of dendritic spine morphogenesis; ISS:BHF-UCL.
DR GO; GO:2000463; P:positive regulation of excitatory postsynaptic membrane potential; ISS:BHF-UCL.
DR GO; GO:1900273; P:positive regulation of long-term synaptic potentiation; ISS:BHF-UCL.
DR GO; GO:0010976; P:positive regulation of neuron projection development; ISS:BHF-UCL.
DR GO; GO:0014068; P:positive regulation of phosphatidylinositol 3-kinase cascade; IEA:Ensembl.
DR GO; GO:0061098; P:positive regulation of protein tyrosine kinase activity; ISS:BHF-UCL.
DR GO; GO:0051057; P:positive regulation of small GTPase mediated signal transduction; ISS:UniProtKB.
DR GO; GO:0090129; P:positive regulation of synapse maturation; ISS:BHF-UCL.
DR GO; GO:0051968; P:positive regulation of synaptic transmission, glutamatergic; ISS:BHF-UCL.
DR GO; GO:0032008; P:positive regulation of TOR signaling cascade; IEA:Ensembl.
DR GO; GO:0097119; P:postsynaptic density protein 95 clustering; IEA:Ensembl.
DR GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW.
DR GO; GO:0097120; P:receptor localization to synapse; IEA:Ensembl.
DR GO; GO:0038026; P:reelin-mediated signaling pathway; ISS:BHF-UCL.
DR GO; GO:0050795; P:regulation of behavior; ISS:BHF-UCL.
DR GO; GO:2000310; P:regulation of N-methyl-D-aspartate selective glutamate receptor activity; ISS:BHF-UCL.
DR GO; GO:0048265; P:response to pain; ISS:UniProtKB.
DR GO; GO:0021511; P:spinal cord patterning; ISS:UniProtKB.
DR GO; GO:0021517; P:ventral spinal cord development; IEA:Ensembl.
DR Gene3D; 2.120.10.10; -; 2.
DR InterPro; IPR000742; EG-like_dom.
DR InterPro; IPR013032; EGF-like_CS.
DR InterPro; IPR002861; Reeler_dom.
DR InterPro; IPR011040; Sialidases.
DR Pfam; PF12661; hEGF; 2.
DR Pfam; PF02014; Reeler; 1.
DR SMART; SM00181; EGF; 5.
DR SUPFAM; SSF50939; SSF50939; 17.
DR PROSITE; PS00022; EGF_1; 7.
DR PROSITE; PS01186; EGF_2; 6.
DR PROSITE; PS50026; EGF_3; 5.
DR PROSITE; PS51019; REELIN; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Calcium; Cell adhesion; Complete proteome;
KW Developmental protein; Disulfide bond; EGF-like domain;
KW Extracellular matrix; Glycoprotein; Hydrolase; Lissencephaly;
KW Metal-binding; Polymorphism; Protease; Reference proteome; Repeat;
KW Secreted; Serine protease; Signal; Zinc.
FT SIGNAL 1 25 Potential.
FT CHAIN 26 3460 Reelin.
FT /FTId=PRO_0000030304.
FT DOMAIN 26 190 Reelin.
FT REPEAT 592 603 BNR 1.
FT DOMAIN 670 701 EGF-like 1.
FT REPEAT 798 809 BNR 2.
FT REPEAT 951 962 BNR 3.
FT DOMAIN 1029 1060 EGF-like 2.
FT REPEAT 1156 1167 BNR 4.
FT REPEAT 1322 1333 BNR 5.
FT DOMAIN 1408 1441 EGF-like 3.
FT REPEAT 1534 1545 BNR 6.
FT REPEAT 1685 1696 BNR 7.
FT DOMAIN 1764 1795 EGF-like 4.
FT REPEAT 1883 1894 BNR 8.
FT REPEAT 2042 2053 BNR 9.
FT DOMAIN 2128 2160 EGF-like 5.
FT REPEAT 2249 2260 BNR 10.
FT REPEAT 2398 2409 BNR 11.
FT DOMAIN 2477 2508 EGF-like 6.
FT REPEAT 2597 2608 BNR 12.
FT REPEAT 2777 2788 BNR 13.
FT DOMAIN 2852 2883 EGF-like 7.
FT REPEAT 2978 2989 BNR 14.
FT REPEAT 3142 3154 BNR 15.
FT DOMAIN 3227 3259 EGF-like 8.
FT REPEAT 3362 3373 BNR 16.
FT COMPBIAS 3431 3460 Arg-rich (basic).
FT METAL 2060 2060 Zinc 1 (By similarity).
FT METAL 2073 2073 Zinc 1 (By similarity).
FT METAL 2178 2178 Zinc 1 (By similarity).
FT METAL 2263 2263 Zinc 1 (By similarity).
FT METAL 2396 2396 Zinc 2 (By similarity).
FT METAL 2398 2398 Zinc 2 (By similarity).
FT METAL 2459 2459 Zinc 2 (By similarity).
FT CARBOHYD 140 140 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 257 257 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 289 289 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 305 305 N-linked (GlcNAc...).
FT CARBOHYD 628 628 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 1266 1266 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 1599 1599 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 1749 1749 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 1920 1920 N-linked (GlcNAc...).
FT CARBOHYD 2144 2144 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 2268 2268 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 2316 2316 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 2568 2568 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 2961 2961 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 3015 3015 N-linked (GlcNAc...).
FT CARBOHYD 3072 3072 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 3184 3184 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 3411 3411 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 3438 3438 N-linked (GlcNAc...) (Potential).
FT DISULFID 40 126 By similarity.
FT DISULFID 154 178 By similarity.
FT DISULFID 539 580 By similarity.
FT DISULFID 608 613 By similarity.
FT DISULFID 674 684 By similarity.
FT DISULFID 691 700 By similarity.
FT DISULFID 894 936 By similarity.
FT DISULFID 967 974 By similarity.
FT DISULFID 1033 1043 By similarity.
FT DISULFID 1050 1059 By similarity.
FT DISULFID 1270 1309 By similarity.
FT DISULFID 1338 1347 By similarity.
FT DISULFID 1632 1672 By similarity.
FT DISULFID 1701 1708 By similarity.
FT DISULFID 2100 2100 Interchain (By similarity).
FT DISULFID 2132 2142 By similarity.
FT DISULFID 2136 2148 By similarity.
FT DISULFID 2150 2159 By similarity.
FT DISULFID 2194 2234 By similarity.
FT DISULFID 2347 2386 By similarity.
FT DISULFID 2392 2558 By similarity.
FT DISULFID 2543 2583 By similarity.
FT DISULFID 2793 2800 By similarity.
FT DISULFID 2856 2866 By similarity.
FT DISULFID 2860 2871 By similarity.
FT DISULFID 2873 2882 By similarity.
FT DISULFID 2918 2965 By similarity.
FT DISULFID 3159 3169 By similarity.
FT DISULFID 3231 3241 By similarity.
FT DISULFID 3235 3247 By similarity.
FT DISULFID 3249 3258 By similarity.
FT DISULFID 3295 3345 By similarity.
FT VAR_SEQ 3428 3460 Missing (in isoform 3).
FT /FTId=VSP_005576.
FT VAR_SEQ 3428 3429 Missing (in isoform 2).
FT /FTId=VSP_005575.
FT VARIANT 978 978 T -> A (in dbSNP:rs3025962).
FT /FTId=VAR_047977.
FT VARIANT 997 997 L -> V (in dbSNP:rs362691).
FT /FTId=VAR_047978.
FT VARIANT 1703 1703 P -> R (in dbSNP:rs2229860).
FT /FTId=VAR_057712.
FT CONFLICT 752 752 D -> E (in Ref. 1; AAC51105).
SQ SEQUENCE 3460 AA; 388388 MW; 9A398EC17FA4EE1B CRC64;
MERSGWARQT FLLALLLGAT LRARAAAGYY PRFSPFFFLC THHGELEGDG EQGEVLISLH
IAGNPTYYVP GQEYHVTIST STFFDGLLVT GLYTSTSVQA SQSIGGSSAF GFGIMSDHQF
GNQFMCSVVA SHVSHLPTTN LSFIWIAPPA GTGCVNFMAT ATHRGQVIFK DALAQQLCEQ
GAPTDVTVHP HLAEIHSDSI ILRDDFDSYH QLQLNPNIWV ECNNCETGEQ CGAIMHGNAV
TFCEPYGPRE LITTGLNTTT ASVLQFSIGS GSCRFSYSDP SIIVLYAKNN SADWIQLEKI
RAPSNVSTII HILYLPEDAK GENVQFQWKQ ENLRVGEVYE ACWALDNILI INSAHRQVVL
EDSLDPVDTG NWLFFPGATV KHSCQSDGNS IYFHGNEGSE FNFATTRDVD LSTEDIQEQW
SEEFESQPTG WDVLGAVIGT ECGTIESGLS MVFLKDGERK LCTPSMDTTG YGNLRFYFVM
GGICDPGNSH ENDIILYAKI EGRKEHITLD TLSYSSYKVP SLVSVVINPE LQTPATKFCL
RQKNHQGHNR NVWAVDFFHV LPVLPSTMSH MIQFSINLGC GTHQPGNSVS LEFSTNHGRS
WSLLHTECLP EICAGPHLPH STVYSSENYS GWNRITIPLP NAALTRNTRI RWRQTGPILG
NMWAIDNVYI GPSCLKFCSG RGQCTRHGCK CDPGFSGPAC EMASQTFPMF ISESFGSSRL
SSYHNFYSIR GAEVSFGCGV LASGKALVFN KDGRRQLITS FLDSSQSRFL QFTLRLGSKS
VLSTCRAPDQ PGEGVLLHYS YDNGITWKLL EHYSYLSYHE PRIISVELPG DAKQFGIQFR
WWQPYHSSQR EDVWAIDEII MTSVLFNSIS LDFTNLVEVT QSLGFYLGNV QPYCGHDWTL
CFTGDSKLAS SMRYVETQSM QIGASYMIQF SLVMGCGQKY TPHMDNQVKL EYSTNHGLTW
HLVQEECLPS MPSCQEFTSA SIYHASEFTQ WRRVIVLLPQ KTWSSATRFR WSQSYYTAQD
EWALDSIYIG QQCPNMCSGH GSCDHGICRC DQGYQGTECH PEAALPSTIM SDFENQNGWE
SDWQEVIGGE IVKPEQGCGV ISSGSSLYFS KAGKRQLVSW DLDTSWVDFV QFYIQIGGES
ASCNKPDSRE EGVLLQYSNN GGIQWHLLAE MYFSDFSKPR FVYLELPAAA KTPCTRFRWW
QPVFSGEDYD QWAVDDIIIL SEKQKQIIPV INPTLPQNFY EKPAFDYPMN QMSVWLMLAN
EGMVKNETFC AATPSAMIFG KSDGDRFAVT RDLTLKPGYV LQFKLNIGCA NQFSSTAPVL
LQYSHDAGMS WFLVKEGCYP ASAGKGCEGN SRELSEPTMY HTGDFEEWTR ITIVIPRSLA
SSKTRFRWIQ ESSSQKNVPP FGLDGVYISE PCPSYCSGHG DCISGVCFCD LGYTAAQGTC
VSNVPNHNEM FDRFEGKLSP LWYKITGAQV GTGCGTLNDG KSLYFNGPGK REARTVPLDT
RNIRLVQFYI QIGSKTSGIT CIKPRTRNEG LIVQYSNDNG ILWHLLRELD FMSFLEPQII
SIDLPQDAKT PATAFRWWQP QHGKHSAQWA LDDVLIGMND SSQTGFQDKF DGSIDLQANW
YRIQGGQVDI DCLSMDTALI FTENIGKPRY AETWDFHVSA STFLQFEMSM GCSKPFSNSH
SVQLQYSLNN GKDWHLVTEE CVPPTIGCLH YTESSIYTSE RFQNWKRITV YLPLSTISPR
TRFRWIQANY TVGADSWAID NVVLASGCPW MCSGRGICDA GRCVCDRGFG GPYCVPVVPL
PSILKDDFNG NLHPDLWPEV YGAERGNLNG ETIKSGTSLI FKGEGLRMLI SRDLDCTNTM
YVQFSLRFIA KSTPERSHSI LLQFSISGGI TWHLMDEFYF PQTTNILFIN VPLPYTAQTN
ATRFRLWQPY NNGKKEEIWI VDDFIIDGNN VNNPVMLLDT FDFGPREDNW FFYPGGNIGL
YCPYSSKGAP EEDSAMVFVS NEVGEHSITT RDLNVNENTI IQFEINVGCS TDSSSADPVR
LEFSRDFGAT WHLLLPLCYH SSSHVSSLCS TEHHPSSTYY AGTMQGWRRE VVHFGKLHLC
GSVRFRWYQG FYPAGSQPVT WAIDNVYIGP QCEEMCNGQG SCINGTKCIC DPGYSGPTCK
ISTKNPDFLK DDFEGQLESD RFLLMSGGKP SRKCGILSSG NNLFFNEDGL RMLMTRDLDL
SHARFVQFFM RLGCGKGVPD PRSQPVLLQY SLNGGLSWSL LQEFLFSNSS NVGRYIALEI
PLKARSGSTR LRWWQPSENG HFYSPWVIDQ ILIGGNISGN TVLEDDFTTL DSRKWLLHPG
GTKMPVCGST GDALVFIEKA STRYVVSTDV AVNEDSFLQI DFAASCSVTD SCYAIELEYS
VDLGLSWHPL VRDCLPTNVE CSRYHLQRIL VSDTFNKWTR ITLPLPPYTR SQATRFRWHQ
PAPFDKQQTW AIDNVYIGDG CIDMCSGHGR CIQGNCVCDE QWGGLYCDDP ETSLPTQLKD
NFNRAPSSQN WLTVNGGKLS TVCGAVASGM ALHFSGGCSR LLVTVDLNLT NAEFIQFYFM
YGCLITPNNR NQGVLLEYSV NGGITWNLLM EIFYDQYSKP GFVNILLPPD AKEIATRFRW
WQPRHDGLDQ NDWAIDNVLI SGSADQRTVM LDTFSSAPVP QHERSPADAG PVGRIAFDMF
MEDKTSVNEH WLFHDDCTVE RFCDSPDGVM LCGSHDGREV YAVTHDLTPT EGWIMQFKIS
VGCKVSEKIA QNQIHVQYST DFGVSWNYLV PQCLPADPKC SGSVSQPSVF FPTKGWKRIT
YPLPESLVGN PVRFRFYQKY SDMQWAIDNF YLGPGCLDNC RGHGDCLREQ CICDPGYSGP
NCYLTHTLKT FLKERFDSEE IKPDLWMSLE GGSTCTECGI LAEDTALYFG GSTVRQAVTQ
DLDLRGAKFL QYWGRIGSEN NMTSCHRPIC RKEGVLLDYS TDGGITWTLL HEMDYQKYIS
VRHDYILLPE DALTNTTRLR WWQPFVISNG IVVSGVERAQ WALDNILIGG AEINPSQLVD
TFDDEGTSHE ENWSFYPNAV RTAGFCGNPS FHLYWPNKKK DKTHNALSSR ELIIQPGYMM
QFKIVVGCEA TSCGDLHSVM LEYTKDARSD SWQLVQTQCL PSSSNSIGCS PFQFHEATIY
NSVNSSSWKR ITIQLPDHVS SSATQFRWIQ KGEETEKQSW AIDHVYIGEA CPKLCSGHGY
CTTGAICICD ESFQGDDCSV FSHDLPSYIK DNFESARVTE ANWETIQGGV IGSGCGQLAP
YAHGDSLYFN GCQIRQAATK PLDLTRASKI MFVLQIGSMS QTDSCNSDLS GPHAVDKAVL
LQYSVNNGIT WHVIAQHQPK DFTQAQRVSY NVPLEARMKG VLLRWWQPRH NGTGHDQWAL
DHVEVVLVST RKQNYMMNFS RQHGLRHFYN RRRRSLRRYP
//

MIM 257320
*RECORD*
*FIELD* NO
257320
*FIELD* TI
#257320 LISSENCEPHALY 2; LIS2
;;LISSENCEPHALY SYNDROME, NORMAN-ROBERTS TYPE;;
NORMAN-ROBERTS SYNDROME
read more*FIELD* TX
A number sign (#) is used with this entry because of evidence that
lissencephaly-2 can be caused by homozygous mutation in the gene
encoding reelin (RELN; 600514) on chromosome 7q22.

For a general phenotypic description and a discussion of genetic
heterogeneity of lissencephaly, see LIS1 (607432).

CLINICAL FEATURES

Dobyns et al. (1984) suggested the designation Norman-Roberts syndrome
for a disorder which, like the Miller-Dieker syndrome (247200), is
associated with type I lissencephaly but has distinctive associated
features. (Type I lissencephaly is characterized by microcephaly and a
thickened cortex with 4 rather than 6 layers.) This disorder, first
reported by Norman et al. (1976), shows a low sloping forehead and a
prominent nasal bridge, features not seen in the Miller-Dieker syndrome.
Furthermore, chromosomes are normal whereas in the latter syndrome an
abnormality of 17p13 has been found. Dobyns et al. (1984) published
photographs demonstrating the craniofacial features of the
Norman-Roberts syndrome. Multiple affected sibs and parental
consanguinity have been observed.

Iannetti et al. (1993) described a 7-year-old boy with microcephaly,
bitemporal hollowing, low sloping forehead, slightly prominent occiput,
widely set eyes, broad and prominent nasal bridge, and severe postnatal
growth deficiency. Neurologic features included hypertonia,
hyperreflexia, seizures, and profound mental retardation. Brain MRI
showed changes consistent with lissencephaly type I, grade 2. Molecular
studies did not demonstrate deletion in the Miller-Dieker/isolated
lissencephaly critical region on 17p.

Hong et al. (2000) studied an autosomal recessive form of lissencephaly
associated with severe abnormalities of the cerebellum, hippocampus, and
brainstem in 2 consanguineous pedigrees. The first consisted of British
parents related as half first cousins (Hourihane et al., 1993). At birth
the 3 affected children showed normal head size, congenital lymphedema,
and hypotonia. Brain magnetic resonance imaging showed moderate
lissencephaly and profound cerebellar hypoplasia. Cognitive development
was delayed, with little or no language and no ability to sit or stand
unsupported. There was also myopia, nystagmus, and generalized seizures
that could be controlled with medication. A second pedigree from Saudi
Arabia consisted of first-cousin parents, with 3 affected offspring. The
affected children showed severe delay in neurologic and cognitive
development, hypotonia, and epilepsy.

Caksen et al. (2004) described 2 Turkish infants with Norman-Roberts
syndrome. Both patients had typical craniofacial abnormalities and
abnormal magnetic resonance imaging findings, but no deletion in
17p13.3, typical of Miller-Dieker syndrome.

CYTOGENETICS

Zaki et al. (2007) reported 2 sibs from a consanguineous Egyptian
marriage who had cortical lissencephaly with cerebellar hypoplasia,
severe epilepsy, and mental retardation. Karyotype analysis identified a
homozygous, apparently balanced reciprocal translocation,
t(7;12)(q22;p13), in both children. Further analysis confirmed a
disruption of the RELN gene at 7q22.1 and undetectable levels of the
protein in the children. The unaffected parents were related as double
first cousins and were heterozygous for the translocation.

MAPPING

In 2 consanguineous pedigrees segregating an autosomal recessive form of
lissencephaly associated with severe abnormalities of the cerebellum,
hippocampus, and brainstem, Hong et al. (2000) found linkage of the
disorder close to the RELN gene on chromosome 7q22.

MOLECULAR GENETICS

In affected members of 2 consanguineous pedigrees segregating an
autosomal recessive form of lissencephaly associated with severe
abnormalities of the cerebellum, hippocampus, and brainstem, Hong et al.
(2000) identified homozygous mutations in the RELN gene
(600514.0001-600514.0002).

*FIELD* RF
1. Caksen, H.; Tuncer, O.; Kirimi, E.; Fryns, J. P.; Uner, A.; Unal,
O.; Cinal, A.; Odabas, D.: Report of two Turkish infants with Normal-Roberts
syndrome. Genet. Counsel. 15: 9-17, 2004.

2. Dobyns, W. B.; Stratton, R. F.; Greenberg, F.: Syndromes with
lissencephaly. I: Miller-Dieker and Norman-Roberts syndromes and isolated
lissencephaly. Am. J. Med. Genet. 18: 509-526, 1984.

3. Hong, S. E.; Shugart, Y. Y.; Huang, D. T.; Al Shahwan, S.; Grant,
P. E.; Hourihane, J. O.; Martin, N. D. T.; Walsh, C. A.: Autosomal
recessive lissencephaly with cerebellar hypoplasia is associated with
human RELN mutations. Nature Genet. 26: 93-96, 2000. Note: Erratum:
Nature Genet. 27: 225 only, 2001.

4. Hourihane, J. O.; Bennett, C. P.; Chaudhuri, R.; Robb, S. A.; Martin,
N. D. T.: A sibship with a neuronal migration defect, cerebellar
hypoplasia and congenital lymphedema. Neuropediatrics 24: 43-46,
1993.

5. Iannetti, P.; Schwartz, C. E.; Dietz-Band, J.; Light, E.; Timmerman,
J.; Chessa, L.: Norman-Roberts syndrome: clinical and molecular studies. Am.
J. Med. Genet. 47: 95-99, 1993.

6. Norman, M. G.; Roberts, M.; Sirois, J.; Tremblay, L. J. M.: Lissencephaly. Canad.
J. Neurol. Sci. 3: 39-46, 1976.

7. Zaki, M.; Shehab, M.; El-Aleem, A. A.; Abdel-Salam, G.; Koeller,
H. B.; Ilkin, Y.; Ross, M. E.; Dobyns, W. B.; Gleeson, J. G.: Identification
of a novel recessive RELN mutation using a homozygous balanced reciprocal
translocation. Am. J. Med. Genet. 143A: 939-944, 2007.

*FIELD* CS

Neuro:
Lissencephaly, type I;
Thick cerebral cortex

HEENT:
Microcephaly;
Low, sloping forehead;
Prominent nasal bridge

Lab:
Normal chromosomes

Inheritance:
Autosomal recessive

*FIELD* CN
Cassandra L. Kniffin - updated: 7/18/2007
Victor A. McKusick - updated: 4/15/2004
Victor A. McKusick - updated: 8/29/2000

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 12/12/2012
carol: 6/2/2011
carol: 7/8/2008
ckniffin: 11/19/2007
wwang: 7/19/2007
ckniffin: 7/18/2007
terry: 6/2/2004
alopez: 4/16/2004
terry: 4/15/2004
alopez: 8/31/2000
terry: 8/29/2000
mimadm: 3/11/1994
carol: 9/1/1993
supermim: 3/17/1992
supermim: 3/20/1990
ddp: 10/27/1989
marie: 3/25/1988

MIM 600514
*RECORD*
*FIELD* NO
600514
*FIELD* TI
*600514 REELIN; RELN
;;RL
*FIELD* TX

DESCRIPTION

The RELN gene encodes reelin, a large secreted glycoprotein that is
read moreproduced by specific cell types within the developing brain and
activates a signaling pathway in postmitotic migrating neurons required
for proper positioning of neurons within laminated nervous system
parenchyma (summary by Zaki et al., 2007).

CLONING

The autosomal recessive mouse mutation 'reeler' (rl) leads to impaired
motor coordination, tremors, and ataxia. Neurons in affected mice fail
to reach their correct locations in the developing brain, disrupting the
organization of the cerebellar and cerebral cortices and other laminated
regions. D'Arcangelo et al. (1995) isolated a gene called reelin (Reln)
that was deleted in 2 reeler alleles. The allele used in cloning the
gene was produced by transgene insertion. Normal but not mutant mice
expressed reelin in embryonic and postnatal neurons during periods of
neuronal migration. The encoded protein resembled extracellular matrix
proteins involved in cell adhesion. D'Arcangelo et al. (1995) found that
the 10,383-bp reelin open reading frame (ORF) begins with a methionine
codon preceded by a consensus sequence for translation initiation. The
stop codon is followed by about 1 kb of 3-prime untranslated sequence
and a potential polyadenylation signal. The ORF encodes a protein of
3,461 amino acids with a relative molecular mass of 388 kD. A single
reelin transcript of about 12 kb was detected in RNA from the brains of
normal mice, but not from brains of affected mice.

Hirotsune et al. (1995) also identified a strong candidate cDNA for the
mouse reeler gene. This 5-kb transcript encoded a 94.4-kD protein
consisting of 881 amino acids and possessing 2 EGF-like motifs. They
analyzed 2 mutant alleles: 'Jackson reeler,' which was found to have a
deletion of the entire gene, and 'Orleans reeler,' which exhibited a
220-bp deletion in the ORF that included the second EGF-like motif and
resulted in a frameshift. In situ hybridization demonstrated that the
transcript is detected exclusively in the pioneer neurons that guide
neuronal cell migration along the radial array. The findings offered an
explanation of how the reeler mutant phenotype causes a disturbance of
the complex architecture of the neuronal network.

DeSilva et al. (1997) found that, like its murine counterpart, human
reelin (RELN) is large, encoding an mRNA of approximately 12 kb. The
mouse and human proteins, predicted from the ORF of the overlapping cDNA
clones, are similar in size (388 kD) and the amino acid and nucleotide
sequences are 94.2% and 87.2% identical, respectively. Northern
hybridization analysis revealed that RELN is expressed in fetal and
postnatal brain as well as in liver. The expression of RELN in postnatal
human brain was high in the cerebellum.

GENE STRUCTURE

Royaux et al. (1997) described the genomic structure of the mouse Reln
gene and the 5-prime-flanking genomic DNA sequences. The gene contains
65 exons spanning approximately 450 kb of genomic DNA. They identified
different reelin transcripts, formed by alternative splicing of a
microexon as well as by use of 2 different polyadenylation sites. All
splice sites conform to the GT-AG rule, except for the splice donor site
of intron 30, which is GC instead of GT. A processed pseudogene was
present in intron 42. Its nucleotide sequence was 86% identical to the
sequence of the rat RDJ1 cDNA which codes for a DnaJ-like protein of the
Hsp40 family. The genomic structures of the mouse and human RELN genes
appear to be highly conserved. The presence of tandemly repeated regions
in the reelin protein suggested that gene duplication events occurred
during evolution. By comparison of the amino acid sequences of the 8
repeats and the positions of introns, Royaux et al. (1997) suggested a
model for the evolution of the repeat coding portion of the reelin gene
from a putative ancestral minigene.

MAPPING

To map the RL gene, D'Arcangelo (1995) used a mouse reelin probe to
isolate a human cDNA from a cerebellum phage library. A P1 clone was
then used for fluorescence in situ hybridization (FISH). The human
reelin gene maps to 7q22, a chromosomal region that had not yet been
linked to any human genetic disease (D'Arcangelo et al., 1995). RL was
also mapped to YAC contigs spanning the 7q22 region. In the mouse, the
rl gene maps to chromosome 5 (Green, 1989), which is known to have a
long region of homology to human chromosome 7. Based on both FISH and
localization within a well-positioned YAC contig, DeSilva et al. (1997)
mapped the RELN gene to chromosome 7q22.

GENE FUNCTION

Impagnatiello et al. (1998) suggested that reelin may have a role in
schizophrenia (181500) because it regulates positioning and/or trophism
of cortical pyramidal neurons, interneurons, and Purkinje cells during
brain development. Another factor that plays an important role in
guiding the migration of embryonic cortical neurons to their final
destinations in the subcortical plate is the gene that is mutant in the
mouse 'disabled-1' mutation. This gene encodes an adaptor protein (Dab1;
603448) that is a phosphorylation target for a signaling cascade
putatively triggered by the Reln protein interaction with extracellular
matrix (ECM) proteins. Dab1 expression is deficient in another
neurologic genetic phenotype, the 'scrambler' mouse, which is
neurologically and behaviorally similar to the reeler mouse. During
ontogenesis of a mammalian brain, including human brain, RELN is
abundantly synthesized by the Cajal-Retzius cells and other pioneer
neurons located in the telencephalic marginal zone and by granule cells
of the external granular layer of the cerebellum. In wildtype and
scrambler mice, Reln is secreted into the ECM, but the reeler mouse
neither synthesizes nor secretes typical Reln protein. During
development, telencephalic migrating neurons and interneurons express
DAB1, but they neither express nor secrete RELN. In the reeler mouse,
the telencephalic neurons (which are misplaced following migration)
express approximately 10-fold more Dab1 than their wildtype counterpart.
Such an increase in the expression of a protein that virtually functions
as a receptor is expected to occur when the specific signal for the
receptor is missing. The function of RELN in embryos may ultimately
depend on the phosphorylation of DAB1 expressed selectively in migrating
telencephalic pyramidal neurons and cerebellar Purkinje neurons.
Impagnatiello et al. (1998) studied postmortem prefrontal cortices,
temporal cortices, hippocampi, caudate nuclei, and cerebella of
schizophrenia patients and their matched nonpsychiatric subjects. In all
of the brain areas studied, RELN and its mRNA were significantly reduced
(approximately 50%) in patients with schizophrenia; this decrease was
similar in patients affected by undifferentiated or paranoid
schizophrenia. On the other hand, DAB1 was expressed at normal levels in
all of these areas that showed a decrease in RELN. The frequency of RELN
DNA polymorphism in schizophrenia patients and the location of this
variation in a stretch of genomic DNA important for the regulation of
RELN protein secretion (Royaux et al., 1997) increased the clinical
interest in RELN gene abnormalities as putative vulnerability factors in
schizophrenia.

Layering of neurons in the cerebral cortex and cerebellum requires RELN
and DAB1. By targeted disruption experiments in mice, Trommsdorff et al.
(1999) showed that 2 cell surface receptors, very low density
lipoprotein receptor (VLDLR; 192977) and apolipoprotein E receptor-2
(APOER2; 602600), are also required. Both receptors bound Dab1 on their
cytoplasmic tails and were expressed in cortical and cerebellar layers
adjacent to layers expressing Reln. Dab1 expression was upregulated in
knockout mice lacking both the Vldlr and Apoer2 genes. Inversion of
cortical layers, absence of cerebellar foliation, and the migration of
Purkinje cells in these animals precisely mimicked the phenotype of mice
lacking Reln or Dab1. These findings established novel signaling
functions for the LDL receptor gene family and suggested that VLDLR and
APOER2 participate in transmitting the extracellular RELN signal to
intracellular signaling processes initiated by DAB1.

Using in vitro binding experiments, Hiesberger et al. (1999) showed that
Reln binds directly and specifically to the extracellular domains of
Vldlr and ApoER2. In primary embryonic neuron cultures, they
demonstrated that blockade of Vldlr and ApoER2 ligand binding correlates
with loss of Reelin-induced tyrosine phosphorylation of Dab1. With
Western blot analysis, they demonstrated that mice that lack either Reln
or Vldlr and ApoER2 (Trommsdorff et al., 1999) exhibit a dramatic
increase in the phosphorylation level of the microtubule-stabilizing
protein tau (MAPT; 157140). Hiesberger et al. (1999) concluded that Reln
acts via Vldlr and ApoER2 to regulate Dab1 tyrosine phosphorylation and
microtubule function in neurons.

D'Arcangelo et al. (1999) transfected 293T cells with expression
constructs encoding full-length VLDLR, APOER2, and LDLR (606945) cDNA.
Cells were incubated in the presence of reelin. By Western blotting, all
3 reelin isoforms (400, 250, and 180 kD) were found to associate with
293T cells expressing VLDLR and APOER2, and to a lower extent with cells
expressing LDLR; no binding was detected using mock transfected cells.
Binding required calcium and was inhibited in the presence of APOE
(107741). Furthermore, the CR-50 monoclonal antibody, which inhibits
reelin function, blocked the association of reelin with VLDLR. After
binding to VLDLR on the cell surface, reelin was internalized into
vesicles. In dissociated embryonic cortical neurons, APOE reduced the
level of reelin-induced intracellular tyrosine phosphorylation of Dab1.
The authors suggested that reelin directs neuronal migration by binding
to VLDLR and APOER2.

Mutation of the Reln gene in the mouse disrupts neuronal migration in
several brain regions and gives rise to functional deficits, such as
ataxic gait and trembling. Thus, reelin is thought to control cell-cell
interactions critical for cell positioning in the brain. Although an
abundance of reelin transcript is found in the embryonic spinal cord, it
was generally thought that neuronal migration in the spinal cord is not
affected by reelin. However, Yip et al. (2000) showed that migration of
sympathetic preganglionic neurons in the spinal cord is affected by
reelin. This study indicated that reelin affects neuronal migration
outside of the brain. Moreover, the relationship between reelin and
migrating preganglionic neurons suggests that reelin acts as a barrier
to neuronal migration.

Using neuronal precursors from postnatal mice in a Matrigel culture
system, Hack et al. (2002) showed that reelin acted as a detachment
signal for chain-migrating interneuron precursors in the olfactory bulb,
inducing their dispersal into individual cells. In vivo studies of
reeler mutant mice showed disrupted organization of the olfactory bulb
as well as failure of individual neuronal migration. Reelin did not act
as a stop signal, did not provide directional cues, and did not affect
migration distance.

Using in vitro and in vivo migration assays, Dulabon et al. (2000)
showed that reelin inhibits migration of cortical neurons in mouse
embryonic brain. Immunoprecipitation experiments showed that reelin
associates with alpha-3-beta-1 integrin (see 605025 and 135630), a
receptor that mediates neuronal adhesion to radial glial fibers and
radial migration. Using alpha-3-beta-1 integrin-deficient mouse embryos
for migration assays, Dulabon et al. (2000) showed that deficiency in
functional alpha-3-beta-1 integrins leads to deficiency in reelin
function. They observed reduced levels of Dab1 protein and elevated
expression of a 180-kD reelin fragment in cerebral cortices of
alpha-3-beta-1 integrin-deficient mice. Dulabon et al. (2000) concluded
that reelin may arrest neuronal migration and promote normal cortical
lamination by binding alpha-3-beta-1 integrin and modulating
integrin-mediated cellular adhesion.

By examining mice deficient in either Reln or Dab1, Rice et al. (2001)
found that expression of both genes was essential for the patterning of
synaptic connectivity in the retina. Physiologic studies of mice
deficient in either gene detected attenuated rod-driven retinal
responses that were associated with a decrease in rod bipolar cell
density and an abnormal distribution of processes in the inner plexiform
layer.

Grayson et al. (2005) found that postmortem brains from patients with
schizophrenia had increased methylation of the RELN gene within the
promoter region, particularly at positions -134 and -139, compared to
controls. The authors hypothesized that hypermethylation of this
promoter region results in decreased expression of RELN in
schizophrenia.

Botella-Lopez et al. (2006) found increased levels of a 180-kD reelin
fragment in CSF from 19 patients with Alzheimer disease (AD; 104300)
compared to 11 nondemented controls. Western blot and PCR analysis
confirmed increased levels of reelin protein and mRNA in tissue samples
from the frontal cortex of AD patients. Reelin was not increased in
plasma samples, suggesting distinct cellular origins. The reelin 180-kD
fragment was also increased in CSF samples of other neurodegenerative
disorders, including frontotemporal dementia (600274), progressive
supranuclear palsy (PSP; 601104), and Parkinson disease (PD; 168600).

Using overexpression and knockdown studies with cultured rat and mouse
hippocampal and cortical neurons, Matsuki et al. (2010) found that a
signaling pathway containing Stk25 (602255), Lkb1 (STK11; 602216), Strad
(STRADA; 608626), and the Golgi protein Gm130 (GOLGA2; 602580) promoted
Golgi condensation and multiple axon outgrowth while inhibiting Golgi
deployment into dendrites and dendritic growth. This signaling pathway
acted in opposition to the reelin-Dab1 pathway, which tended to inhibit
Golgi condensation and axon outgrowth and favor Golgi deployment into
dendrites and dendrite outgrowth.

Thirty percent of all cortical interneurons arise from a relatively
novel source within the ventral telencephalon, the caudal ganglionic
eminence (CGE) (summary by De Marco Garcia et al., 2011). Owing to their
late birth date, these interneurons populate the cortex only after the
majority of other interneurons and pyramidal cells are already in place
and have started to functionally integrate. De Marco Garcia et al.
(2011) demonstrated in mice that for CGE-derived reelin-positive and
calretinin (114051)-positive, but not vasoactive intestinal peptide
(VIP; 192320)-positive, interneurons, activity is essential before
postnatal day 3 for correct migration, and that after postnatal day 3,
glutamate-mediated activity controls the development of their axons and
dendrites. Furthermore, De Marco Garcia et al. (2011) showed that the
engulfment and cell motility-1 gene (Elmo1; 606420), a target of the
transcription factor distal-less homeobox-1 (Dlx1; 600029), is
selectively expressed in reelin-positive and calretinin-positive
interneurons and is both necessary and sufficient for activity-dependent
interneuron migration. De Marco Garcia et al. (2011) concluded that
their findings revealed a selective requirement for activity in shaping
the cortical integration of specific neuronal subtypes.

Senturk et al. (2011) showed that the neuronal guidance cues ephrin B
proteins are essential for Reelin signaling during the development of
laminated structures in the brain. They showed that ephrin Bs
genetically interact with Reelin. Notably, compound mouse mutants (Reln
heterozygotes null for either Efnb2 (600527) or Efnb3 (602297)) and
triple Efnb1 (300035)/Efnb2/Efnb3 knockouts showed neuronal migration
defects that recapitulated the ones observed in the neocortex,
hippocampus, and cerebellum of the reeler mouse. Mechanistically,
Senturk et al. (2011) showed that Reelin binds to the extracellular
domain of ephrin Bs, which associate at the membrane with VLDLR (192977)
and ApoER2 (602600) in neurons. Clustering of ephrin Bs leads to the
recruitment and phosphorylation of Dab1 (603448) which is necessary for
Reelin signaling. Conversely, loss of function of ephrin Bs severely
impairs Reelin-induced Dab1 phosphorylation. Importantly, activation of
ephrin Bs can rescue the reeler neuronal migration defects in the
absence of Reelin protein. Senturk et al. (2011) concluded that their
results identified ephrin Bs as essential components of the Reelin
receptor/signaling pathway to control neuronal migration during the
development of the nervous system.

Shim et al. (2012) showed that SOX4 (184430) and SOX11 (600898) are
crucial in regulating reelin expression and the inside-out pattern of
cortical layer formation. This regulation is independent of E4, a
conserved nonexonic element required for the specification of
corticospinal neuron identity and connectivity, and Fezf2 (607414), and
probably involves interactions with distinct regulatory elements.
Cortex-specific double deletion of Sox4 and Sox11 in mice led to the
loss of Fezf2 expression, failed specification of corticospinal neurons
and, independent of Fezf2, a reeler-like inversion of layers.

CYTOGENETICS

Zaki et al. (2007) reported 2 sibs from a consanguineous Egyptian
marriage who had cortical lissencephaly with cerebellar hypoplasia,
severe epilepsy, and mental retardation. Karyotype analysis identified a
homozygous, apparently balanced reciprocal translocation,
t(7;12)(q22;p13), in both children. Further analysis confirmed
disruption of the RELN gene at chromosome 7q22.1 and undetectable levels
of the protein in both children. The unaffected parents were related as
double first cousins were heterozygous for the translocation.

MOLECULAR GENETICS

Normal development of the cerebral cortex requires long-range migration
of cortical neurons from proliferative regions deep in the brain.
Lissencephaly ('smooth brain,' from 'lissos,' meaning 'smooth,' and
'encephalos,' meaning 'brain') is a severe developmental disorder in
which neuronal migration is impaired, leading to a thickened cerebral
cortex whose normally folded contour is simplified and smooth. X-linked
lissencephaly (300067) is caused by mutation in the gene encoding
doublecortin (DCX; 300121). Deletion of or mutation in the PAFAH1B1 gene
(601545), located on 17p, causes isolated lissencephaly sequence (LIS1;
607432), and haploinsufficiency of this and other neighboring genes is
responsible for the Miller-Dieker lissencephaly syndrome (247200), a
contiguous gene deletion syndrome. Hong et al. (2000) studied an
autosomal recessive form of lissencephaly associated with severe
abnormalities of the cerebellum, hippocampus, and brainstem; see
lissencephaly syndrome, Norman-Roberts type (LIS2; 257320). They tested
for linkage to markers near RELN on chromosome 7 and DAB1 on chromosome
1p32-p31, because mutations in the mouse homologs of these 2 genes cause
brain defects in mice that resemble lissencephaly, including hypoplasia
of the cerebellum, brainstem abnormalities, and a neuronal migration
disorder of the neocortex and hippocampus. In 2 unrelated pedigrees,
they found substantial regions of homozygosity in affected children near
the RELN gene on chromosome 7q22. In these 2 families, they demonstrated
different splice site mutations in the RELN gene (600514.0001 and
600514.0002, respectively). The study of these human patients pointed to
several previously unsuspected functions of reelin in and outside of the
brain. Although abnormalities of RELN mRNA had been reported in
postmortem brains of schizophrenic humans (Impagnatiello et al., 1998),
no evidence of schizophrenia was found in individuals with heterozygous
or homozygous RELN mutations. On the other hand, one of the
lissencephaly patients studied with a muscle biopsy showed evidence of
abnormal neuromuscular connectivity (Hourihane et al., 1993). Moreover,
at least 3 patients had persistent lymphedema neonatally, and one showed
accumulation of chylous (i.e., fatty) ascites fluid that required
peritoneal shunting (Hourihane et al., 1993). The apparent role for
reelin in serum homeostasis may reflect reelin interactions with LDL
superfamily receptors outside the brain, as well as in the brain.

For discussion of a possible association between variation in the RELN
gene and otosclerosis, see 166800.

ANIMAL MODEL

To investigate Reln function, Magdaleno et al. (2002) generated
transgenic mice using the nestin (NES; 600915) promoter to drive ectopic
expression of Reln in the ventricular zone during early brain
development. Ectopic Reln expression in transgenic reelin mice, which
lack endogenous Reln expression, induced tyrosine phosphorylation of
Dab1 in the ventricular zone. The transgene also rescued some, but not
all, of the neuroanatomic and behavioral abnormalities characteristic of
the reeler phenotype, including ataxia and the migration of Purkinje
cells. Magdaleno et al. (2002) hypothesized that Reln functions in
concert with other positional cues to promote cell-cell interactions
that are required for layer formation during development.

Assadi et al. (2003) investigated interactions between the reelin
signaling pathway and Lis1 in brain development. Compound mutant mice
with disruptions in the Reln pathway and heterozygous mutations in the
Pafah1b1 gene, which encodes Lis1, had a higher incidence of
hydrocephalus and enhanced cortical and hippocampal layering defects.
The Dab1 signaling molecule and Lis1 bound in a reelin-induced
phosphorylation-dependent manner. These data indicated genetic and
biochemical interaction between the reelin signaling pathway and LIS1.

In the mouse ventral spinal cord, Hochstim et al. (2008) identified 3
subtypes of white matter astrocytes with differential gene expression
corresponding to position. Astrocytes expressing both Reln and Slit1
(603742) were in the ventrolateral domain, those expressing Reln only
were at the dorsolateral domain, and those expressing Slit1 only were at
the ventromedial domain. The distinct positions of these astrocytes were
specified by varying expression of the homeodomain transcription factors
Pax6 (607108) and Nkx6.1 (602563). The findings indicated that
positional identity is an organizing principle underlying phenotypic
diversity among white matter astrocytes, as well as among neurons, and
that this diversity is prespecified within precursor cells in the
germinal zone of the CNS.

Miller and Sweatt (2007) found that DNA methylation, which is mediated
by DNA methyltransferase, was dynamically regulated during learning and
memory consolidation in adult rats. Animals exposed to an associative
context plus shock showed increased Dnmt3a (602769) and Dnmt3b (602900)
mRNA in hippocampal area CA1 compared to context-only animals. Context
plus shock rats showed increased methylation and decreased mRNA of the
memory suppressor gene PP1C-beta (PPP1CB; 600590) compared to shock-only
controls, as well as increased demethylation and increased mRNA levels
of reelin, which is involved in synaptic plasticity, compared to
controls. The methylation levels of both these target genes returned to
baseline within a day, indicating rapid and dynamic changes. Treatment
with a DNMT inhibitor blocked the methylation changes and prevented
memory consolidation of fear-conditioned learning, but the memory
changes were plastic, and memory consolidation was reestablished after
the inhibitor wore off. Miller and Sweatt (2007) noted that DNA
methylation has been viewed as having an exclusive role in development,
but they emphasized that their findings indicated that rapid and dynamic
alteration of DNA methylation can occur in the adult central nervous
system in response to environmental stimuli during associative learning
in the hippocampus.

HISTORY

Quattrocchi et al. (2003) concluded that mouse reelin functions
postnatally to regulate the development of the neuromuscular junction.
Because these results could not be replicated, Quattrocchi et al. (2004)
retracted their paper from Science of 2003. The results had been called
into question by Bidoia et al. (2004) and others. D'Arcangelo (2004)
could not reproduce the findings described by Quattrocchi et al. (2003)
and concluded that reelin does not regulate the development of the
neuromuscular junction.

*FIELD* AV
.0001
LISSENCEPHALY SYNDROME, NORMAN-ROBERTS TYPE
RELN, IVS37AS, G-A, -1

In a Saudi Arabian family with first-cousin parents and 3 children with
lissencephaly-2 (257320), Hong et al. (2000) found a splice acceptor
site mutation in the RELN gene: IVS37AS, G-A, -1. The patients were
homozygous for the splice acceptor mutation and both parents were
heterozygous. In their paper Hong et al. (2000) referred to this
mutation as IVS36AS, G-A, -1; however, in an erratum, they noted that
their system for exon numbering differed from that adopted in the mouse
and clarified the human-mouse comparison so that a single numbering
system could be used in both species.

.0002
LISSENCEPHALY SYNDROME, NORMAN-ROBERTS TYPE
RELN, 148-BP DEL

Hong et al. (2000) studied a family in which 3 brothers, including a set
of identical twins, had lissencephaly-2 (257320) and the parents were
related as half first cousins. The brothers were found to have a 148-bp
deletion in the RELN gene corresponding to the removal of exon 42
(EX42DEL). The family was British and had previously been reported by
Hourihane et al. (1993). At birth, affected children showed normal head
size, congenital lymphedema, and hypotonia. Brain MRI showed moderate
lissencephaly and profound cerebellar hypoplasia. Cognitive development
was delayed for all affected children, with little or no language and no
ability to sit or stand unsupported. There was also myopia, nystagmus,
and generalized seizures that could be controlled with medication. In
one patient in this family muscle biopsy showed evidence of abnormal
neuromuscular connectivity. Patients from this family had persistent
lymphedema neonatally, and 1 showed accumulation of chylous (that is,
fatty) ascites fluid that required peritoneal shunting.

*FIELD* RF
1. Assadi, A. H.; Zhang, G.; Beffert, U.; McNeil, R. S.; Renfro, A.
L.; Niu, S.; Quattrocchi, C. C.; Antalffy, B. A.; Sheldon, M.; Armstrong,
D. D.; Wynshaw-Boris, A.; Herz, J.; D'Arcangelo, G.; Clark, G. D.
: Interaction of reelin signaling and Lis1 in brain development. Nature
Genet. 35: 270-276, 2003.

2. Bidoia, C.; Misgeld, T.; Weinzierl, E.; Buffelli, M.; Feng, G.;
Cangiano, A.; Lichtman, J. W.; Sanes, J. R.: Comment on 'reelin promotes
peripheral synapse elimination and maturation.' Science 303: 1977b,
2004.

3. Botella-Lopez, A.; Burgaya, F.; Gavin, R.; Garcia-Ayllon, M. S.;
Gomez-Tortosa, E.; Pena-Casanova, J.; Urena, J. M.; Del Rio, J. A.;
Blesa, R.; Soriano, E.; Saez-Valero, J.: Reelin expression and glycosylation
patterns are altered in Alzheimer's disease. Proc. Nat. Acad. Sci. 103:
5573-5578, 2006.

4. D'Arcangelo, G.: Personal Communication. Nutley, N. J. 6/2/1995.

5. D'Arcangelo, G.: Response to comment on 'reelin promotes peripheral
synapse elimination and maturation.' Science 303: 1977c only, 2004.

6. D'Arcangelo, G.; Homayouni, R.; Keshvara, L.; Rice, D. S.; Sheldon,
M.; Curran, T.: Reelin is a ligand for lipoprotein receptors. Neuron 24:
471-479, 1999.

7. D'Arcangelo, G.; Miao, G. G.; Chen, S.-C.; Soares, H. D.; Morgan,
J. I.; Curran, T.: A protein related to extracellular matrix proteins
deleted in the mouse mutant reeler. Nature 374: 719-723, 1995.

8. De Marco Garcia, N. V.; Karayannis, T.; Fishell, G.: Neuronal
activity is required for the development of specific cortical interneuron
subtypes. Nature 472: 351-355, 2011.

9. DeSilva, U.; D'Arcangelo, G.; Braden, V. V.; Chen, J.; Miao, G.
G.; Curran, T.; Green, E. D.: The human reelin gene: isolation, sequencing,
and mapping on chromosome 7. Genome Res. 7: 157-164, 1997.

10. Dulabon, L.; Olson, E. C.; Taglienti, M. G.; Eisenhuth, S.; McGrath,
B.; Walsh, C. A.; Kreidberg, J. A.; Anton, E. S.: Reelin binds alpha-3-beta-1
integrin and inhibits neuronal migration. Neuron 27: 33-44, 2000.

11. Grayson, D. R.; Jia, X.; Chen, Y.; Sharma, R. P.; Mitchell, C.
P.; Guidotti, A.; Costa, E.: Reelin promoter hypermethylation in
schizophrenia. Proc. Nat. Acad. Sci. 102: 9341-9346, 2005.

12. Green, M. C.: Catalog of mutant genes and polymorphic loci.In:
Lyon, M. F.; Searle, A. G.: Genetic Variants and Strains of the Laboratory
Mouse. Oxford: Oxford Univ. Press (pub.) (2nd ed.): 1989.

13. Hack, I.; Bancila, M.; Loulier, K.; Carroll, P.; Cremer, H.:
Reelin is a detachment signal in tangential chain-migration during
postnatal neurogenesis. Nature Neurosci. 5: 939-945, 2002.

14. Hiesberger, T.; Trommsdorff, M.; Howell, B. W.; Goffinet, A.;
Mumby, M. C.; Cooper, J. A.; Herz, J.: Direct binding of reelin to
VLDL receptor and apoE receptor 2 induces tyrosine phosphorylation
of disabled-1 and modulates tau phosphorylation. Neuron 24: 481-489,
1999.

15. Hirotsune, S.; Takahara, T.; Sasaki, N.; Hirose, K.; Yoshiki,
A.; Ohashi, T.; Kusakabe, M.; Murakami, Y.; Muramatsu, M.; Watanabe,
S.; Nakao, K.; Katsuki, M.; Hayashizaki, Y.: The reeler gene encodes
a protein with an EGF-like motif expressed by pioneer neurons. Nature
Genet. 10: 77-83, 1995.

16. Hochstim, C.; Deneen, B.; Lukaszewicz, A.; Zhou, Q.; Anderson,
D. J.: Identification of positionally distinct astrocyte subtypes
whose identities are specified by a homeodomain code. Cell 133:
510-522, 2008.

17. Hong, S. E.; Shugart, Y. Y.; Huang, D. T.; Al Shahwan, S.; Grant,
P. E.; Hourihane, J. O.; Martin, N. D. T.; Walsh, C. A.: Autosomal
recessive lissencephaly with cerebellar hypoplasia is associated with
human RELN mutations. Nature Genet. 26: 93-96, 2000. Note: Erratum:
Nature Genet. 27: 225 only, 2001.

18. Hourihane, J. O.; Bennett, C. P.; Chaudhuri, R.; Robb, S. A.;
Martin, N. D. T.: A sibship with a neuronal migration defect, cerebellar
hypoplasia and congenital lymphedema. Neuropediatrics 24: 43-46,
1993.

19. Impagnatiello, F.; Guidotti, A. R.; Pesold, C.; Dwivedi, Y.; Caruncho,
H.; Pisu, M. G.; Uzunov, D. P.; Smalheiser, N. R.; Davis, J. M.; Pandey,
G. N.; Pappas, G. D.; Tueting, P.; Sharma, R. P.; Costa, E.: A decrease
of reelin expression as a putative vulnerability factor in schizophrenia. Proc.
Nat. Acad. Sci. 95: 15718-15723, 1998.

20. Magdaleno, S.; Keshvara, L.; Curran, T.: Rescue of ataxia and
preplate splitting by ectopic expression of reelin in reeler mice. Neuron 33:
573-586, 2002.

21. Matsuki, T.; Matthews, R. T.; Cooper, J. A.; van der Brug, M.
P.; Cookson, M. R.; Hardy, J. A.; Olson, E. C.; Howell, B. W.: Reelin
and Stk25 have opposing roles in neuronal polarization and dendritic
Golgi deployment. Cell 143: 826-836, 2010.

22. Miller, C. A.; Sweatt, J. D.: Covalent modification of DNA regulates
memory formation. Neuron 53: 857-869, 2007. Note: Erratum: Neuron
59: 1051 only, 2008.

23. Quattrocchi, C. C.; Huang, C.; Niu, S.; Sheldon, M.; Benhayon,
D.; Cartwright, J., Jr.; Mosier, D. R.; Keller, F.; D'Arcangelo, G.
: Reelin promotes peripheral synapse elimination and maturation. Science 301:
649-653, 2003. Note: Erratum: Science 301: 1849 only, 2003. Retraction:
Science 303: 1974 only, 2004.

24. Quattrocchi, C. C.; Huang, C.; Niu, S.; Sheldon, M.; Benhayon,
D.; Cartwright, J., Jr.; Mosier, D. R.; Keller, F.; D'Arcangelo, G.
: Retraction. (Letter) Science 303: 1974 only, 2004.

25. Rice, D. S.; Nusinowitz, S.; Azimi, A. M.; Martinez, A.; Soriano,
E.; Curran, T.: The reelin pathway modulates the structure and function
of retinal synaptic circuitry. Neuron 31: 929-941, 2001.

26. Royaux, I.; Lambert de Rouvroit, C.; D'Arcangelo, G.; Demirov,
D.; Goffinet, A. M.: Genomic organization of the mouse reelin gene. Genomics 46:
240-250, 1997.

27. Senturk, A.; Pfennig, S.; Weiss, A.; Burk, K.; Acker-Palmer, A.
: Ephrin Bs are essential components of the Reelin pathway to regulate
neuronal migration. Nature 472: 356-360, 2011. Note: Erratum: Nature
478: 274 only, 2011.

28. Shim, S.; Kwan, K. Y.; Li, M.; Lefebvre, V.; Sestan, N.: Cis-regulatory
control of corticospinal system development and evolution. Nature 486:
74-79, 2012.

29. Trommsdorff, M.; Gotthardt, M.; Hiesberger, T.; Shelton, J.; Stockinger,
W.; Nimpf, J.; Hammer, R. E.; Richardson, J. A.; Herz, J.: Reeler/Disabled-like
disruption of neuronal migration in knockout mice lacking the VLDL
receptor and ApoE receptor 2. Cell 97: 689-701, 1999.

30. Yip, J. W.; Yip, Y. P. L.; Nakajima, K.; Capriotti, C.: Reelin
controls position of autonomic neurons in the spinal cord. Proc.
Nat. Acad. Sci. 97: 8612-8616, 2000.

31. Zaki, M.; Shehab, M.; El-Aleem, A. A.; Abdel-Salam, G.; Koeller,
H. B.; Ilkin, Y.; Ross, M. E.; Dobyns, W. B.; Gleeson, J. G.: Identification
of a novel recessive RELN mutation using a homozygous balanced reciprocal
translocation. Am. J. Med. Genet. 143A: 939-944, 2007.

*FIELD* CN
Ada Hamosh - updated: 07/17/2012
Ada Hamosh - updated: 7/8/2011
Patricia A. Hartz - updated: 2/10/2011
Marla J. F. O'Neill - updated: 4/13/2009
Cassandra L. Kniffin - updated: 5/15/2008
Cassandra L. Kniffin - updated: 7/18/2007
Cassandra L. Kniffin - updated: 5/24/2006
Patricia A. Hartz - updated: 12/7/2005
Cassandra L. Kniffin - updated: 7/11/2005
Ada Hamosh - updated: 4/7/2004
Victor A. McKusick - updated: 10/31/2003
Ada Hamosh - updated: 8/12/2003
Dawn Watkins-Chow - updated: 10/31/2002
Cassandra L. Kniffin - updated: 9/16/2002
Dawn Watkins-Chow - updated: 6/13/2002
Dawn Watkins-Chow - updated: 11/25/2001
Victor A. McKusick - updated: 9/27/2000
Victor A. McKusick - updated: 8/29/2000
Wilson H. Y. Lo - updated: 4/6/2000
Stylianos E. Antonarakis - updated: 7/8/1999
Victor A. McKusick - updated: 3/1/1999
Victor A. McKusick - updated: 4/8/1997

*FIELD* CD
Victor A. McKusick: 5/4/1995

*FIELD* ED
alopez: 07/17/2012
carol: 5/24/2012
alopez: 11/29/2011
alopez: 7/12/2011
terry: 7/8/2011
carol: 6/2/2011
mgross: 2/16/2011
terry: 2/10/2011
alopez: 1/10/2011
carol: 11/15/2010
carol: 11/11/2010
wwang: 1/13/2010
wwang: 4/14/2009
terry: 4/13/2009
carol: 7/8/2008
wwang: 6/16/2008
ckniffin: 5/15/2008
wwang: 7/19/2007
ckniffin: 7/18/2007
wwang: 5/25/2006
ckniffin: 5/24/2006
wwang: 12/15/2005
wwang: 12/7/2005
wwang: 7/28/2005
ckniffin: 7/11/2005
terry: 6/3/2004
alopez: 4/8/2004
terry: 4/7/2004
tkritzer: 11/3/2003
terry: 10/31/2003
mgross: 8/12/2003
terry: 8/12/2003
carol: 11/4/2002
tkritzer: 10/31/2002
alopez: 10/18/2002
carol: 9/16/2002
ckniffin: 9/16/2002
cwells: 6/13/2002
ckniffin: 6/5/2002
carol: 11/25/2001
carol: 3/13/2001
alopez: 1/29/2001
mcapotos: 10/13/2000
mcapotos: 10/10/2000
terry: 9/27/2000
alopez: 8/31/2000
terry: 8/29/2000
carol: 4/7/2000
terry: 4/6/2000
mgross: 7/8/1999
carol: 3/22/1999
terry: 3/1/1999
alopez: 1/19/1999
carol: 8/12/1998
mark: 7/22/1997
mark: 4/8/1997
terry: 4/2/1997
mark: 6/29/1995
mark: 5/23/1995
mark: 5/4/1995