RBCC Red Blood Cell Collection

PAFAH1B1 (LIS1, MDCR, MDS, PAFAHA) [Confidence: low (only semi-automatic identification from reviews)]
Platelet-activating factor acetylhydrolase IB subunit alpha (Lissencephaly-1 protein; LIS-1; PAF acetylhydrolase 45 kDa subunit; PAF-AH 45 kDa subunit; PAF-AH alpha; PAFAH alpha)

UniProt P43034
ID LIS1_HUMAN Reviewed; 410 AA.
AC P43034; B2R7Q7; Q8WZ88; Q8WZ89;
DT 01-NOV-1995, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 2.
DT 22-JAN-2014, entry version 146.
DE RecName: Full=Platelet-activating factor acetylhydrolase IB subunit alpha;
DE AltName: Full=Lissencephaly-1 protein;
DE Short=LIS-1;
DE AltName: Full=PAF acetylhydrolase 45 kDa subunit;
DE Short=PAF-AH 45 kDa subunit;
DE AltName: Full=PAF-AH alpha;
DE Short=PAFAH alpha;
GN Name=PAFAH1B1; Synonyms=LIS1, MDCR, MDS, PAFAHA;
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).
RC TISSUE=Brain, and Kidney;
RX PubMed=8355785; DOI=10.1038/364717a0;
RA Reiner O., Carrozzo R., Shen Y., Wehnert M., Faustinella F.,
RA Dobyns W.B., Caskey C.T., Ledbetter D.H.;
RT "Isolation of a Miller-Dieker lissencephaly gene containing G protein
RT beta-subunit-like repeats.";
RL Nature 364:717-721(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT LIS1 ARG-149.
RX PubMed=9063735; DOI=10.1093/hmg/6.2.157;
RA Lo Nigro C., Chong S.S., Smith A.C.M., Dobyns W.B., Carrozzo R.,
RA Ledbetter D.H.;
RT "Point mutations and an intragenic deletion in LIS1, the lissencephaly
RT causative gene in isolated lissencephaly sequence and Miller-Dieker
RT syndrome.";
RL Hum. Mol. Genet. 6:157-164(1997).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Liver;
RA Zhao M.J., Xia S.L., Li T.P.;
RT "High expression of the lissencephaly gene in hepatocarcinoma
RT patients.";
RL Submitted (NOV-1999) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RA Feng Z., Zhang B., Peng X., Yuan J., Qiang B.;
RL Submitted (JUL-2001) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Hippocampus;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Colon;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [7]
RP 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 [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Uterus;
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 [9]
RP INTERACTION WITH DCX.
RX PubMed=11001923;
RA Caspi M., Atlas R., Kantor A., Sapir T., Reiner O.;
RT "Interaction between LIS1 and doublecortin, two lissencephaly gene
RT products.";
RL Hum. Mol. Genet. 9:2205-2213(2000).
RN [10]
RP INTERACTION WITH NDE1, AND CHARACTERIZATION OF VARIANTS LIS1 ARG-149
RP AND SBH PRO-169.
RX PubMed=11163258; DOI=10.1016/S0896-6273(00)00145-8;
RA Feng Y., Olson E.C., Stukenberg P.T., Flanagan L.A., Kirschner M.W.,
RA Walsh C.A.;
RT "LIS1 regulates CNS lamination by interacting with mNudE, a central
RT component of the centrosome.";
RL Neuron 28:665-679(2000).
RN [11]
RP SELF-ASSOCIATION, INTERACTION WITH RSN; DYNEIN AND DYNACTIN, AND
RP SUBCELLULAR LOCATION.
RX PubMed=11889140; DOI=10.1083/jcb.200109046;
RA Tai C.-Y., Dujardin D.L., Faulkner N.E., Vallee R.B.;
RT "Role of dynein, dynactin, and CLIP-170 interactions in LIS1
RT kinetochore function.";
RL J. Cell Biol. 156:959-968(2002).
RN [12]
RP SUBCELLULAR LOCATION.
RX PubMed=11940666; DOI=10.1128/MCB.22.9.3089-3102.2002;
RA Coquelle F.M., Caspi M., Cordelieres F.P., Dompierre J.P.,
RA Dujardin D.L., Koifman C., Martin P., Hoogenraad C.C., Akhmanova A.,
RA Galjart N., De Mey J.R., Reiner O.;
RT "LIS1, CLIP-170's key to the dynein/dynactin pathway.";
RL Mol. Cell. Biol. 22:3089-3102(2002).
RN [13]
RP INTERACTION WITH NDEL1.
RX PubMed=12556484; DOI=10.1128/MCB.23.4.1239-1250.2003;
RA Yan X., Li F., Liang Y., Shen Y., Zhao X., Huang Q., Zhu X.;
RT "Human Nudel and NudE as regulators of cytoplasmic dynein in poleward
RT protein transport along the mitotic spindle.";
RL Mol. Cell. Biol. 23:1239-1250(2003).
RN [14]
RP INTERACTION WITH NDEL1.
RX PubMed=14970193; DOI=10.1083/jcb.200308058;
RA Liang Y., Yu W., Li Y., Yang Z., Yan X., Huang Q., Zhu X.;
RT "Nudel functions in membrane traffic mainly through association with
RT Lis1 and cytoplasmic dynein.";
RL J. Cell Biol. 164:557-566(2004).
RN [15]
RP FUNCTION, SUBCELLULAR LOCATION, AND CHARACTERIZATION OF VARIANTS LIS1
RP ARG-149; SBH PRO-169 AND LIS1 HIS-317.
RX PubMed=15173193; DOI=10.1083/jcb.200309025;
RA Tanaka T., Serneo F.F., Higgins C., Gambello M.J., Wynshaw-Boris A.,
RA Gleeson J.G.;
RT "Lis1 and doublecortin function with dynein to mediate coupling of the
RT nucleus to the centrosome in neuronal migration.";
RL J. Cell Biol. 165:709-721(2004).
RN [16]
RP INTERACTION WITH DISC1.
RX PubMed=14962739; DOI=10.1016/j.mcn.2003.09.009;
RA Brandon N.J., Handford E.J., Schurov I., Rain J.-C., Pelling M.,
RA Duran-Jimeniz B., Camargo L.M., Oliver K.R., Beher D., Shearman M.S.,
RA Whiting P.J.;
RT "Disrupted in Schizophrenia 1 and Nudel form a neurodevelopmentally
RT regulated protein complex: implications for schizophrenia and other
RT major neurological disorders.";
RL Mol. Cell. Neurosci. 25:42-55(2004).
RN [17]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-53, AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [18]
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 [19]
RP INTERACTION WITH ASUN.
RX PubMed=23097494; DOI=10.1091/mbc.E12-07-0558;
RA Jodoin J.N., Shboul M., Sitaram P., Zein-Sabatto H., Reversade B.,
RA Lee E., Lee L.A.;
RT "Human Asunder promotes dynein recruitment and centrosomal tethering
RT to the nucleus at mitotic entry.";
RL Mol. Biol. Cell 23:4713-4724(2012).
RN [20]
RP VARIANT SBH PRO-169.
RX PubMed=10441340; DOI=10.1093/hmg/8.9.1757;
RA Pilz D.T., Kuc J., Matsumoto N., Bodurtha J., Bernadi B.,
RA Tassinari C.A., Dobyns W.B., Ledbetter D.H.;
RT "Subcortical band heterotopia in rare affected males can be caused by
RT missense mutations in DCX (XLIS) or LIS1.";
RL Hum. Mol. Genet. 8:1757-1760(1999).
RN [21]
RP VARIANTS LIS1 SER-31; SER-162 AND HIS-317.
RX PubMed=11502906;
RA Leventer R.J., Cardoso C., Ledbetter D.H., Dobyns W.B.;
RT "LIS1 missense mutations cause milder lissencephaly phenotypes
RT including a child with normal IQ.";
RL Neurology 57:416-422(2001).
RN [22]
RP VARIANT SBH PRO-241.
RX PubMed=14581661;
RA Sicca F., Kelemen A., Genton P., Das S., Mei D., Moro F., Dobyns W.B.,
RA Guerrini R.;
RT "Mosaic mutations of the LIS1 gene cause subcortical band
RT heterotopia.";
RL Neurology 61:1042-1046(2003).
RN [23]
RP VARIANT LIS1 PRO-277.
RX PubMed=15007136;
RA Torres F.R., Montenegro M.A., Marques-de-Faria A.P., Guerreiro M.M.,
RA Cendes F., Lopes-Cendes I.;
RT "Mutation screening in a cohort of patients with lissencephaly and
RT subcortical band heterotopia.";
RL Neurology 62:799-802(2004).
CC -!- FUNCTION: Required for proper activation of Rho GTPases and actin
CC polymerization at the leading edge of locomoting cerebellar
CC neurons and postmigratory hippocampal neurons in response to
CC calcium influx triggered via NMDA receptors. Non-catalytic subunit
CC of an acetylhydrolase complex which inactivates platelet-
CC activating factor (PAF) by removing the acetyl group at the SN-2
CC position (By similarity). Positively regulates the activity of the
CC minus-end directed microtubule motor protein dynein. May enhance
CC dynein-mediated microtubule sliding by targeting dynein to the
CC microtubule plus end. Required for several dynein- and
CC microtubule-dependent processes such as the maintenance of Golgi
CC integrity, the peripheral transport of microtubule fragments and
CC the coupling of the nucleus and centrosome. Required during brain
CC development for the proliferation of neuronal precursors and the
CC migration of newly formed neurons from the
CC ventricular/subventricular zone toward the cortical plate.
CC Neuronal migration involves a process called nucleokinesis,
CC whereby migrating cells extend an anterior process into which the
CC nucleus subsequently translocates. During nucleokinesis dynein at
CC the nuclear surface may translocate the nucleus towards the
CC centrosome by exerting force on centrosomal microtubules. May also
CC play a role in other forms of cell locomotion including the
CC migration of fibroblasts during wound healing.
CC -!- SUBUNIT: Component of cytosolic PAF-AH IB, which is composed of
CC PAFAH1B1 (alpha), PAFAH1B2 (beta) and PAFAH1B3 (gamma) subunits.
CC Trimer formation is not essential for the catalytic activity of
CC the enzyme which is contributed solely by the PAFAH1B2 (beta) and
CC PAFAH1B3 (gamma) subunits. Interacts with IQGAP1, KATNB1 and NUDC.
CC Interacts with DAB1 when DAB1 is phosphorylated in response to
CC RELN/reelin signaling (By similarity). Can self-associate.
CC Interacts with DCX, dynein, dynactin, NDE1, NDEL1 and RSN.
CC Interacts with DISC1, and this interaction is enhanced by NDEL1.
CC Interacts with ASUN.
CC -!- INTERACTION:
CC Q9CZA6:Nde1 (xeno); NbExp=6; IntAct=EBI-720620, EBI-309934;
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton. Cytoplasm,
CC cytoskeleton, microtubule organizing center, centrosome.
CC Cytoplasm, cytoskeleton, spindle (By similarity). Nucleus membrane
CC (Potential). Note=Redistributes to axons during neuronal
CC development. Also localizes to the microtubules of the manchette
CC in elongating spermatids and to the meiotic spindle in
CC spermatocytes (By similarity). Localizes to the plus end of
CC microtubules and to the centrosome. May localize to the nuclear
CC membrane.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P43034-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P43034-2; Sequence=VSP_019376, VSP_019377, VSP_019378,
CC VSP_019379;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Fairly ubiquitous expression in both the
CC frontal and occipital areas of the brain.
CC -!- DOMAIN: Dimerization mediated by the LisH domain may be required
CC to activate dynein (By similarity).
CC -!- DISEASE: Lissencephaly 1 (LIS1) [MIM:607432]: A classical
CC lissencephaly. It is characterized by agyria or pachygyria and
CC disorganization of the clear neuronal lamination of normal six-
CC layered cortex. The cortex is abnormally thick and poorly
CC organized with 4 primitive layers. Associated with enlarged and
CC dysmorphic ventricles and often hypoplasia of the corpus callosum.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- DISEASE: Subcortical band heterotopia (SBH) [MIM:607432]: SBH is a
CC mild brain malformation of the lissencephaly spectrum. It is
CC characterized by bilateral and symmetric plates or bands of gray
CC matter found in the central white matter between the cortex and
CC cerebral ventricles, cerebral convolutions usually appearing
CC normal. Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- DISEASE: Miller-Dieker lissencephaly syndrome (MDLS) [MIM:247200]:
CC A contiguous gene deletion syndrome of chromosome 17p13.3,
CC characterized by classical lissencephaly and distinct facial
CC features. Additional congenital malformations can be part of the
CC condition. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- SIMILARITY: Belongs to the WD repeat LIS1/nudF family.
CC -!- SIMILARITY: Contains 1 LisH domain.
CC -!- SIMILARITY: Contains 7 WD repeats.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAA02882.1; Type=Miscellaneous discrepancy; Note=Chimeric cDNA;
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/PAFAH1B1";
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DR EMBL; L13385; AAA02880.1; -; mRNA.
DR EMBL; L13386; AAA02881.1; -; mRNA.
DR EMBL; L13387; AAA02882.1; ALT_SEQ; mRNA.
DR EMBL; U72342; AAC51111.1; -; Genomic_DNA.
DR EMBL; U72334; AAC51111.1; JOINED; Genomic_DNA.
DR EMBL; U72335; AAC51111.1; JOINED; Genomic_DNA.
DR EMBL; U72336; AAC51111.1; JOINED; Genomic_DNA.
DR EMBL; U72337; AAC51111.1; JOINED; Genomic_DNA.
DR EMBL; U72338; AAC51111.1; JOINED; Genomic_DNA.
DR EMBL; U72339; AAC51111.1; JOINED; Genomic_DNA.
DR EMBL; U72340; AAC51111.1; JOINED; Genomic_DNA.
DR EMBL; U72341; AAC51111.1; JOINED; Genomic_DNA.
DR EMBL; AF208837; AAL34972.1; -; mRNA.
DR EMBL; AF208838; AAL34973.1; -; mRNA.
DR EMBL; AF400434; AAK92483.1; -; mRNA.
DR EMBL; AK313078; BAG35904.1; -; mRNA.
DR EMBL; BX538346; CAD98141.1; -; mRNA.
DR EMBL; CH471108; EAW90536.1; -; Genomic_DNA.
DR EMBL; BC064638; AAH64638.1; -; mRNA.
DR PIR; S36113; S36113.
DR RefSeq; NP_000421.1; NM_000430.3.
DR UniGene; Hs.77318; -.
DR ProteinModelPortal; P43034; -.
DR SMR; P43034; 1-79, 92-408.
DR DIP; DIP-35691N; -.
DR IntAct; P43034; 12.
DR MINT; MINT-5004233; -.
DR STRING; 9606.ENSP00000380378; -.
DR PhosphoSite; P43034; -.
DR DMDM; 1170794; -.
DR PaxDb; P43034; -.
DR PeptideAtlas; P43034; -.
DR PRIDE; P43034; -.
DR Ensembl; ENST00000397195; ENSP00000380378; ENSG00000007168.
DR GeneID; 5048; -.
DR KEGG; hsa:5048; -.
DR UCSC; uc002fuw.4; human.
DR CTD; 5048; -.
DR GeneCards; GC17P002496; -.
DR HGNC; HGNC:8574; PAFAH1B1.
DR HPA; CAB004489; -.
DR HPA; HPA020036; -.
DR MIM; 247200; phenotype.
DR MIM; 601545; gene.
DR MIM; 607432; phenotype.
DR neXtProt; NX_P43034; -.
DR Orphanet; 217385; 17p13.3 microduplication syndrome.
DR Orphanet; 95232; Lissencephaly due to LIS1 mutation.
DR Orphanet; 531; Miller-Dieker syndrome.
DR Orphanet; 99796; Subcortical band heterotopia.
DR PharmGKB; PA32905; -.
DR eggNOG; COG2319; -.
DR HOGENOM; HOG000184015; -.
DR HOVERGEN; HBG006271; -.
DR InParanoid; P43034; -.
DR KO; K16794; -.
DR OMA; WVRGLAF; -.
DR PhylomeDB; P43034; -.
DR Reactome; REACT_115566; Cell Cycle.
DR Reactome; REACT_21300; Mitotic M-M/G1 phases.
DR SignaLink; P43034; -.
DR ChiTaRS; PAFAH1B1; human.
DR GeneWiki; PAFAH1B1; -.
DR GenomeRNAi; 5048; -.
DR NextBio; 19452; -.
DR PRO; PR:P43034; -.
DR ArrayExpress; P43034; -.
DR Bgee; P43034; -.
DR CleanEx; HS_PAFAH1B1; -.
DR Genevestigator; P43034; -.
DR GO; GO:0000235; C:astral microtubule; IDA:UniProtKB.
DR GO; GO:0005938; C:cell cortex; IDA:UniProtKB.
DR GO; GO:0031252; C:cell leading edge; IEA:Ensembl.
DR GO; GO:0005813; C:centrosome; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; ISS:BHF-UCL.
DR GO; GO:0030426; C:growth cone; IEA:Ensembl.
DR GO; GO:0005871; C:kinesin complex; IEA:Ensembl.
DR GO; GO:0000776; C:kinetochore; IDA:UniProtKB.
DR GO; GO:0005875; C:microtubule associated complex; IDA:UniProtKB.
DR GO; GO:0031512; C:motile primary cilium; ISS:BHF-UCL.
DR GO; GO:0043025; C:neuronal cell body; IEA:Ensembl.
DR GO; GO:0005635; C:nuclear envelope; IDA:UniProtKB.
DR GO; GO:0031965; C:nuclear membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; ISS:BHF-UCL.
DR GO; GO:0031982; C:vesicle; IEA:Ensembl.
DR GO; GO:0034452; F:dynactin binding; ISS:BHF-UCL.
DR GO; GO:0045502; F:dynein binding; IDA:UniProtKB.
DR GO; GO:0008201; F:heparin binding; ISS:BHF-UCL.
DR GO; GO:0008017; F:microtubule binding; ISS:BHF-UCL.
DR GO; GO:0043274; F:phospholipase binding; ISS:BHF-UCL.
DR GO; GO:0051219; F:phosphoprotein binding; ISS:BHF-UCL.
DR GO; GO:0042803; F:protein homodimerization activity; ISS:BHF-UCL.
DR GO; GO:0001675; P:acrosome assembly; ISS:BHF-UCL.
DR GO; GO:0030036; P:actin cytoskeleton organization; ISS:BHF-UCL.
DR GO; GO:0008344; P:adult locomotory behavior; IMP:BHF-UCL.
DR GO; GO:0001667; P:ameboidal cell migration; IEA:Ensembl.
DR GO; GO:0048854; P:brain morphogenesis; IMP:BHF-UCL.
DR GO; GO:0021895; P:cerebral cortex neuron differentiation; IEA:Ensembl.
DR GO; GO:0021540; P:corpus callosum morphogenesis; IMP:BHF-UCL.
DR GO; GO:0051660; P:establishment of centrosome localization; IEA:Ensembl.
DR GO; GO:0000132; P:establishment of mitotic spindle orientation; IMP:UniProtKB.
DR GO; GO:0000086; P:G2/M transition of mitotic cell cycle; TAS:Reactome.
DR GO; GO:0021766; P:hippocampus development; ISS:BHF-UCL.
DR GO; GO:0021819; P:layer formation in cerebral cortex; ISS:BHF-UCL.
DR GO; GO:0007611; P:learning or memory; ISS:BHF-UCL.
DR GO; GO:0016042; P:lipid catabolic process; IEA:UniProtKB-KW.
DR GO; GO:0031023; P:microtubule organizing center organization; IMP:UniProtKB.
DR GO; GO:0007067; P:mitosis; IEA:UniProtKB-KW.
DR GO; GO:0046329; P:negative regulation of JNK cascade; IEA:Ensembl.
DR GO; GO:0010977; P:negative regulation of neuron projection development; IEA:Ensembl.
DR GO; GO:0007405; P:neuroblast proliferation; ISS:BHF-UCL.
DR GO; GO:0050885; P:neuromuscular process controlling balance; IMP:BHF-UCL.
DR GO; GO:0001764; P:neuron migration; IMP:UniProtKB.
DR GO; GO:0051081; P:nuclear envelope disassembly; IEA:Ensembl.
DR GO; GO:0007097; P:nuclear migration; IEA:Ensembl.
DR GO; GO:0036035; P:osteoclast development; IEA:Ensembl.
DR GO; GO:0046469; P:platelet activating factor metabolic process; ISS:BHF-UCL.
DR GO; GO:0045773; P:positive regulation of axon extension; IEA:Ensembl.
DR GO; GO:0001961; P:positive regulation of cytokine-mediated signaling pathway; IEA:Ensembl.
DR GO; GO:0045931; P:positive regulation of mitotic cell cycle; IEA:Ensembl.
DR GO; GO:0009306; P:protein secretion; IEA:Ensembl.
DR GO; GO:0032319; P:regulation of Rho GTPase activity; ISS:BHF-UCL.
DR GO; GO:0008090; P:retrograde axon cargo transport; ISS:BHF-UCL.
DR GO; GO:0017145; P:stem cell division; IEA:Ensembl.
DR GO; GO:0007268; P:synaptic transmission; ISS:BHF-UCL.
DR GO; GO:0047496; P:vesicle transport along microtubule; ISS:BHF-UCL.
DR Gene3D; 2.130.10.10; -; 1.
DR HAMAP; MF_03141; lis1; 1; -.
DR InterPro; IPR017252; Dynein_regulator_LIS1.
DR InterPro; IPR020472; G-protein_beta_WD-40_rep.
DR InterPro; IPR006594; LisH_dimerisation.
DR InterPro; IPR013720; LisH_dimerisation_subgr.
DR InterPro; IPR015943; WD40/YVTN_repeat-like_dom.
DR InterPro; IPR001680; WD40_repeat.
DR InterPro; IPR019775; WD40_repeat_CS.
DR InterPro; IPR017986; WD40_repeat_dom.
DR Pfam; PF08513; LisH; 1.
DR Pfam; PF00400; WD40; 7.
DR PIRSF; PIRSF037647; Dynein_regulator_Lis1; 1.
DR PRINTS; PR00320; GPROTEINBRPT.
DR SMART; SM00667; LisH; 1.
DR SMART; SM00320; WD40; 7.
DR SUPFAM; SSF50978; SSF50978; 1.
DR PROSITE; PS50896; LISH; 1.
DR PROSITE; PS00678; WD_REPEATS_1; 4.
DR PROSITE; PS50082; WD_REPEATS_2; 7.
DR PROSITE; PS50294; WD_REPEATS_REGION; 1.
PE 1: Evidence at protein level;
KW Acetylation; Alternative splicing; Cell cycle; Cell division;
KW Coiled coil; Complete proteome; Cytoplasm; Cytoskeleton;
KW Developmental protein; Differentiation; Disease mutation;
KW Lipid degradation; Lipid metabolism; Lissencephaly; Membrane;
KW Microtubule; Mitosis; Neurogenesis; Nucleus; Reference proteome;
KW Repeat; Transport; WD repeat.
FT CHAIN 1 410 Platelet-activating factor
FT acetylhydrolase IB subunit alpha.
FT /FTId=PRO_0000051061.
FT DOMAIN 7 39 LisH.
FT REPEAT 106 147 WD 1.
FT REPEAT 148 187 WD 2.
FT REPEAT 190 229 WD 3.
FT REPEAT 232 271 WD 4.
FT REPEAT 274 333 WD 5.
FT REPEAT 336 377 WD 6.
FT REPEAT 378 410 WD 7.
FT REGION 1 102 Interaction with NDEL1 (By similarity).
FT REGION 1 66 Interaction with NDE1 (By similarity).
FT REGION 1 38 Required for self-association and
FT interaction with PAFAH1B2 and PAFAH1B3
FT (By similarity).
FT REGION 83 410 Interaction with dynein and dynactin.
FT REGION 367 409 Interaction with DCX.
FT REGION 388 410 Interaction with NDEL1 (By similarity).
FT COILED 56 82 Potential.
FT MOD_RES 53 53 N6-acetyllysine.
FT VAR_SEQ 12 64 Missing (in isoform 2).
FT /FTId=VSP_019376.
FT VAR_SEQ 134 170 Missing (in isoform 2).
FT /FTId=VSP_019377.
FT VAR_SEQ 237 237 V -> I (in isoform 2).
FT /FTId=VSP_019378.
FT VAR_SEQ 238 410 Missing (in isoform 2).
FT /FTId=VSP_019379.
FT VARIANT 31 31 F -> S (in LIS1).
FT /FTId=VAR_015398.
FT VARIANT 149 149 H -> R (in LIS1; abrogates interaction
FT with NDE1 and reduces neuronal migration
FT in vitro).
FT /FTId=VAR_007724.
FT VARIANT 162 162 G -> S (in LIS1; dbSNP:rs28936410).
FT /FTId=VAR_015399.
FT VARIANT 169 169 S -> P (in SBH; abrogates interaction
FT with NDE1 and reduces neuronal migration
FT in vitro).
FT /FTId=VAR_010203.
FT VARIANT 241 241 R -> P (in SBH; somatic mosaicism in 18%
FT of lymphocytes and 21% of hair root
FT cells; dbSNP:rs28936411).
FT /FTId=VAR_037300.
FT VARIANT 277 277 H -> P (in LIS1).
FT /FTId=VAR_037301.
FT VARIANT 317 317 D -> H (in LIS1; reduces neuronal
FT migration in vitro; dbSNP:rs28936689).
FT /FTId=VAR_015400.
FT CONFLICT 21 21 S -> P (in Ref. 3; AAL34972/AAL34973).
FT CONFLICT 93 93 E -> G (in Ref. 3; AAL34973).
FT CONFLICT 177 177 W -> R (in Ref. 3; AAL34973).
SQ SEQUENCE 410 AA; 46638 MW; 3AB68D2641BA31C9 CRC64;
MVLSQRQRDE LNRAIADYLR SNGYEEAYSV FKKEAELDVN EELDKKYAGL LEKKWTSVIR
LQKKVMELES KLNEAKEEFT SGGPLGQKRD PKEWIPRPPE KYALSGHRSP VTRVIFHPVF
SVMVSASEDA TIKVWDYETG DFERTLKGHT DSVQDISFDH SGKLLASCSA DMTIKLWDFQ
GFECIRTMHG HDHNVSSVAI MPNGDHIVSA SRDKTIKMWE VQTGYCVKTF TGHREWVRMV
RPNQDGTLIA SCSNDQTVRV WVVATKECKA ELREHEHVVE CISWAPESSY SSISEATGSE
TKKSGKPGPF LLSGSRDKTI KMWDVSTGMC LMTLVGHDNW VRGVLFHSGG KFILSCADDK
TLRVWDYKNK RCMKTLNAHE HFVTSLDFHK TAPYVVTGSV DQTVKVWECR
//

MIM 247200
*RECORD*
*FIELD* NO
247200
*FIELD* TI
#247200 MILLER-DIEKER LISSENCEPHALY SYNDROME; MDLS
;;MDS
CHROMOSOME 17p13.3 DELETION SYNDROME, INCLUDED;;
read moreMILLER-DIEKER SYNDROME CHROMOSOME REGION, INCLUDED; MDCR, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because Miller-Dieker
lissencephaly syndrome is a contiguous gene deletion syndrome involving
genes on chromosome 17p13.3.

See also the 17p13.3 duplication syndrome (613215), which involves the
same chromosomal region.

DESCRIPTION

Features of the Miller-Dieker syndrome include classic lissencephaly
(pachygyria, incomplete or absent gyration of the cerebrum),
microcephaly, wrinkled skin over the glabella and frontal suture,
prominent occiput, narrow forehead, downward slanting palpebral
fissures, small nose and chin, cardiac malformations, hypoplastic male
extrenal genitalia, growth retardation, and mental deficiency with
seizures and EEG abnormalities. Life expectancy is grossly reduced, with
death most often occurring during early childhood (summary by Schinzel,
1988).

Lissencephaly means 'smooth brain,' i.e., brain without convolutions or
gyri.

Deletion of or mutation in the LIS1 gene (PAFAH1B1; 601545) appears to
cause the lissencephaly because point mutations have been identified in
this gene in isolated lissencephaly sequence (ILS; see 607432). Facial
dysmorphism and other anomalies in Miller-Dieker patients appear to be
the consequence of deletion of additional genes distal to LIS1. Toyo-oka
et al. (2003) presented evidence that the gene whose deletion is
responsible for the greater severity of Miller-Dieker syndrome compared
to isolated lissencephaly is the gene encoding 14-3-3-epsilon (YWHAE;
605066).

CLINICAL FEATURES

Miller (1963) described this condition in a brother and sister who were
the fifth and sixth children of unrelated parents. The features were
microcephaly, small mandible, bizarre facies, failure to thrive,
retarded motor development, dysphagia, decorticate and decerebrate
postures, and death at 3 and 4 months, respectively. Autopsy showed
anomalies of the brain, kidney, heart, and gastrointestinal tract. The
brains were smooth with large ventricles and a histologic architecture
more like normal fetal brain of 3 to 4 months' gestation.

Dieker et al. (1969) described 2 affected brothers and an affected
female maternal first cousin. They also emphasized that this should be
termed the lissencephaly syndrome because malformations of the heart,
kidneys, and other organs, as well as polydactyly and unusual facial
appearance, are associated.

Reznik and Alberca-Serrano (1964) described 2 brothers with congenital
hypertelorism, mental defect, intractable epilepsy, progressive spastic
paraplegia, and death at ages 19 and 9 years. The mother showed
hypertelorism and short-lived epileptiform attacks. Autopsy showed
lissencephaly with massive neuronal heterotopia, and large ventricular
cavities of embryonic type. (The findings in the mother made X-linked
recessive inheritance a possibility.) The patients of Reznik and
Alberca-Serrano (1964) may have suffered from a disorder distinct from
that described by Miller (1963) and Dieker et al. (1969). All patients
with the Miller-Dieker syndrome are severely retarded. None learned to
speak. They may walk by 3 to 5 years but spastic diplegia with spastic
gait is evident. As in other forms of stationary forebrain developmental
anomalies, decerebrate posturing with head retraction emerges in the
first year of life.

Dobyns et al. (1983) stated that the most characteristic finding on
computerized tomography is complete failure of opercularization of the
frontal and temporal lobes, and that this most likely accounts for
bitemporal hollowing. (Opercularization is formation of the parts of the
lobes that cover part of the insula.) The form of lissencephaly in the
Miller-Dieker syndrome was designated classic or type I lissencephaly by
Dobyns et al. (1984). It is characterized by microcephaly and a
thickened cortex with 4 rather than 6 layers.

Bordarier et al. (1986) pointed out that agyria was considered a rare
malformation until the recent progress in neuroradiology.

Selypes and Laszlo (1988) described the Miller-Dieker syndrome in a
12-year-old boy with a de novo terminal deletion of 17p13. He had growth
retardation, microcephaly, ptosis of the left eyelid, low-set ears,
prominent philtrum, thin upper lip, clinodactyly of the fifth fingers,
and atrial septal defect. Lissencephaly was demonstrated by computerized
tomography. MDS is a severe neuronal migration abnormality.

Dobyns et al. (1988) found the most consistent features of the facies in
MDLS to be bitemporal hollowing, prominent forehead, short nose with
upturned nares, prominent upper lip, thin vermilion border of the upper
lip, and small jaw. Agenesis of the corpus callosum was demonstrated by
computerized tomography in about 90% of cases. The cerebellum was normal
in all. Striking midline calcifications were found in most patients with
visible chromosomal change.

Allanson et al. (1998) reported pattern profiles on 5 children with MDLS
and 25 children and adolescents with isolated lissencephaly sequence.
The patients with ILS at all ages showed reduced head circumference and
a wide and flat face with a broad nose and widely spaced eyes. In the
age group of 6 months to 4 years of age, there was similarity between
the pattern profiles of ILS and MDLS, with a correlation coefficient of
0.812 (p less than 0.001). In MDLS there are a few distinguishing
features, including brachycephaly, a slightly wider face, and a
considerably shorter nose. Allanson et al. (1998) concluded that given
the striking similarity of the pattern profiles, the principal
diagnostic discriminators are qualitative features, specifically the
tall, furrowed forehead and the long, broad thickened upper lip in MDLS.
They also concluded that their observations were consistent with the
concept of additional gene(s) telomeric to LIS1 contributing to the
facial phenotype of MDLS.

CYTOGENETICS

Dobyns et al. (1983) found a ring chromosome 17 in 1 patient and were
prompted to study 2 other cases. They found partial monosomy of 17p13 in
one of these. A review of the literature uncovered abnormality of 17p in
5 other patients in 3 families. Sharief et al. (1991) reported a case of
MDS associated with ring chromosome 17.

Ledbetter (1983) studied the parents of the patients reported by Miller
(1963), Dieker et al. (1969), and Norman et al. (1976). The father of
Miller's sibs had a 15q;17p translocation; the father of Dieker's
patients 1 and 3 had a 12q;17p translocation and both parents of
Norman's patient had normal karyotypes. An autosomal recessive form of
lissencephaly was suggested also by the parental consanguinity in
Norman's case (see LIS2, 257320).

Stratton et al. (1984) further narrowed the monosomy to 17p13.3. They
also reported prenatal diagnosis. In a patient with MDS and no
cytogenetically detectable deletion, vanTuinen and Ledbetter (1987)
found evidence of deletion by use of a DNA marker located at 17p13.3.
Greenberg et al. (1986) described a family in which the mother had a
pericentric inversion of chromosome 17 and 2 of her children had MDS.
One of them was shown to carry a recombinant 17 consisting of dup(17q)
and del(17p). The patient described by Selypes and Laszlo (1988) had a
de novo terminal deletion of 17p13.

Bordarier et al. (1986) reported anatomoclinical observations on a case
of partial deletion of 17p. Golgi stains showed many inverted pyramidal
cells in the superficial part of the cortex.

Dhellemmes et al. (1988) found a microdeletion of 17p in 1 of 12 cases
with lissencephaly. They subscribed to the 4-way classification of
lissencephalies proposed by Dobyns et al. (1984): the Miller-Dieker
syndrome with abnormality of chromosome 17; the Miller-Dieker syndrome
without evident abnormality of chromosome 17; a disorder with
manifestations unlike those of the Miller-Dieker syndrome but with
familial occurrence and normal chromosomes (Norman-Roberts syndrome;
257320); and a form without characteristic facial dysmorphism and
without familial occurrence. In the study of Dhellemmes et al. (1988), 1
patient was in category 1 and the other 11 were in category 4.

Dobyns et al. (1991) reviewed the results of their clinical,
cytogenetic, and molecular studies in 27 patients with MDS from 25
families. All had severe type I lissencephaly with grossly normal
cerebellum and a distinctive facial appearance consisting of prominent
forehead, bitemporal hollowing, short nose with upturned nares,
protuberant upper lip, thin vermilion border, and small jaw. Chromosome
analysis showed deletion of band 17p13 in 14 of 25 MDS probands. Studies
using probes from the 17p13.3 region detected deletions in 19 of 25
probands tested, including 7 in whom chromosome analysis was normal.
When the cytogenetic and molecular data were combined, deletions were
detected in 21 of 25 probands. Of the 11 patients in whom parental
origin of the de novo deletion was determined, paternal origin was
demonstrated in 7 and maternal origin in 4.

De Rijk-van Andel et al. (1991) identified a submicroscopic deletion of
2 DNA markers located at 17p13 in a patient with isolated grade 3
lissencephaly. The findings suggested that MDS and isolated
lissencephaly have a common etiology.

About 90% of MDS patients have visible or submicroscopic deletions of
17p13.3; Ledbetter et al. (1992) investigated the possibility that some
patients with 'isolated lissencephaly sequence' (ILS) had smaller
deletions in that chromosomal region. Their studies uncovered 6
submicroscopic deletions in 45 ILS patients with gyral abnormalities
ranging from complete agyria to mixed agyria/pachygyria and complete
pachygyria. In situ hybridization proved to be the most rapid and
sensitive method of deletion detection. The centromeric boundary of
these deletions overlapped that of MDS patients, while the telomeric
boundary for 4 of them was proximal to that of MDS.

Oostra et al. (1991) studied 5 patients with MDS, 17 patients with
isolated lissencephaly sequence, 1 patient with an unclassified form of
lissencephaly, and 9 patients with an atypical cortical dysplasia. All
patients had normal chromosomes except for a deletion of 17p13.3 in 1 of
the 5 MDS patients. The 5 MDS patients showed deletion of markers
YNZ22.1 and YNH37.3. Dobyns et al. (1993) reviewed the clinical
phenotype, pathologic changes, and results of cytogenetic and molecular
genetic studies in 90 probands with lissencephaly, with emphasis on
patients with the classic form (type I).

A cryptic translocation in one of the parents of MDS patients had been
found using fluorescence in situ hybridization (FISH) (Kuwano et al.,
1991). Masuno et al. (1995) described a patient with MDS and a maternal
cryptic translocation. Kingston et al. (1996) described a boy who, in
addition to lissencephaly and facial features of MDS, had rhizomelic
shortening of the limbs, cleft palate, hypospadias, and sacral tail.
Banded chromosome analysis did not reveal any abnormality of chromosome
17. FISH studies with the alpha satellite probe D17Z1 and 3 overlapping
cosmids from the MDS critical region showed that his mother and
grandmother carried a balanced inv(17)(p13.3q25.1). The proband's
karyotype was 46,XY,rec(17),dup q,inv(17)(p13.3q25.1)mat. Additional
manifestations in the proband were due to distal 17q trisomy. Masuno et
al. (1995) and Kingston et al. (1996) stated that FISH analysis is
crucial to exclude subtle rearrangements in affected children and their
parents.

INHERITANCE

McKusick (1996) noted that this disorder was originally classified as an
autosomal recessive disorder in Mendelian Inheritance in Man; it was
later found that both isolated lissencephaly sequence and the
Miller-Dieker syndrome are due to haploinsufficiency of one or more
genes on 17p and are autosomal dominant disorders.

MAPPING

VanTuinen et al. (1988) found that the genes for myosin heavy chain-2
(160740), tumor antigen p53, and RNA polymerase II (180660), previously
mapped to 17p, are not included in the MDS deletion region and therefore
are unlikely to play a role in its pathogenesis.

MOLECULAR GENETICS

Ledbetter et al. (1988) described 2 variable number tandem repeat (VNTR)
probes that revealed a 15-kb region containing HTF islands that are
likely to be markers of expressed sequences. Use of these probes showed
homology to chromosome 11 in the mouse. Because of the close location of
MDCR to tumor antigen p53 (TP53; 191170) and MYHSA1 (160730) in man, the
homologous locus in the mouse is probably close to the corresponding
loci in that species. Several neurologic mutants in the mouse map to
that region.

In 2 MDS patients with normal chromosomes, a combination of somatic cell
hybrid, RFLP, and densitometric studies demonstrated deletion of
polymorphic anonymous probes in the paternally derived chromosome 17
(VanTuinen et al., 1988). This demonstration of submicroscopic deletion
suggests that all MDS patients may have deletions at the molecular
level. In an addendum, the authors stated that 3 additional MDS patients
without cytogenetically detectable deletions had been found to have
molecular deletions and that 'to date' 13 of 13 MDS patients had
molecular deletions. Using anonymous probes, Schwartz et al. (1988)
likewise found molecular deletions in 3 MDS patients, 2 of whom had no
visible abnormalities of chromosome 17. None of the 3 RFLP loci studied
was absent in a case of lissencephaly without MDS.

Ledbetter et al. (1989) found that in all of 7 patients 3 overlapping
cosmids spanning more than 100 kb were completely deleted, thus
providing a minimum estimate of the size of the MDS critical region. A
hypomethylated island and evolutionarily conserved sequences were
identified within this 100-kb region--indications of the presence of one
or more expressed sequences potentially involved in the pathophysiology
of this disorder.

Reiner et al. (1993) cloned a gene called LIS1 (lissencephaly-1) in
17p13.3 that is deleted in Miller-Dieker patients. Nonoverlapping
deletions involving either the 5-prime or the 3-prime end of the gene
were found in 2 patients, identifying LIS1 as the disease gene. The
deduced amino acid sequence showed significant homology to beta subunits
of heterotrimeric G proteins, suggesting that it may be involved in a
signal transduction pathway crucial for cerebral development. Since
haploinsufficiency appears to lead to the syndrome, half the normal
dosage of the gene product is apparently inadequate for normal
development. It may be that improper proportions of beta and gamma
subunits of a G protein disturb formation of the normal protein complex,
as in hemoglobin H disease, which is caused by an imbalance in the ratio
of alpha- to beta-globin. About 15% of patients with isolated
lissencephaly and more than 90% of patients with Miller-Dieker syndrome
have microdeletions in a critical 350-kb region of 17p13.3.
Genotype/phenotype studies are necessary to explain the phenotypic
differences. Neer et al. (1993) commented on the nature of the newly
found gene and the usefulness of identifying families of genes and the
proteins they encode.

Platelet-activating factor (PAF) is involved in a variety of biologic
and pathologic processes (Hanahan, 1986). PAF acetylhydrolase, which
inactivates PAF by removing the acetyl group at the sn-2 position, is
widely distributed in plasma and tissue cytosols. One isoform of PAF
acetylhydrolase present in bovine brain cortex is a heterotrimer
comprising subunits with relative molecular masses of 45, 30, and 29 kD
(Hattori et al., 1993). Hattori et al. (1994) isolated the cDNA for the
45-kD subunit. Sequence analysis revealed 99% identity with the LIS1
gene, indicating that the LIS1 gene product is a human homolog of the
45-kD subunit of intracellular PAF acetylhydrolase. The results raised
the possibility that PAF and PAF acetylhydrolase are important in the
formation of the brain cortex during differentiation and development.

Kohler et al. (1995) searched for microdeletions in 17p13.3 in 5
patients with lissencephaly-1, typical features of Miller-Dieker
syndrome and apparently normal karyotypes. Analysis of loci D17S5 and
D17S379 by PCR and FISH revealed a deletion in 3 of the 5 cases. No
deletion was observed in the other 2. Given the almost identical
clinical picture of the 5 patients, the great variation in the molecular
findings argued against Miller-Dieker syndrome being a contiguous gene
syndrome.

Chong et al. (1996) characterized the LIS1 gene (PAFAB1B1; 601545),
demonstrating the presence of 11 exons. SSCP analysis of individual
exons was performed on 18 patients with isolated lissencephaly sequence
(ILS; see 607432) who showed no deletions detectable by FISH. In 3 of
these patients, point mutations were identified: a missense mutation, a
nonsense mutation, and a 22-bp deletion at the exon 9-intron 9 junction
predicted to result in a splicing error. The findings confirmed the view
that mutations of LIS1 are the cause of the lissencephaly phenotype in
ILS and in the Miller-Dieker syndrome. Together with the results of
deletion analysis for other ILS and Miller-Dieker syndrome patients,
these data are also consistent with the previous suggestion that
additional genes distal to LIS1 are responsible for the facial
dysmorphism and other anomalies in MDS patients.

Cardoso et al. (2003) completed a physical and transcriptional map of
the chromosome 17p13.3 region from LIS1 to the telomere. Using FISH,
Cardoso et al. (2003) mapped the deletion size in 19 children with ILS
(607432), 11 children with MDS, and 4 children with 17p13.3 deletions
not involving LIS1. Cardoso et al. (2003) showed that the critical
region that differentiates ILS from MDS at the molecular level can be
reduced to 400 kb. Using somatic cell hybrids from selected patients,
Cardoso et al. (2003) identified 8 genes consistently deleted in
patients classified as having MDS: PRP8 (607300), RILP (607848), SREC
(SCARF1; 607873), PITPNA (600174), SKIP (603055), MYO1C (606538), CRK
(164762), and 14-3-3-epsilon (YWHAE; 605066). These genes defined the
telomeric MDS critical region, which contains additional genes distal to
LIS1 that are responsible for the clinical features that distinguish MDS
from ILS. In addition, deletion of the CRK and YWHAE genes delineated
patients with the most severe lissencephaly grade. Deletion of the ABR
gene (600365), which is outside the MDS critical region, was associated
with no apparent phenotype. On the basis of recent functional data and
the creation of a mouse model suggesting a role for YWHAE in cortical
development, Cardoso et al. (2003) suggested that deletion of 1 or both
of these genes in combination with deletion of LIS1 may contribute to
the more severe form of lissencephaly seen only in patients with
Miller-Dieker syndrome.

- Chromosome 17p13.3 Deletion Syndrome

Nagamani et al. (2009) reported 5 patients with 17q13.3 deletions
involving YWHAE but not PAFAH1B1, 2 with deletion including PAFAH1B1 but
not YWHAE, and 1 with deletion of YWHAE and mosaic for deletion of
PAFAH1B1. Three deletions were terminal, and 5 were interstitial; all
were de novo. Patients with deletions including YWHAE but not PAFAH1B1
had significant growth restriction, cognitive impairment, and shared
craniofacial features, including tall vertex, prominent forehead, broad
nasal root, and epicanthal folds. Brain imaging was abnormal in all but
1 individual. The most common brain imaging abnormalities included
prominent Virchow-Robin spaces, periventricular and white matter
signals, Chiari I malformation, and abnormal corpus callosum. Patients
with deletions including PAFAH1B1 but not YWHAE presented with seizures,
significant developmental delay, and classic lissencephaly. Growth
restriction was not observed in 1 patient with deletion of YWHAE,
suggesting that another gene, perhaps CRK, may be involved in growth
regulation. The interstitial genomic rearrangements were likely
generated by diverse mechanisms.

Mignon-Ravix et al. (2009) reported a patient with developmental delay
and facial dysmorphism who was found to have a heterozygous deletion of
394 to 411 kb on chromosome 17p13.3. The mother did not carry the
deletion, and the father was not available for study. At age 3 years 7
months, the boy had macrocephaly and facial anomalies reminiscent of
MDS, including high forehead with bitemporal hollowing, hypertelorism,
epicanthus, downslanting palpebral fissures, anteverted nares,
pronounced cupid bow, and small low-set posteriorly rotated ears with
irregular helices. Brain MRI showed pronounced hypoplasia of the corpus
callosum with posterior agenesis and ependymal and periventricular
nodular heterotopias, mostly in the occipital areas. Anterior regions
displayed malformation of cortical development with polymicrogyric like
appearance of the frontal lobes associated with foci of pachygyria and
subcortical heterotopias. The deleted region contained 5 genes: TIMM22
(607251), ABR, BHLHA9 (615416), TUSC5 (612211) and YWHAE, but only
haploinsufficiency of YWHAE was considered to be pathogenic. The
phenotype was similar to that described in heterozygous Ywhae-deficient
mice (see Toyo-oka et al., 2003). The facial features in this patient
also suggested that genes located in this region could contribute to the
facial phenotype of MDS.

Bruno et al. (2010) identified 8 unrelated individuals with
microdeletions at chromosome 17p13.3. One patient had a complex deletion
and duplication. All except 1 were de novo and included the YWHAE gene,
which was found in an affected sib and a less severely affected mother.
The smallest deletion was 328 kb in size, and all breakpoints were
distinct. In a comparison with previous studies (Mignon-Ravix et al.,
2009 and Nagamani et al., 2009), Bruno et al. (2010) determined that the
delineated critical region spanned approximately 258 kb and included 6
genes: TUSC5, YWHAE, CRK, MYO1C, SKIP and part of PITPNA. YWHAE was
considered to play a large role in the phenotype, and CRK was the likely
candidate for growth restriction. The variable phenotype included
postnatal growth retardation and mild facial features such as laterally
extended eyebrows, infraorbital folds, broad nasal tip, maxillary
prominence and prominent upper and/or lower lip. The 2 affected sibs had
developmental delay, but their mother who had the deletion had normal
cognition; facial features in this family were minimal. Brain MRI
performed in 5 individuals showed no evidence of lissencephaly, but
showed mild structural anomalies in the white matter.

DIAGNOSIS

For rapid diagnosis, Batanian et al. (1990) used PCR in connection with
probe YNZ22 (D17S5), a highly polymorphic, variable number tandem repeat
(VNTR) marker previously shown to be deleted in all patients with MDS,
but not in patients with isolated lissencephaly sequence. Analysis of
118 normal persons revealed 12 alleles (differing in copy number of a
70-bp repeat unit) ranging in size from 168 to 938 bp.

Pollin et al. (1999) evaluated the risk of abnormal pregnancy outcome in
carriers of balanced reciprocal translocations involving the MDS
critical region in 17p13.3. Fourteen families were ascertained on the
basis of an affected index case. In these 14 families, 38 balanced
translocation carriers had 127 pregnancies, corrected for ascertainment
bias by the exclusion of all index cases and carriers in the line of
descent to the index cases. An abnormal phenotype, an unbalanced
chromosome constitution, or both, were found in 33 of the 127 (26%)
pregnancies: 15 of 127 (12%) had MDS and an unbalanced karyotype with
del(17p); 9 of 127 (7%) had a less severe phenotype with dup(17p); and 9
were unstudied, although MDS with der(17) was usually suspected based on
early death and multiple congenital anomalies. When unexplained
pregnancy losses, including miscarriages and stillbirths, were excluded
from the total, 33 of 99 (33%) pregnancies were phenotypically or
genotypically abnormal. The overall risk of abnormal pregnancy outcome
of 26% was in the upper range of the reported risk for unbalanced
offspring of carrier parents ascertained through liveborn aneuploid
offspring. The risk increased to 33% when unexplained pregnancy losses
were excluded from the total.

ANIMAL MODEL

The condition of so-called inverted pyramids is observed in the 'reeler'
mutation in mice (Landrieu and Goffinet, 1981). The 'reeler' mutation
(re) is located on mouse chromosome 5, a chromosome that carries no gene
known thus far to be homologous to a gene on human chromosome 17. Thus,
there is no support from homology of synteny for the notion that agyria
in man is the same as 'reeler' in the mouse.

The conserved sequences identified by Ledbetter et al. (1989) were
mapped to mouse chromosome 11 by using mouse-rat somatic cell hybrids,
thus extending the remarkable homology between human chromosome 17 and
mouse chromosome 11 by 30 cM, into the 17p telomere region.

Yingling et al. (2003) discussed the prospects of using the mouse to
model Miller-Dieker syndrome. Null and conditional knockout alleles in
the mouse had been generated for Lis1 and Mnt (603039), and null alleles
had been produced for Hic1 (603825) and 14-3-3-epsilon. For Lis1 and
Pitpna (600174), hypomorphic alleles also existed.

Toyo-oka et al. (2004) produced knockout mice for Mnt. Virtually all
homozygote mutants in a mixed (129S6 x NIH Black Swiss) or inbred
(129S6) genetic background died perinatally. Mnt-deficient embryos
exhibited small size throughout development and showed reduced levels of
c-Myc (190080) and N-Myc (164840). In addition, 37% of mixed-background
mutants displayed cleft palate as well as retardation of skull
development, a phenotype not observed in the inbred mutants. The authors
proposed an important role for Mnt in embryonic development and
survival, and suggested that Mnt may play a role in the craniofacial
defects displayed by MDLS patients.

*FIELD* SA
Garcia et al. (1978)
*FIELD* RF
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14. Dobyns, W. B.; vanTuinen, P.; Ledbetter, D. H.: Clinical diagnostic
criteria for Miller-Dieker syndrome. (Abstract) Am. J. Hum. Genet. 43:
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15. Garcia, C. A.; Dunn, D.; Trevor, R.: The lissencephaly (agyria)
syndrome in siblings: computerized tomographic and neuropathologic
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16. Greenberg, F.; Stratton, R. F.; Lockhart, L. H.; Elder, F. F.
B.; Dobyns, W. B.; Ledbetter, D. H.: Familial Miller-Dieker syndrome
associated with pericentric inversion of chromosome 17. Am. J. Med.
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17. Hanahan, D. J. A.: Platelet activating factor: a biologically
active phosphoglyceride. Annu. Rev. Biochem. 55: 483-509, 1986.

18. Hattori, M.; Adachi, H.; Tsujimoto, M.; Arai, H.; Inoue, K.:
Miller-Dieker lissencephaly gene encodes a subunit of brain platelet-activating
factor acetylhydrolase. Nature 370: 216-218, 1994. Note: Erratum:
Nature 370: 391 only, 1994.

19. Hattori, M.; Arai, H.; Inoue, K.: Purification and characterization
of bovine brain platelet-activating factor acetylhydrolase. J. Biol.
Chem. 268: 18748-18753, 1993.

20. Kingston, H. M.; Ledbetter, D. H.; Tomlin, P. I.; Gaunt, K. L.
: Miller-Dieker syndrome resulting from rearrangement of a familial
chromosome 17 inversion detected by fluorescence in situ hybridisation. J.
Med. Genet. 33: 69-72, 1996.

21. Kohler, A.; Hain, J.; Muller, U.: Clinical and molecular genetic
findings in five patients with Miller-Dieker syndrome. Clin. Genet. 47:
161-164, 1995.

22. Kuwano, A.; Ledbetter, S. A.; Dobyns, W. B.; Emanuel, B. S.; Ledbetter,
D. H.: Detection of deletions and cryptic translocations in Miller-Dieker
syndrome by in situ hybridization. Am. J. Hum. Genet. 49: 707-714,
1991.

23. Landrieu, P.; Goffinet, A.: Inverted pyramidal neurons and their
axons in the neocortex of reeler mutant mice. Cell Tissue Res. 218:
293-301, 1981.

24. Ledbetter, D. H.: Personal Communication. Houston, Texas 5/27/1983.

25. Ledbetter, D. H.; Ledbetter, S. A.; vanTuinen, P.; Summers, K.
M.; Nakamura, Y.: Two VNTR probes reveal HTF islands and conserved
sequences in a microdeletion syndrome. (Abstract) Am. J. Hum. Genet. 43:
A111, 1988.

26. Ledbetter, D. H.; Ledbetter, S. A.; vanTuinen, P.; Summers, K.
M.; Robinson, T. J.; Nakamura, Y.; Wolff, R.; White, R.; Barker, D.
F.; Wallace, M. R.; Collins, F. S.; Dobyns, W. B.: Molecular dissection
of a contiguous gene syndrome: frequent submicroscopic deletions,
evolutionarily conserved sequences, and a hypomethylated 'island'
in the Miller-Dieker chromosome region. Proc. Nat. Acad. Sci. 86:
5136-5140, 1989.

27. Ledbetter, S. A.; Kuwano, A.; Dobyns, W. B.; Ledbetter, D. H.
: Microdeletions of chromosome 17p13 as a cause of isolated lissencephaly. Am.
J. Hum. Genet. 50: 182-189, 1992.

28. Masuno, M.; Imaizumi, K.; Nakamura, M.; Matsui, K.; Goto, A.;
Kuroki, Y.: Miller-Dieker syndrome due to maternal cryptic translocation
t(10;17)(q26.3;p13.3). Am. J. Med. Genet. 59: 441-443, 1995.

29. McKusick, V. A.: Personal Communication. Baltimore, Md. 1996.

30. Mignon-Ravix, C.; Cacciagli, P.; El-Waly, B.; Mencla, A.; Milh,
M.; Girard, N.; Chabrol, B.; Philip, N.; Villard, L.: Deletion of
YWHAE in a patient with periventricular heterotopias and pronounced
corpus callosum hypoplasia. J. Med. Genet. 47: 132-136, 2009.

31. Miller, J. Q.: Lissencephaly in 2 siblings. Neurology 13: 841-850,
1963.

32. Nagamani, S. C. S.; Zhang, F.; Shchelochkov, O. A.; Bi, W.; Ou,
Z.; Scaglia, F.; Probst, F. J.; Shinawi, M.; Eng, C.; Hunter, J. V.;
Sparagana, S.; Lagoe, E.; and 13 others: Microdeletions including
YWHAE in the Miller-Dieker syndrome region on chromosome 17p13.3 result
in facial dysmorphisms, growth restriction, and cognitive impairment. J.
Med. Genet. 46: 825-833, 2009.

33. Neer, E. J.; Schmidt, C. J.; Smith, T.: LIS is more. Nature
Genet. 5: 3-4, 1993.

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

35. Oostra, B. A.; de Rijk-van Andel, J. F.; Eussen, H. J.; van Hemel,
J. O.; Halley, D. J. J.; Niermeijer, M. F.: DNA analysis in patients
with lissencephaly type I and other cortical dysplasias. Am. J. Med.
Genet. 40: 383-386, 1991.

36. Pollin, T. I.; Dobyns, W. B.; Crowe, C. A.; Ledbetter, D. H.;
Bailey-Wilson, J. E.; Smith, A. C. M.: Risk of abnormal pregnancy
outcome in carriers of balanced reciprocal translocations involving
the Miller-Dieker syndrome (MDS) critical region in chromosome 17p13.3. Am.
J. Med. Genet. 85: 369-375, 1999.

37. Reiner, O.; Carrozzo, R.; Shen, Y.; Wehnert, M.; Faustinella,
F.; Dobyns, W. B.; Caskey, C. T.; Ledbetter, D. H.: Isolation of
a Miller-Dieker lissencephaly gene containing G protein beta-subunit-like
repeats. Nature 364: 717-721, 1993.

38. Reznik, M.; Alberca-Serrano, R.: Forme familiale d'hypertelorisme
avec lissencephalie se presentant cliniquement sous forme d'une arrieration
mentale avec epilepsie et paraplegie spasmodique. J. Neurol. Sci. 1:
40-58, 1964.

39. Schinzel, A.: Microdeletion syndromes, balanced translocations,
and gene mapping. J. Med. Genet. 25: 454-462, 1988.

40. Schwartz, C. E.; Johnson, J. P.; Holycross, B.; Mandeville, T.
M.; Sears, T. S.; Graul, E. A.; Carey, J. C.; Schroer, R. J.; Phelan,
M. C.; Szollar, J.; Flannery, D. B.; Stevenson, R. E.: Detection
of submicroscopic deletions in band 17p13 in patients with the Miller-Dieker
syndrome. Am. J. Hum. Genet. 43: 597-604, 1988.

41. Selypes, A.; Laszlo, A.: Miller-Dieker syndrome and monosomy
17p13: a new case. Hum. Genet. 80: 103-104, 1988.

42. Sharief, N.; Craze, J.; Summers, D.; Butler, L.; Wood, C. B. S.
: Miller-Dieker syndrome with ring chromosome 17. Arch. Dis. Child. 66:
710-712, 1991.

43. Stratton, R. F.; Dobyns, W. B.; Airhart, S. D.; Ledbetter, D.
H.: New chromosomal syndrome: Miller-Dieker syndrome and monosomy
17p13. Hum. Genet. 67: 193-200, 1984.

44. Toyo-oka, K.; Hirotsune, S.; Gambello, M. J.; Zhou, Z.-Q.; Olson,
L.; Rosenfeld, M. G.; Eisenman, R.; Hurlin, P.; Wynshaw-Boris, A.
: Loss of the Max-interacting protein Mnt in mice results in decreased
viability, defective embryonic growth and craniofacial defects: relevance
to Miller-Dieker syndrome. Hum. Molec. Genet. 13: 1057-1067, 2004.

45. Toyo-oka, K.; Shionoya, A.; Gambello, M. J.; Cardoso, C.; Leventer,
R.; Ward, H. L.; Ayala, R.; Tsai, L.-H.; Dobyns, W.; Ledbetter, D.;
Hirotsune, S.; Wynshaw-Boris, A.: 14-3-3-epsilon is important for
neuronal migration by binding to NUDEL: a molecular explanation for
Miller-Dieker syndrome. Nature Genet. 34: 274-285, 2003.

46. vanTuinen, P.; Dobyns, W. B.; Rich, D. C.; Summers, K. M.; Robinson,
T. J.; Nakamura, Y.; Ledbetter, D. H.: Molecular detection of microscopic
and submicroscopic deletions associated with Miller-Dieker syndrome. Am.
J. Hum. Genet. 43: 587-596, 1988.

47. vanTuinen, P.; Ledbetter, D. H.: Construction and utilization
of a detailed somatic cell hybrid mapping panel for human chromosome
17: localization of an anonymous clone to the critical region of Miller-Dieker
syndrome, deletion 17p13. (Abstract) Cytogenet. Cell Genet. 46:
708-709, 1987.

48. Yingling, J.; Toyo-oka, K.; Wynshaw-Boris, A.: Miller-Dieker
syndrome: analysis of a human contiguous gene syndrome in the mouse. Am.
J. Hum. Genet. 73: 475-488, 2003.

*FIELD* CS
INHERITANCE:
Autosomal dominant

GROWTH:
[Height];
Intrauterine growth retardation;
[Other];
Failure to thrive

HEAD AND NECK:
[Head];
Microcephaly;
[Face];
Bitemporal hollowing;
Furrowing of forehead;
Micrognathia;
[Ears];
Low-set ears;
Posteriorly rotated ears;
[Eyes];
Cataract;
Upslanting palpebral fissures;
[Nose];
Small nose;
Upturned nares;
[Mouth];
Prominent upper lip;
Thin vermilion border of upper lip;
Cleft palate;
[Teeth];
Late tooth eruption

CARDIOVASCULAR:
[Heart];
Congenital heart defect

RESPIRATORY:
[Lung];
Aspiration pneumonia

ABDOMEN:
[External features];
Inguinal hernia;
[Gastrointestinal];
Duodenal atresia;
Omphalocele

GENITOURINARY:
[Internal genitalia, male];
Cryptorchidism;
[Kidneys];
Cystic kidney;
Pelvic kidney

SKELETAL:
[Hands];
Polydactyly;
Transverse palmar creases;
Clinodactyly;
Camptodactyly

SKIN, NAILS, HAIR:
[Skin];
Transverse palmar creases

NEUROLOGIC:
[Central nervous system];
Agyria;
Pachygyria;
Hypotonia early;
Hypertonia late;
Motor retardation;
Mental retardation;
Decorticate posture;
Decerebrate posture;
Progressive spastic paraplegia;
Infantile spasms;
Seizures;
Heterotopias;
Absent/Hypoplastic corpus callosum;
Large cavum septi pellucidi;
Failure of opercularization of the frontal and temporal lobes on CT;
Midline brain calcifications

PRENATAL MANIFESTATIONS:
[Movement];
Decreased fetal activity;
[Amniotic fluid];
Polyhydramnios

LABORATORY ABNORMALITIES:
Cytogenetic deletion of chromosome 17p13.3;
Fluorescence in situ hybridization specific probe for MDS critical
region

MISCELLANEOUS:
Death often before age 2;
Contiguous gene syndrome

MOLECULAR BASIS:
A contiguous gene syndrome caused by deletion of the lissencephaly
1 gene (LIS1, 601545) and the tyrosine 3-monooxygenase/tryptophan
5-monooxygenase activation protein, epsilon isoform gene (YWHAE, 605066)

*FIELD* CN
Joanna S. Amberger - updated: 12/30/2005
Ada Hamosh - reviewed: 4/11/2000
Kelly A. Przylepa - revised: 3/13/2000

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 04/20/2010
joanna: 4/16/2009
joanna: 12/30/2005
joanna: 12/12/2005
joanna: 3/30/2004
joanna: 2/19/2002
joanna: 12/3/2001
joanna: 4/18/2001
joanna: 4/12/2000
joanna: 4/11/2000
kayiaros: 3/13/2000

*FIELD* CN
Cassandra L. Kniffin - updated: 6/3/2010
George E. Tiller - updated: 9/6/2006
Victor A. McKusick - updated: 10/13/2003
Victor A. McKusick - updated: 6/9/2003
Ada Hamosh - updated: 5/9/2003
Victor A. McKusick - updated: 8/31/1999
Michael J. Wright - updated: 2/12/1999
Iosif W. Lurie - updated: 8/6/1996

*FIELD* CD
Victor A. McKusick: 6/3/1986

*FIELD* ED
mgross: 09/16/2013
alopez: 3/21/2013
terry: 6/21/2011
carol: 6/2/2011
wwang: 6/9/2010
ckniffin: 6/3/2010
carol: 1/12/2010
ckniffin: 1/12/2010
carol: 11/6/2009
terry: 6/3/2009
alopez: 9/6/2006
tkritzer: 10/16/2003
terry: 10/13/2003
alopez: 7/28/2003
alopez: 6/10/2003
terry: 6/9/2003
cwells: 5/13/2003
terry: 5/9/2003
ckniffin: 1/3/2003
carol: 3/14/2001
jlewis: 9/14/1999
terry: 8/31/1999
mgross: 3/4/1999
mgross: 3/1/1999
terry: 2/12/1999
alopez: 1/25/1999
carol: 11/30/1998
psherman: 3/31/1998
terry: 3/26/1998
joanna: 5/14/1997
mark: 12/4/1996
terry: 11/21/1996
mark: 9/3/1996
carol: 8/6/1996
mark: 1/17/1996
terry: 1/16/1996
mark: 6/8/1995
terry: 6/3/1995
pfoster: 5/23/1995
carol: 12/2/1994
mimadm: 4/29/1994
warfield: 4/15/1994

MIM 601545
*RECORD*
*FIELD* NO
601545
*FIELD* TI
*601545 PLATELET-ACTIVATING FACTOR ACETYLHYDROLASE, ISOFORM 1B, ALPHA SUBUNIT;
PAFAH1B1
read more;;LIS1 GENE; LIS1
*FIELD* TX

DESCRIPTION

Platelet-activating factor acetylhydrolase (PAFAH) catalyzes the removal
of the acetyl group at the sn-2 position of the glycerol backbone of
platelet-activating factor (PAF), producing biologically inactive
lyso-PAF. Isoform 1B of PAFAH consists of 3 subunits: alpha (PAFAH1B1),
beta (PAFAH1B2; 602508), and gamma (PAFAH1B3; 603074). The catalytic
activity of the enzyme resides in the beta and gamma subunits, whereas
the alpha subunit has regulatory activity (summary by Adachi et al.,
1995).

CLONING

The search for the gene involved in Miller-Dieker lissencephaly syndrome
(MDLS; 247200), a disorder of neural development characterized by agyria
and facial abnormalities, and classic lissencephaly (type I, LIS1;
601545), a disorder of isolated agyria, resulted in the identification
and characterization of the PAFAH1B1 (LIS1) gene. Ledbetter et al.
(1992) noted that about 90% of patients with MDLS have deletions of
17p13.3 and demonstrated that some patients with isolated lissencephaly
had smaller deletions in that chromosomal region. Reiner et al. (1993)
used degenerate PCR primers designed for conserved beta-transducin-like
repeats to screen a human fetal brain cDNA library. Using the
amplification product to screen the same library, they identified a cDNA
encoding a deduced 411-amino acid protein with 8 WD40 repeats
characteristic of heterotrimeric G proteins. Northern blot analysis of
human tissues revealed transcripts of at least 4 different sizes
(2.2-7.5 kb). Expression was detected in all tissues tested but was most
pronounced in brain, heart, and skeletal muscle. After mapping the cDNA
to chromosome 17p, Reiner et al. (1993) analyzed the cDNA in somatic
cell hybrids containing chromosome 17 from patients with MDLS.
Nonoverlapping deletions involving either the 5-prime or the 3-prime end
of the gene were found in 2 MDLS patients, identifying the gene, which
they called LIS1 (lissencephaly-1), as the disease gene.

Neer et al. (1993) commented on the nature of the LIS1 gene and the
usefulness of identifying families of genes and the proteins they
encode.

Platelet-activating factor (PAF) is involved in a variety of biologic
and pathologic processes (Hanahan, 1986). PAF acetylhydrolase, which
inactivates PAF by removing the acetyl group at the sn-2 position, is
widely distributed in plasma and tissue cytosols. One isoform of PAF
acetylhydrolase present in bovine brain cortex is a heterotrimer
comprising subunits with relative molecular masses of 45, 30 (PAFAH1B2;
602508), and 29 kD (PAFAH1B3; 603074) (Hattori et al., 1993). Hattori et
al. (1994) isolated the cDNA for the 45-kD subunit. Sequence analysis
revealed 99% identity with the LIS1 gene, indicating that the LIS1 gene
product is a human homolog of the 45-kD subunit of intracellular PAF
acetylhydrolase. The results raised the possibility that PAF and PAF
acetylhydrolase are important in the formation of the brain cortex
during differentiation and development.

GENE STRUCTURE

Chong et al. (1996) and Lo Nigro et al. (1997) characterized the LIS1
gene, demonstrating the presence of 11 exons.

MAPPING

Chong et al. (1997) corrected the positioning of the 5-prime end of the
LIS1 gene, constructed a genomic contig of approximately 500 kb
encompassing LIS1, and estimated the LIS1 gene extent to be 80 kb.
Fluorescence in situ hybridization (FISH) analysis of an ILS patient
with a de novo balanced translocation, as well as analysis of several
other key MDS and ILS deletion patients, localized the lissencephaly
minimal critical region to a 100-kb region centromeric to D17S379 and
telomeric to D17S1566, within the LIS1 gene.

- Pseudogenes

Reiner et al. (1995) identified 2 genes on chromosome 2 showing high
homology to the LIS1 gene. One, designated LIS2, at 2p was considered a
potential candidate for a form of lissencephaly; the other, designated
LIS2P, at 2q, was determined to be a pseudogene. By sequencing genomic
clones that were mapped by means of 2p- and 2q-only hybrids, Fogli et
al. (1999) determined that both genes are LIS1 processed pseudogenes
mapping to 2p11.2 (PAFAH1P1) and 2q13 (PAFAH1P2).

GENE FUNCTION

Reiner et al. (1993) suggested that the LIS1 gene may be involved in a
signal transduction pathway crucial for cerebral development. Since
haploinsufficiency appears to lead to the lissencephaly syndrome, half
the normal dosage of the gene product is apparently inadequate for
normal development. They speculated that improper proportions of beta
and gamma subunits of a G protein disturb formation of the normal
protein complex, as in hemoglobin H disease, which is caused by an
imbalance in the ratio of alpha- to beta-globin.

Smith et al. (2000) showed that LIS1 in mammals is enriched in neurons
relative to levels in other cell types, and that LIS1 interacts with the
microtubule motor cytoplasmic dynein (see 600112). Production of more
LIS1 in nonneuronal cells increases retrograde movement of cytoplasmic
dynein and leads to peripheral accumulation of microtubules. These
changes may reflect neuron-like dynein behaviors induced by abundant
LIS1. LIS1 deficiency produced the opposite phenotype. The results
indicated that abundance of LIS1 in neurons may stimulate specific
dynein functions that are involved in neuronal migration and axon
growth.

Caspi et al. (2000) demonstrated an interaction of LIS1 with
doublecortin (DCX; 300121) by coimmunoprecipitation, both in transiently
transfected cells and in embryonic brain extracts. Immunofluorescence
studies revealed that the 2 protein products colocalized in transfected
cells and in primary neuronal cells. LIS1 and DCX enhanced tubulin
polymerization in an additive fashion, as measured by a light-scattering
assay in vitro. The authors hypothesized that the interaction of LIS1
and DCX is important to proper microtubule function in the developing
cerebral cortex.

Faulkner et al. (2000) showed that LIS1 protein coimmunoprecipitates
with cytoplasmic dynein and dynactin (601143), and localizes to the cell
cortex and to mitotic kinetochores, which are known sites for binding of
cytoplasmic dynein. Overexpression of LIS1 in cultured mammalian cells
interfered with mitotic progression and led to spindle misorientation.
Injection of anti-LIS1 antibodies interfered with attachment of
chromosomes to the metaphase plate, and led to chromosome loss. Faulkner
et al. (2000) concluded that LIS1 participates in a subset of dynein
functions and may regulate the division of neuronal progenitor cells in
the developing brain.

Using database mining and protein structural prediction programs, Emes
and Ponting (2001) identified a sequence motif in the products of genes
mutated in MDLS, Treacher Collins syndrome (TCOF1, treacle; 606847),
oral-facial-digital syndrome type I (CXORF5; 300170), and ocular
albinism with late-onset sensorineural deafness (TBL1X; 300196). Over
100 eukaryotic intracellular proteins were found to possess a LIS1
homology motif, including several katanin p60 (606696) subunits,
muskelin (605623), Nopp140 (602394), the plant proteins tonneau and
LEUNIG, slime mold protein aimless, and numerous WD repeat-containing
beta-propeller proteins. The authors suggested that LIS1 homology motifs
may contribute to the regulation of microtubule dynamics, either by
mediating dimerization, or by binding cytoplasmic dynein heavy chain or
microtubules directly. The predicted secondary structure of LIS1
homology motifs, and their occurrence in homologs of G-beta
beta-propeller subunits, suggests that they are analogs of G-gamma
subunits, and might associate with the periphery of beta-propeller
domains. The finding of LIS1 homology motifs in both treacle and Nopp140
reinforces previous observations of functional similarities between
these nucleolar proteins.

Kitagawa et al. (2000) found that rat Nude (NDE1; 609449) and the
catalytic subunits of Pafah interacted with Pafah1b1 in a competitive
manner. They suggested that PAFAH1B1 functions in nuclear migration by
interacting with multiple intracellular proteins, including NUDE.

By analysis of crystalline structures of murine proteins, Tarricone et
al. (2004) determined that a Lis1 homodimer binds with either a
homodimer of Pafah1b2 (602508) or Ndel1 (607538) to form a tetramer.
Ndel1 competes with the Pafah1b2 homodimer for Lis1, but the interaction
is complex and requires both the N- and C-terminal domains of Lis1. The
data suggested that the Lis1 molecule undergoes major conformational
changes when switching from a complex with the acetylhydrolase subunit
to that with Ndel1.

Using RNA interference (RNAi) with cultured cell lines and mouse
embryonic day-15 cortical neurons, Shu et al. (2004) determined that
Ndel1 regulates dynein activity by facilitating the interaction between
Lis1 and dynein. Loss of Ndel1, Lis1, or dynein function in developing
neocortex impaired neuronal positioning and caused the uncoupling of
centrosomes and nuclei. Overexpression of Lis1 partially rescued the
positioning defect caused by Ndel1 RNAi but not that caused by dynein
RNAi, whereas overexpression of Ndel1 did not rescue the phenotype
induced by Lis1 RNAi. Shu et al. (2004) concluded that NDEL1 interacts
with LIS1 to sustain the function of dynein, which in turn impacts
microtubule organization, nuclear translocation, and neuronal
positioning.

Zhu et al. (2010) showed that NUDC (610325) and HSP90-alpha (HSP90AA1;
140571) formed an ATPase-dependent chaperone complex with LIS1. An
inactivating mutation in NUDC or pharmacologic inhibition of HSP90-alpha
resulted in LIS1 destabilization.

MOLECULAR GENETICS

Chong et al. (1996) performed SSCP analysis of individual exons in 19
patients with isolated lissencephaly sequence (LIS1; 607432) who showed
no deletions detectable by FISH. In 3 of these patients, point mutations
were identified: an A-to-G transition in exon 6 resulting in a
his149-to-arg missense mutation (601545.0001), a C-to-T transition in
exon 8 causing an arg247-to-ter nonsense mutation (610545.0002), and a
22-bp deletion at the exon 9-intron 9 junction predicted to result in a
splicing error (601545.0003). Lo Nigro et al. (1997) stated that these
data confirmed mutations of LIS1 as the cause of the lissencephaly
phenotype in LIS and in the Miller-Dieker syndrome. Together with the
results of deletion analysis for other LIS and Miller-Dieker syndrome
patients, these data were also consistent with the previous suggestion
that additional genes distal to LIS1 are responsible for the facial
dysmorphism and other anomalies in MDLS patients, thus supporting the
original concept of MDLS as a contiguous gene deletion syndrome.

Kurahashi et al. (1998) reported the case of a Japanese patient with
isolated lissencephaly sequence who carried a balanced chromosomal
translocation that disrupted the 5-prime untranslated region of the LIS1
gene. Sakamoto et al. (1998) examined the LIS1 gene in 8 additional
Japanese LIS patients and 4 MDS patients. FISH analysis showed deletion
of part of the LIS1 gene or of the chromosomal region surrounding it in
3 of the LIS cases and in 3 of the MDS cases. In 1 of the remaining 5
LIS cases, SSCP analysis and subsequent sequencing identified a 1-bp
deletion in exon 4, which would be expected to result in premature
termination of the gene product.

Cardoso et al. (2000) analyzed 29 nondeletion LIS patients carrying an
LIS1 mutation and reported 15 novel mutations. Patients with missense
mutations had a milder lissencephaly grade compared with those with
mutations leading to a shortened or truncated protein (P = 0.022). Early
truncation/deletion mutations in the putative microtubule-binding domain
resulted in a more severe lissencephaly than later truncation/deletion
mutations (P less than 0.001). Using a spectrum of LIS patients, the
importance of specific WD40 repeats and a putative microtubule-binding
domain for PAFAH1B1 function was confirmed. The authors suggested that
the small number of missense mutations identified may be due to
underdiagnosis of milder phenotypes, and hypothesized that the greater
lissencephaly severity seen in Miller-Dieker syndrome may be secondary
to the loss of another cortical development gene in the deletion of
17p13.3.

Leventer et al. (2001) described in detail 5 patients with missense
mutations in the LIS1 gene (601545.0001, 601545.0004-601545.0007) and
noted that the mild and highly variable spectrum of cortical
malformations and clinical sequelae are likely due to suboptimal
function of a mutant LIS1 protein rather than to complete loss of
function of the protein. The authors suggested that patients with LIS1
missense mutations are underrecognized and that abnormalities of the
LIS1 gene may account for a greater spectrum of neurologic problems in
childhood than previously appreciated.

In an investigation of 220 children with lissencephaly or subcortical
band heterotopia, Cardoso et al. (2002) found 65 large deletions of the
LIS1 gene detected by FISH and 41 intragenic mutations, including 4 not
previously reported. All intragenic mutations were de novo, and there
were no familial recurrences. In 88% (36 of 41) of the mutations a
truncated or internally deleted protein resulted; missense mutations
were found in only 12% (5 of 41). Mutations occurred throughout the gene
except for exon 7, with clustering of 3 of the 5 missense mutations in
exon 6. Only 5 intragenic mutations were recurrent. In general, the most
severe LIS phenotype was seen in patients with large deletions of
17p13.3, with milder phenotypes seen with intragenic mutations. Of
these, the mildest phenotypes were seen in patients with missense
mutations.

Mei et al. (2008) identified mutations in the LIS1 gene in 20 (44%) of
45 patients with isolated lissencephaly showing a posterior to anterior
gradient. In 19 (76%) of 25 patients in whom FISH and direct sequencing
had failed to detect mutations, MLPA analysis identified 18 small
genomic deletions and 1 duplication. Overall, small genomic
deletions/duplications represented 49% of all LIS1 alterations
identified, and LIS1 involvement was demonstrated in 39 (87%) of 45
patients. Breakpoint characterization in 5 patients suggested that
Alu-mediated recombination is a major molecular mechanism underlying
LIS1 deletions. Mei et al. (2008) noted the high diagnostic yield with
MLPA.

Among 63 patients with posterior predominant lissencephaly, Saillour et
al. (2009) identified 40 with LIS1 gene defects. There were 8 small
deletions and 31 heterozygous LIS1 mutations, including 12 nonsense, 8
frameshift, 6 missense, and 5 splicing defects. The mutations were found
scattered throughout the gene, except in exons 3 and 9, and all were
confirmed to be de novo. One patient had a somatic truncating mutation
present in 30% of the blood, but other tissues were not available for
testing.

Using multiplex ligation-dependent probe amplification (MLPA) analysis,
Haverfield et al. (2009) identified 12 deletions and 6 duplications
involving the LIS1 gene in 18 (35%) of 52 patients with an
anterior-to-posterior lissencephaly gradient in whom no molecular defect
had previously been identified. The majority of patients with LIS1
deletions or duplications had grade 3 lissencephaly. Most deletions and
duplications were scattered within the gene, but several deletions
included genes flanking LIS1, such as HIC1 (603825), or only included
noncoding putative upstream regulatory elements of LIS1. Haverfield et
al. (2009) suggested that genetic testing for isolated lissencephaly
should include both mutation and deletion/duplication analysis of the
LIS1 gene.

GENOTYPE/PHENOTYPE CORRELATIONS

Uyanik et al. (2007) identified 14 novel and 7 previously described LIS1
mutations in 21 unrelated patients, including 18 with type 1
lissencephaly, 1 with subcortical band heterotopia, and 2 with
lissencephaly with cerebellar hypoplasia. There were 9 truncating
mutations, 6 splice site mutations, 5 missense mutations, and an
in-frame deletion. Somatic mosaicism was assumed in 3 patients with
partial subcortical band heterotopia or mild pachygyria. Uyanik et al.
(2007) concluded that the severity of the phenotype is independent of
the type of mutation and its site within the coding region of the LIS1
gene.

Bi et al. (2009) reported 7 unrelated individuals with different
submicroscopic duplications of chromosome 17p13.3 (613215) involving the
LIS1 and/or the YWHAE (605066) gene. Four individuals had a duplication
of YWHAE but not LIS1, and 1 had a duplication of LIS1 but not YWHAE. A
sixth patient had a triplication of LIS1, and a seventh had duplication
of both genes. Analysis of the clinical features for each individual
indicated that individuals with LIS1 duplications had subtle brain
defects, including microcephaly, dysgenesis of the corpus callosum, and
cerebellar atrophy, as well as neurobehavioral disorders, including
delayed development, mental retardation, and attention
deficit-hyperactivity disorder. Patients with duplications of YWHAE
tended to have macrosomia, facial dysmorphism, and mild developmental
delay. Transgenic mice overexpressing Lis1 showed decreased brain size
and distorted cellular organization in the ventricular zone. Bi et al.
(2009) concluded that variations in dosage of LIS1 play a role in the
development of brain anomalies in humans and mice.

EVOLUTION

Human evolution is characterized by a dramatic increase in brain size
and complexity. To probe its genetic basis, Dorus et al. (2004) examined
the evolution of genes involved in diverse aspects of nervous system
biology. These genes, including PAFAH1B1, displayed significantly higher
rates of protein evolution in primates than in rodents. This trend was
most pronounced for the subset of genes implicated in nervous system
development. Moreover, within primates, the acceleration of protein
evolution was most prominent in the lineage leading from ancestral
primates to humans. Dorus et al. (2004) concluded that the phenotypic
evolution of the human nervous system has a salient molecular correlate,
i.e., accelerated evolution of the underlying genes, particularly those
linked to nervous system development.

ANIMAL MODEL

To understand further the function of platelet-activating factor
acetylhydrolase, Hirotsune et al. (1998) produced 3 different mutant
alleles in the mouse Pafah1b1 gene. Homozygous-null mice died early in
embryogenesis soon after implantation. Mice with 1 inactive allele
displayed cortical, hippocampal, and olfactory bulb disorganization
resulting from delayed neuronal migration by a cell-autonomous neuronal
pathway. Mice with further reduction of Pafah1b1 activity displayed more
severe brain disorganization as well as cerebellar defects. The results
demonstrated an essential, dosage-sensitive neuronal-specific role for
Pafah1b1 in neuronal migration throughout the brain, and an essential
role in early embryonic development. The phenotypes observed were
distinct from those of other mouse mutants with neuronal migration
defects, suggesting that Pafah1b1 participates in a novel pathway for
neuronal migration.

To study the function of the LIS1 gene, Cahana et al. (2001) deleted the
first coding exon from the mouse Lis1 gene. The deletion resulted in a
shorter protein that initiated from the second methionine, a unique
situation because most LIS1 mutations result in a null allele. This
mutation mimicked a mutation described in 1 lissencephaly patient with a
milder phenotype (Fogli et al., 1999). Homozygotes were early lethal,
although heterozygotes were viable and fertile. The morphology of
cortical neurons and radial glia was aberrant in the developing cortex,
and the neurons migrated more slowly. This was the first demonstration
of a cellular abnormality in the migrating neurons after Lis1 mutation.
Moreover, cortical plate splitting and thalamocortical innervation were
also abnormal. Biochemically, the mutant protein was not capable of
dimerization, and enzymatic activity was elevated in the embryos, thus a
demonstration of the in vivo role of LIS1 as a subunit of
platelet-activating factor acetylhydrolase.

Reduced LIS1 activity in both humans and mice results in a neuronal
migration defect. Liu et al. (2000) showed that Drosophila Lis1 is
highly expressed in the nervous system. It is, furthermore, essential
for neuroblast proliferation and axonal transport, as shown by a mosaic
analysis using a Lis1-null mutation. Analogous mosaic analysis showed
that neurons containing a mutated cytoplasmic dynein heavy chain
exhibited phenotypes similar to Lis1 mutants. These results implicated
LIS1 as a regulator of the microtubule cytoskeleton and showed that it
is important for diverse physiologic functions in the nervous system.

Yan et al. (2003) noted that PAF had been shown to affect sperm motility
and acrosomal function, thereby altering fertility. PAFAH1B hydrolyzes
PAF and is composed of 3 subunits--the LIS1 protein and PAFAH1B2 and
PAFAH1B3, which they called alpha-2 and alpha-1, respectively--and
structurally resembles a GTP-hydrolyzing protein. In addition to the
brain, transcripts for LIS1, alpha-1, and alpha-2 are localized to
meiotic and early haploid germ cells. Yan et al. (2003) disrupted the
alpha-2 and alpha-1 genes in mice. Male mice homozygous-null for alpha-2
were infertile and spermatogenesis was disrupted at mid- or late
pachytene stages of meiosis or early spermiogenesis. Whereas mice
homozygous mutant for alpha-1 had normal fertility and normal
spermatogenesis, those with disruption of both alpha-1 and alpha-2
manifested an earlier disturbance of spermatogenesis with an onset at
preleptotene or leptotene stages of meiosis. Testicular Lis1 protein
levels were upregulated in the alpha-2-null and alpha-1/alpha-2
double-null mice. Lowering Lis1 levels by inactivating 1 allele of Lis1
in alpha-2-null or alpha-1/alpha-2-null genetic backgrounds restored
spermatogenesis and male fertility. The data provided evidence for
unique roles of the PAFAH1B complex, particularly the LIS1 protein, in
spermatogenesis.

Assadi et al. (2003) investigated interactions between the reelin (Reln;
600514) signaling pathway and Lis1 in brain development. Compound mutant
mice with disruptions in the Reln pathway and heterozygous mutations in
the Pafah1b1 gene had a higher incidence of hydrocephalus and enhanced
cortical and hippocampal layering defects. The Dab1 (603448) 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.

Williams et al. (2004) showed that convulsions mimicking epilepsy can be
induced by a mutation in a C. elegans lis1 allele (pnm1), in combination
with a chemical antagonist of gamma-aminobutyric acid (GABA)
neurotransmitter signaling. Identical convulsions were obtained using C.
elegans mutants defective in GABA transmission, whereas mutations or
GABA antagonist alone did not cause convulsions, indicating a threshold
was exceeded in response to this combination. Crosses between pnm1 worms
and fluorescent-marker strains, which are designed to exclusively
illuminate either the processes of GABAergic neurons or synaptic
vesicles, showed no deviations in neuronal architecture, but presynaptic
defects in GABAergic vesicle distribution were clearly evident and could
be phenocopied by RNAi directed against cytoplasmic dynein (see 600112),
a known LIS1 interactor. Mutations in unc104 (ATSV; 601255) and snb1
(VAMP1; 185880) exhibited similar convulsion phenotypes following
chemical induction.

Interaction between Nde1 (609449) and Lis1 is critical in the
development of the mouse central nervous system (CNS). Pawlisz et al.
(2008) analyzed a series of Nde1 and Lis1 double mutations in mice and
showed that the Nde1-Lis1 complex was specifically required by the
radial glial/neuroepithelial progenitor cells during CNS development.
Besides mitotic spindle regulation, Lis1 and Nde1 maintained the
morphology and lateral cell-cell contacts of progenitors in the cortical
ventricular zone. This cell shape and organization control appeared
necessary for symmetrical cell division and the self-renewal of neural
progenitors during the early phase of corticogenesis. Loss of Lis1-Nde1
function led to dramatically increased neuronal differentiation at the
onset of cortical neurogenesis, resulting in overproduction of the
earliest-born preplate and Cajal-Retzius neurons, with consequent loss
of the laminar pattern and over 80% mass and surface area of the
cerebral cortex.

Yamada et al. (2009) demonstrated that inhibition or knockdown of
calpains (see, e.g., CAPN1; 114220) protected the Lis1 protein from
proteolysis in Lis1 +/- mouse embryonic fibroblasts. Increased protein
levels rescued the aberrant distribution of cytoplasmic dynein and
mitochondria observed in Lis1 +/- cells, consistent with an improvement
in function. Calpain inhibitors also improved neuronal migration of Lis1
+/- cerebellar granular neurons. Intraperitoneal injection of the
calpain inhibitor to pregnant Lis1 +/- dams rescued apoptotic neuronal
cell death and partially rescued neuronal migration defects in Lis1 +/-
offspring. Furthermore, in utero knockdown of calpain by short hairpin
RNA rescued defective cortical layering in Lis1+/- mice. Yamada et al.
(2009) suggested that LIS1 is specifically degraded by calpain, and that
calpain inhibition could be a potential therapeutic intervention for
lissencephaly due to haploinsufficiency of LIS1.

Greenwood et al. (2009) demonstrated that Lis1 +/- mice develop
spontaneous seizures. Electrophysiologic studies on hippocampal slices
derived from these mice had a nearly 2-fold increase in the frequency of
spontaneous and miniature excitatory postsynaptic currents (EPSC)
associated with increased glutamate-mediated excitation without a change
in receptor patterns. Electron microscopic analysis showed a large
increase in presynaptic vesicle number, which corresponded with enhanced
excitatory drive. Use of a nonspecific calcium channel blocker restored
abnormal paired-pulse facilitation to normal.

*FIELD* AV
.0001
LISSENCEPHALY 1
PAFAH1B1, HIS149ARG

In a patient with lissencephaly 1 (607432) in whom no deletions of 17p
were detectable by FISH, Chong et al. (1996) identified an A-to-G
transition at nucleotide 446 in exon 6 of the PAFAH1B1 gene, resulting
in a his149-to-arg substitution. See also Lo Nigro et al. (1997).
Leventer et al. (2001) described the patient reported by Chong et al.
(1996) in greater detail. From infancy, the patient showed developmental
delay, myoclonic jerks and spasms, seizures, generalized hypotonia,
microcephaly, and dysmorphic facies. Brain MRI revealed moderate agyria
in the occipital lobes transitioning to pachygyria anteriorly as well as
flattening of the corpus callosum and mild dilation of the posterior
horns of the lateral ventricles. The patient developed progressive
spasticity and died of sepsis at age 4 years. Leventer et al. (2001)
noted that this mutation interrupts a highly conserved invariant amino
acid and is predicted to change the protein conformation significantly.

.0002
LISSENCEPHALY 1
PAFAH1B1, ARG273TER

In a patient with isolated lissencephaly sequence (607432) in whom no
deletions of 17p were detectable by FISH, Chong et al. (1996) identified
a C-to-T transition at nucleotide 817 in exon 8 of the PAFAH1B1 gene,
resulting in an arg273-to-ter mutation. See also Lo Nigro et al. (1997).

.0003
LISSENCEPHALY 1
PAFAH1B1, 22-BP DEL

In a patient with isolated lissencephaly sequence (607432) in whom no
deletions of 17p were detectable by FISH, Chong et al. (1996) identified
a 22-bp deletion at the exon 9-intron 9 junction of the PAFAH1B1 gene
from nucleotide 988 to 1002+7, predicted to result in a splicing error.
Lo Nigro et al. (1997) noted that the deletion abolished amino acids 301
to 334 of the mature predicted protein.

.0004
SUBCORTICAL LAMINAR HETEROTOPIA
PAFAH1B1, SER169PRO

In a boy with subcortical band heterotopia (607432), Pilz et al. (1999)
identified a T-to-C transition at nucleotide 499 in exon 6 of the
PAFAH1B1 gene, resulting in a ser169-to-pro substitution. The mutation
was not found in the boy's parents. Leventer et al. (2001) described the
boy reported by Pilz et al. (1999) in greater detail. As a child, he had
mild global developmental delay and complex partial seizures. MRI showed
posterior subcortical band heterotopia and mild dilation of the
posterior horns of the lateral ventricles. At age 23 years, he worked as
an unskilled manual laborer and enjoyed normal activities, although
seizures remained a problem. Leventer et al. (2001) suggested that the
milder phenotype may be due to somatic mosaicism.

.0005
LISSENCEPHALY 1
PAFAH1B1, ASP317HIS

Leventer et al. (2001) reported a patient with generalized hypotonia and
poor visual and social interaction who later developed complex partial
seizures. MRI revealed moderate pachygyria, consistent with isolated
lissencephaly sequence (607432), that was most severe in the
parietooccipital regions, hypoplasia of the rostral corpus callosum, and
mild dilation of the posterior horns of the lateral ventricles.
Sequencing of the LIS1 gene showed a 949G-C mutation in exon 9,
resulting in an asp317-to-his substitution. At age 4 years, the patient
could feed himself and understand simple commands.

.0006
LISSENCEPHALY 1
PAFAH1B1, PHE31SER

Leventer et al. (2001) reported a girl with isolated lissencephaly
sequence (607432) who had global developmental delay and hypotonia and
later developed myoclonic jerks, absence seizures, and febrile seizures.
Brain MRI showed moderate generalized pachygyria that was most severe in
the occipitoparietal regions, hypoplasia of the cerebellar vermis,
hypoplasia of the rostral corpus callosum, and mild dilation of the
lateral ventricles. Sequencing of the LIS1 gene showed a 92T-C change in
exon 3, resulting in a phe31-to-ser substitution, in the N-terminal
region outside of the WD repeats which confer correct protein structure
and folding. At age 12 years, she walked with assistance, was
toilet-trained, and had limited communication skills.

.0007
LISSENCEPHALY 1
PAFAH1B1, GLY162SER

Leventer et al. (2001) reported a boy with speech and walking delay and
strabismus who later developed complex partial seizures. Brain MRI
showed moderate pachygyria restricted to the occipital and posterior
parietal lobes, consistent with isolated lissencephaly sequence
(607432). Sequencing of the LIS1 gene showed a 484G-A transition in exon
6, resulting in a gly162-to-ser substitution. At age 6 years, the boy
attended a developmental preschool, played sports, and was found to have
an IQ of 100. The authors noted that this amino acid change has been
found as a variant in other WD proteins, which may explain the mild LIS1
phenotype in this patient.

.0008
SUBCORTICAL LAMINAR HETEROTOPIA
PAFAH1B1, ARG241PRO

In a male patient with subcortical band heterotopia (607432), Sicca et
al. (2003) identified somatic mosaicism for a 722G-C transversion in
exon 8 of the LIS1 gene, resulting in an arg241-to-pro (R241P)
substitution. The mutant allele was present in 18% of lymphocyte DNA and
21% of hair root DNA. The patient had delayed language and motor
development as a child, and later showed severe mental retardation,
spasticity, and seizures. Brain MRI showed subcortical band heterotopia
in posterior regions. Sicca et al. (2003) noted that the patient had a
less severe phenotype than those with lissencephaly, likely due to the
somatic mosaicism.

.0009
SUBCORTICAL LAMINAR HETEROTOPIA
LISSENCEPHALY 1
PAFAH1B1, ARG8TER

In a male patient with subcortical laminar heterotopia (607432), Sicca
et al. (2003) identified somatic mosaicism for a 22C-T transition in
exon 2 of the LIS1 gene, resulting in an arg8-to-ter (R8X) mutation. The
mutant allele was present in 24% of lymphocyte DNA and 31% of hair root
DNA. The patient had seizures and mild mental retardation as well as
posterior subcortical laminar heterotopia. The phenotype was relatively
mild compared to full-blown lissencephaly. In a male patient with
lissencephaly, Sicca et al. (2003) identified the R8X mutation. The
patient did not show somatic mosaicism and had a very severe phenotype.
The authors noted that these examples suggested that somatic mosaicism
results in a less severe phenotype.

.0010
LISSENCEPHALY 1
PAFAH1B1, HIS277PRO

In a patient with a severe form of isolated lissencephaly sequence
(607432), Torres et al. (2004) identified a 1385A-C transversion in the
LIS1 gene, resulting in a his277-to-pro (H277P) substitution in the
fifth WD-40 domain of the protein. Sequence alignment showed that the
mutated histidine is a conserved amino acid in different organisms, but
not when compared to different proteins with WD domains. The authors
emphasized that missense mutations in LIS1 are not always associated
with milder phenotypes.

*FIELD* RF
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14. Greenwood, J. S. F.; Wang, Y.; Estrada, R. C.; Ackerman, L.; Ohara,
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17. Hattori, M.; Arai, H.; Inoue, K.: Purification and characterization
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18. Haverfield, E. V.; Whited, A. J.; Petras, K. S.; Dobyns, W. B.;
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20. Kitagawa, M.; Umezu, M.; Aoki, J.; Koizumi, H.; Arai, H.; Inoue,
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21. Kurahashi, H.; Sakamoto, M.; Ono, J.; Honda, A.; Okada, S.; Nakamura,
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22. Ledbetter, S. A.; Kuwano, A.; Dobyns, W. B.; Ledbetter, D. H.
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23. Leventer, R. J.; Cardoso, C.; Ledbetter, D. H.; Dobyns, W. B.
: LIS1 missense mutations cause milder lissencephaly phenotypes including
a child with normal IQ. Neurology 57: 416-422, 2001.

24. Liu, Z.; Steward, R.; Luo, L.: Drosophila Lis1 is required for
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25. Lo Nigro, C.; Chong, S. S.; Smith, A. C. M.; Dobyns, W. B.; Carrozzo,
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1997.

26. Mei, D.; Lewis, R.; Parrini, E.; Lazarou, L. P.; Marini, C.; Pilz,
D. T.; Guerrini, R.: High frequency of genomic deletions--and a duplication
--in the LIS1 gene in lissencephaly: implications for molecular diagnosis. J.
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27. Neer, E. J.; Schmidt, C. J.; Smith, T.: LIS is more. Nature
Genet. 5: 3-4, 1993.

28. Pawlisz, A. S.; Mutch, C.; Wynshaw-Boris, A.; Chenn, A.; Walsh,
C. A.; Feng, Y.: Lis1-Nde1-dependent neuronal fate control determines
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2008.

29. Pilz, D. T.; Kuc, J.; Matsumoto, N.; Bodurtha, J.; Bernadi, B.;
Tassinari, C. A.; Dobyns, W. B.; Ledbetter, D. H.: Subcortical band
heterotopia in rare affected males can be caused by missense mutations
in DCX (XLIS) or LIS1. Hum. Molec. Genet. 8: 1757-1760, 1999.

30. Reiner, O.; Bar-Am, I.; Sapir, T.; Shmueli, O.; Carrozzo, R.;
Lindsay, E. A.; Baldini, A.; Ledbetter, D. H.; Cahana, A.: LIS2,
gene and pseudogene, homologous to LIS1 (lissencephaly 1), located
on the short and long arms of chromosome 2. Genomics 30: 251-256,
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31. Reiner, O.; Carrozzo, R.; Shen, Y.; Wehnert, M.; Faustinella,
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repeats. Nature 364: 717-721, 1993.

32. Saillour, Y.; Carion, N.; Quelin, C.; Leger, P.-L.; Boddaert,
N.; Elie, C.; Toutain, A.; Mercier, S.; Barthez, M. A.; Milh, M.;
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lissencephaly: spectrum of mutations and relationships with malformation
severity. Arch. Neurol. 66: 1007-1015, 2009.

33. Sakamoto, M.; Ono, J.; Okada, S.; Masuno, M.; Nakamura, Y.; Kurahashi,
H.: Alteration of the LIS1 gene in Japanese patients with isolated
lissencephaly sequence or Miller-Dieker syndrome. Hum. Genet. 103:
586-589, 1998.

34. Shu, T.; Ayala, R.; Nguyen, M.-D.; Xie, Z.; Gleeson, J. G.; Tsai,
L.-H.: Ndel1 operates in a common pathway with LIS1 and cytoplasmic
dynein to regulate cortical neuronal positioning. Neuron 44: 263-277,
2004.

35. Sicca, F.; Kelemen, A.; Genton, P.; Das, S.; Mei, D.; Moro, F.;
Dobyns, W. B.; Guerrini, R.: Mosaic mutations of the LIS1 gene cause
subcortical band heterotopia. Neurology 61: 1042-1046, 2003.

36. Smith, D. S.; Niethammer, M.; Ayala, R.; Zhou, Y.; Gambello, M.
J.; Wynshaw-Boris, A.; Tsai, L.-H.: Regulation of cytoplasmic dynein
behaviour and microtubule organization by mammalian Lis1. Nature
Cell Biol. 2: 767-775, 2000.

37. Tarricone, C.; Perrina, F.; Monzani, S.; Massimiliano, L.; Kim,
M.-H.; Derewenda, Z. S.; Knapp, S.; Tsai, L.-H.; Musacchio, A.: Coupling
PAF signaling to dynein regulation: structure of LIS1 in complex with
PAF-acetylhydrolase. Neuron 44: 809-821, 2004.

38. Torres, F. R.; Montenegro, M. A.; Marques-de-Faria, A. P.; Guerreiro,
M. M.; Cendes, F.; Lopes-Cendes, I.: Mutation screening in a cohort
of patients with lissencephaly and subcortical band heterotopia. Neurology 62:
799-802, 2004.

39. Uyanik, G.; Morris-Rosendahl, D. J.; Stiegler, J.; Klapecki, J.;
Gross, C.; Berman, Y.; Martin, P.; Dey, L.; Spranger, S.; Korenke,
G. C.; Schreyer, I.; Hertzberg, C.; and 25 others: Location and
type of mutation in the LIS1 gene do not predict phenotypic severity. Neurology 69:
442-447, 2007.

40. Williams, S. N.; Locke, C. J.; Braden, A. L.; Caldwell, K. A.;
Caldwell, G. A.: Epileptic-like convulsions associated with LIS-1
in the cytoskeletal control of neurotransmitter signaling in Caenorhabditis
elegans. Hum. Molec. Genet. 13: 2043-2059, 2004.

41. Yamada, M.; Yoshia, Y.; Mori, D.; Takitoh, T.; Kengaku, M.; Umeshima,
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42. Yan, W.; Assadi, A. H.; Wynshaw-Boris, A.; Eichele, G.; Matzuk,
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43. Zhu, X.-J.; Liu, X.; Jin, Q.; Cai, Y.; Yang, Y.; Zhou, T.: The
L279P mutation of nuclear distribution gene C (NudC) influences its
chaperone activity and lissencephaly protein 1 (LIS1) stability. J.
Biol. Chem. 285: 29903-29910, 2010.

*FIELD* CN
Patricia A. Hartz - updated: 2/10/2012
Cassandra L. Kniffin - updated: 1/28/2011
Cassandra L. Kniffin - updated: 7/19/2010
Cassandra L. Kniffin - updated: 11/18/2009
Patricia A. Hartz - updated: 11/3/2009
Cassandra L. Kniffin - updated: 3/10/2009
Cassandra L. Kniffin - updated: 10/2/2008
Cassandra L. Kniffin - updated: 11/26/2007
George E. Tiller - updated: 3/21/2007
Patricia A. Hartz - updated: 6/28/2005
Patricia A. Hartz - updated: 5/16/2005
Cassandra L. Kniffin - updated: 4/5/2005
Stylianos E. Antonarakis - updated: 1/10/2005
Cassandra L. Kniffin - updated: 9/15/2004
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Victor A. McKusick - updated: 7/14/2003
Cassandra L. Kniffin - reorganized: 1/3/2003
Cassandra L. Kniffin - updated: 12/10/2002
George E. Tiller - updated: 6/11/2002
Victor A. McKusick - updated: 1/15/2002
Victor A. McKusick - updated: 6/27/2001
Carol A. Bocchini - updated: 3/14/2001
George E. Tiller - updated: 3/5/2001
Victor A. McKusick - updated: 1/12/2001
George E. Tiller - updated: 12/14/2000
Victor A. McKusick - updated: 10/13/1999
Victor A. McKusick - updated: 12/10/1998
Victor A. McKusick - updated: 7/27/1998
Victor A. McKusick - updated: 4/15/1997
Victor A. McKusick - updated: 2/25/1997

*FIELD* CD
Victor A. McKusick: 12/2/1996

*FIELD* ED
alopez: 03/21/2013
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mark: 2/25/1997
terry: 2/24/1997
mark: 12/4/1996

MIM 607432
*RECORD*
*FIELD* NO
607432
*FIELD* TI
#607432 LISSENCEPHALY 1; LIS1
;;LISSENCEPHALY SEQUENCE, ISOLATED; ILS;;
LISSENCEPHALY, CLASSIC
read moreSUBCORTICAL LAMINAR HETEROTOPIA, INCLUDED; SCLH, INCLUDED;;
SUBCORTICAL BAND HETEROTOPIA, INCLUDED; SBH, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because lissencephaly-1 and
subcortical band heterotopia can both be caused by heterozygous mutation
in the PAFAH1B1 gene (601545) on chromosome 17p13.3.

DESCRIPTION

Lissencephaly (LIS), literally meaning smooth brain, is characterized by
smooth or nearly smooth cerebral surface and a paucity of gyral and
sulcal development, encompassing a spectrum of brain surface
malformations ranging from complete agyria to subcortical band
heterotopia (SBH). Classic lissencephaly is associated with an
abnormally thick cortex, reduced or abnormal lamination, and diffuse
neuronal heterotopia. SBH consists of circumferential bands of
heterotopic neurons located just beneath the cortex and separated from
it by a thin band of white matter. SBH represents the less severe end of
the lissencephaly spectrum of malformations (Pilz et al., 1999, summary
by Kato and Dobyns, 2003). Agyria, i.e., brain without convolutions or
gyri, was considered a rare malformation until recent progress in
neuroradiology (Bordarier et al., 1986). With this technical advantage,
a number of lissencephaly syndromes have been distinguished.

Classic lissencephaly (formerly type I) is a brain malformation caused
by abnormal neuronal migration at 9 to 13 weeks' gestation, resulting in
a spectrum of agyria, mixed agyria/pachygyria, and pachygyria. It is
characterized by an abnormally thick and poorly organized cortex with 4
primitive layers, diffuse neuronal heterotopia, enlarged and dysmorphic
ventricles, and often hypoplasia of the corpus callosum. (Lo Nigro et
al., 1997).

Kato and Dobyns (2003) presented a classification system for neuronal
migration disorders based on brain imaging findings and molecular
analysis. The authors also reviewed the contributions and interactions
of the 5 genes then known to cause human lissencephaly: LIS1 or
PAFAH1B1, 14-3-3-epsilon (YWHAE), DCX, RELN, and ARX.

- Genetic Heterogeneity of Lissencephaly

Lissencephaly is a genetically heterogeneous disorder. See also LIS2
(257320), caused by mutation in the RELN gene (600514) on chromosome
7q22; LIS3 (611603), caused by mutation in the TUBA1A gene (602529) on
chromosome 12q13; LIS4 (614019), caused by mutation in the NDE1 gene
(609449) on chromosome 16p13; and LIS5 (615191), caused by mutation in
the LAMB1 gene (150240) on chromosome 7q. X-linked forms include LISX1
(300067), caused by mutation in the DCX gene (300121) on chromosome
Xq22.3-q23, and LISX2 (300215), caused by mutation in the ARX gene
(300382) on chromosome Xp22.3-p21.1.

See also Miller-Dieker lissencephaly syndrome (MDLS; 247200), a
contiguous gene microdeletion syndrome involving chromosome 17p13 and
including the PAFAH1B1 and YWHAE (605066) genes. Lissencephaly caused by
mutations in the PAFAH1B1 gene is also called 'isolated' lissencephaly
to distinguish it from the accompanying features of MDLS.

CLINICAL FEATURES

Chong et al. (1996) reported a patient with isolated lissencephaly who
had a mutation in the LIS1 gene (601545.0001; see MOLECULAR GENETICS).
Leventer et al. (2001) described the patient reported by Chong et al.
(1996) in greater detail. From infancy, the patient showed developmental
delay, myoclonic jerks and spasms, seizures, generalized hypotonia,
microcephaly, and dysmorphic facies. Brain MRI revealed moderate agyria
in the occipital lobes transitioning to pachygyria anteriorly as well as
flattening of the corpus callosum and mild dilation of the posterior
horns of the lateral ventricles. The patient developed progressive
spasticity and died of sepsis at age 4 years.

Leventer et al. (2001) reported a patient with generalized hypotonia and
poor visual and social interaction who later developed complex partial
seizures. MRI revealed moderate pachygyria, consistent with isolated
lissencephaly sequence, that was most severe in the parietooccipital
regions, hypoplasia of the rostral corpus callosum, and mild dilation of
the posterior horns of the lateral ventricles. At age 4 years, the
patient could feed himself and understand simple commands.

Leventer et al. (2001) reported a girl with isolated lissencephaly
sequence who had global developmental delay and hypotonia and later
developed myoclonic jerks, absence seizures, and febrile seizures. Brain
MRI showed moderate generalized pachygyria that was most severe in the
occipitoparietal regions, hypoplasia of the cerebellar vermis,
hypoplasia of the rostral corpus callosum, and mild dilation of the
lateral ventricles. At age 12 years, she walked with assistance, was
toilet-trained, and had limited communication skills.

Leventer et al. (2001) reported a boy with speech and walking delay and
strabismus who later developed complex partial seizures. Brain MRI
showed moderate pachygyria restricted to the occipital and posterior
parietal lobes, consistent with isolated lissencephaly sequence. At age
6 years, the boy attended a developmental preschool, played sports, and
was found to have an IQ of 100.

Saillour et al. (2009) found that 40 of 63 patients with posterior
predominant lissencephaly had a LIS1 mutation or deletion, including 1
patient with somatic mosaicism for a nonsense mutation. Most patients
with LIS1 mutations had posterior agyria and anterior pachygyria
(55.3%). Diffuse agyria was observed in 9 (23.7%) patients, and
posterior predominant pachygyria was seen in 6 (15.8%). Twenty-two
(64.7%) of 34 patients had corpus callosum abnormalities, with either
thinning or abnormal thickening. Prominent perivascular spaces were seen
in 23 (67.4%) cases and enlarged ventricles in 28 (73.7%). The degree of
neuromotor impairment was in accordance with the severity of
lissencephaly, with a high incidence of tetraplegia (61.1%). However,
the severity of epilepsy could not show the same reliability, because
82.9% had early onset of seizures, and 48.7% had seizures more often
than daily. Mutation type and location did not predict the severity of
LIS1-related lissencephaly. In comparison, patients without LIS1
mutation tended to have less severe lissencephaly and no additional
brain abnormalities.

- Subcortical Laminar Heterotopia

Pilz et al. (1999) reported a boy with subcortical band heterotopia who
had a mutation in the LIS1 gene (601545.0004, see MOLECULAR GENETICS).
Leventer et al. (2001) described the boy reported by Pilz et al. (1999)
in greater detail. As a child, he had mild global developmental delay
and complex partial seizures. MRI showed posterior subcortical band
heterotopia and mild dilation of the posterior horns of the lateral
ventricles. At age 23 years, he worked as an unskilled manual laborer
and enjoyed normal activities, although seizures remained a problem.
Leventer et al. (2001) suggested that the milder phenotype may be due to
somatic mosaicism.

In 2 male patients with subcortical band heterotopia, Sicca et al.
(2003) identified somatic mosaicism for mutations in the LIS1 gene:
arg241 to pro (R241P; 601545.0008) and arg8 to ter (R8X; 601545.0009),
respectively. The mutant alleles were present in 18% and 24% of
lymphocyte DNA and 21% and 31% of hair root DNA, respectively. The
patients had mental retardation, seizures, and posterior SBH on brain
MRI, but the phenotype was not as severe as full-blown lissencephaly. In
a male patient with lissencephaly, Sicca et al. (2003) identified the
R8X mutation. This third patient did not show somatic mosaicism and had
a very severe phenotype. The authors noted that these examples suggested
that somatic mosaicism results in a less severe phenotype.

MOLECULAR GENETICS

The majority of patients with classic lissencephaly have deletions in
the LIS1 gene. Cardoso et al. (2002) found that 65 of 98 patients with
isolated lissencephaly or MLDS had large deletions of the LIS1 gene.
Among 41 intragenic LIS1 mutations, 36 (88%) resulted in a truncated or
internally deletion protein. Only 5 (12%) of 41 were missense mutations.
mutations were found in only 12% (5 of 41). Mutations occurred
throughout the gene except for exon 7.

In 3 patients with isolated lissencephaly sequence in whom no deletions
of 17p were detectable by FISH, Chong et al. (1996) identified 3
mutations in the PAFAH1B1 gene (601545.0001-601545.0003). See also Lo
Nigro et al. (1997). Leventer et al. (2001) reported 3 novel mutations
in the PAFAH1B1 gene in patients with ILS (601545.0005-601545.0007). In
a patient with subcortical laminar heterotopia, Pilz et al. (1999)
identified a mutation in the PAFAH1B1 gene (601545.0004).

Cardoso et al. (2003) completed a physical and transcriptional map of
the 17p13.3 region from LIS1 to the telomere. Using FISH, they mapped
the deletion size in 19 children with ILS, 11 children with MDS, and 4
children with 17p13.3 deletions not involving LIS1. They showed that the
critical region that differentiates ILS from MDS at the molecular level
can be reduced to 400 kb. Using somatic cell hybrids from selected
patients, the authors identified 8 genes that are consistently deleted
in patients classified as having MDS. These genes include ABR (600365),
14-3-3-epsilon (605066), CRK (164762), MYO1C (606538), SKIP (603055),
PITPNA (600174), SCARF1, RILP, PRP8 (607300), and SERPINF1 (172860). In
addition, deletion of the genes CRK and 14-3-3-epsilon delineates
patients with the most severe lissencephaly grade. On the basis of
recent functional data and the creation of a mouse model suggesting a
role for 14-3-3-epsilon in cortical development, Cardoso et al. (2003)
suggested that deletion of 1 or both of these genes in combination with
deletion of LIS1 may contribute to the more severe form of lissencephaly
seen only in patients with Miller-Dieker syndrome.

Mei et al. (2008) identified mutations in the LIS1 gene in 20 (44%) of
45 patients with isolated lissencephaly showing a posterior to anterior
gradient. In 19 (76%) of 25 patients in whom FISH and direct sequencing
had failed to detect mutations, MLPA analysis identified 18 small
genomic deletions and 1 duplication. Overall, small genomic
deletions/duplications represented 49% of all LIS1 alterations
identified, and LIS1 involvement was demonstrated in 39 (87%) of 45
patients. Breakpoint characterization in 5 patients suggested that
Alu-mediated recombination is a major molecular mechanism underlying
LIS1 deletions. Mei et al. (2008) noted the high diagnostic yield with
MLPA.

Among 63 patients with posterior predominant lissencephaly, Saillour et
al. (2009) identified 40 with LIS1 gene defects. There were 8 small
deletions and 31 heterozygous LIS1 mutations, including 12 nonsense, 8
frameshift, 6 missense, and 5 splicing defects. The mutations were found
scattered throughout the gene, except in exons 3 and 9, and all were
confirmed to be de novo. One patient had a somatic truncating mutation
present in 30% of the blood, but other tissues were not available for
testing.

Using multiplex ligation-dependent probe amplification (MLPA) analysis,
Haverfield et al. (2009) identified 12 deletions and 6 duplications
involving the LIS1 gene in 18 (35%) of 52 patients with an
anterior-to-posterior lissencephaly gradient in whom no molecular defect
had previously been identified. The majority of patients with LIS1
deletions or duplications had grade 3 lissencephaly. Most deletions and
duplications were scattered within the gene, but several deletions
included genes flanking LIS1, such as HIC1 (603825), or only included
noncoding putative upstream regulatory elements of LIS1. Haverfield et
al. (2009) suggested that genetic testing for isolated lissencephaly
should include both mutation and deletion/duplication analysis of the
LIS1 gene.

GENOTYPE/PHENOTYPE CORRELATIONS

By direct DNA sequencing of the LIS1 and DCX genes in 25 children with
sporadic lissencephaly and no deletion of the LIS1 gene by FISH
analysis, Pilz et al. (1998) identified LIS1 mutations in 8 (32%)
patients and DCX mutations in 5 (20%). All the LIS1 mutations were de
novo: 6 were truncating, and 2 were splice site mutations. Two
additional patients were found to have de novo LIS1 rearrangements by
Southern blot analysis. Phenotypic studies showed that those with LIS1
mutation had more severe lissencephaly over the parietal and occipital
brain regions, whereas those with DCX mutations had the reverse
gradient, with more severe lissencephaly over the frontal regions. All
DCX mutation carriers also had mild hypoplasia and upward rotation of
the cerebellar vermis, but these changes were only seen in about 20% of
patients with LIS1 mutations. Overall, mutations of LIS1 or DCX were
found in 60% of patients in this study. Combined with the previously
observed frequency of LIS1 mutations detected by FISH, Pilz et al.
(1998) concluded that these 2 genes account for about 76% of sporadic
lissencephaly.

Dobyns et al. (1999) compared the phenotype of 48 children with
lissencephaly, including 12 with MDLS with large deletions including
LIS1, 24 with isolated lissencephaly sequence caused by smaller LIS1
deletions or mutations, and 12 with DCX mutations. There were consistent
differences in the gyral patterns, with LIS1 mutations associated with
more severe malformations posteriorly, and DCX mutations associated with
more severe malformations anteriorly. In addition, hypoplasia of the
cerebellar vermis was more common in those with DCX mutations.

Fogli et al. (1999) reported 7 patients with lissencephaly-1 and a
heterozygous mutation in the LIS1 gene, 6 with a truncating mutation and
1 with a splice site mutation resulting in the skipping of exon 4.
Western blot analysis on lymphoblastoid cells of 2 patients with
truncating mutations showed that the mutated allele did not produce a
detectable amount of the LIS1 protein, whereas analysis of fibroblasts
from the patient with the splice site mutation showed partial protein
synthesis. Patients with the truncating mutations had severe
developmental delay with early-onset seizures, hypotonia, and spastic
quadriparesis; the patient with the splice site mutation had a less
severe clinical course. Fogli et al. (1999) noted that intracellular
dosage of the LIS1 protein is important to the neuronal migration
process.

The mutations in the LIS1 and DCX genes causing classic lissencephaly
(formerly type I) are thought to occur during corticogenesis and operate
on radial migratory pathways. Viot et al. (2004) noted that heterozygous
mutations in the LIS1 gene and hemizygous mutations in the DCX gene had
been thought to produce a similar histologic pattern. They reported
detailed neuropathologic studies in 2 unrelated fetuses, 1 with a
mutation in the LIS1 gene and the other with a mutation in the DCX gene.
In the fetus with the LIS1 mutation, the cortical ribbon displayed a
characteristic inverted organization, also called '4-layered cortex,'
whereas in the fetus with the DCX mutation, the cortex displayed a
roughly ordered '6-layered' lamination. Viot et al. (2004) hypothesized
that mutations in these 2 genes may not affect the same neuronal
arrangement in the neocortex.

Forman et al. (2005) proposed a classification of lissencephaly based on
the neuropathologic findings of 16 patients. Six had LIS1 deletions, 2
had DCX mutations, 2 had ARX mutations, and 6 had no defined genetic
defect, One of the patients had SBH consistent with a DCX mutation. The
cortex was thickened in all cases. Those with LIS1 and DCX mutations had
4-layer involvement, with more posterior and anterior involvement,
respectively. Brains with ARX mutations showed 3-layer cortical
involvement. Two of 5 patients with no known genetic defect showed a
fourth type of histopathology characterized by a 2-layered cortex; these
brains also had profound brainstem and cerebellar abnormalities. Forman
et al. (2005) proposed that LIS1- and DCX-related lissencephaly be
termed 'classic' lissencephaly and that ARX-related and the other
entities with hindbrain involvement be termed 'variant' lissencephaly.

Uyanik et al. (2007) identified 14 novel and 7 previously described LIS1
mutations in 21 unrelated patients, including 18 with lissencephaly-1, 1
with subcortical band heterotopia, and 2 with lissencephaly with
cerebellar hypoplasia. There were 9 truncating mutations, 6 splice site
mutations, 5 missense mutations, and an in-frame deletion. Somatic
mosaicism was assumed in 3 patients with partial subcortical band
heterotopia or mild pachygyria. Uyanik et al. (2007) concluded that the
severity of the phenotype is independent of the type of mutation and its
site within the coding region of the LIS1 gene.

In a retrospective review of MRI scans from 111 patients with
lissencephaly, Jissendi-Tchofo et al. (2009) found a correlation between
the extent of cerebral lissencephaly and midbrain-hindbrain involvement.
However, most patients with LIS1 had normal midbrain-hindbrain findings,
and those with midbrain-hindbrain involvement tended to have 'variant'
lissencephaly, as defined by Forman et al. (2005).

ANIMAL MODEL

Hirotsune et al. (1998) produced 3 different mutant alleles in the mouse
Pafah1b1 gene. Homozygous-null mice died early in embryogenesis soon
after implantation. Mice with 1 inactive allele displayed cortical,
hippocampal, and olfactory bulb disorganization resulting from delayed
neuronal migration by a cell-autonomous neuronal pathway. Mice with
further reduction of Pafah1b1 activity displayed more severe brain
disorganization as well as cerebellar defects. The results demonstrated
an essential, dosage-sensitive neuronal-specific role for Pafah1b1 in
neuronal migration throughout the brain, and an essential role in early
embryonic development. The phenotypes observed were distinct from those
of other mouse mutants with neuronal migration defects, suggesting that
Pafah1b1 participates in a novel pathway for neuronal migration.

Cahana et al. (2001) deleted the first coding exon from the mouse Lis1
gene. The deletion resulted in a shorter protein that initiated from the
second methionine, a unique situation because most LIS1 mutations result
in a null allele. This mutation mimicked a mutation described in 1
lissencephaly patient with a milder phenotype (Fogli et al., 1999).
Homozygotes were early lethal, although heterozygotes were viable and
fertile. The morphology of cortical neurons and radial glia was aberrant
in the developing cortex, and the neurons migrated more slowly. This was
the first demonstration of a cellular abnormality in the migrating
neurons after Lis1 mutation. Moreover, cortical plate splitting and
thalamocortical innervation were also abnormal. Biochemically, the
mutant protein was not capable of dimerization, and enzymatic activity
was elevated in the embryos, thus a demonstration of the in vivo role of
LIS1 as a subunit of platelet-activating factor acetylhydrolase.

Yamada et al. (2009) demonstrated that inhibition or knockdown of
calpains (see, e.g., CAPN1; 114220) protected the Lis1 protein from
proteolysis in Lis1 +/- mouse embryonic fibroblasts. Increased protein
levels rescued the aberrant distribution of cytoplasmic dynein and
mitochondria observed in Lis1 +/- cells, consistent with an improvement
in function. Calpain inhibitors also improved neuronal migration of Lis1
+/- cerebellar granular neurons. Intraperitoneal injection of the
calpain inhibitor to pregnant Lis1 +/- dams rescued apoptotic neuronal
cell death and partially rescued neuronal migration defects in Lis1 +/-
offspring. Furthermore, in utero knockdown of calpain by short hairpin
RNA rescued defective cortical layering in Lis1 +/- mice. Yamada et al.
(2009) suggested that LIS1 is specifically degraded by calpain and that
calpain inhibition could be a potential therapeutic intervention for
lissencephaly due to haploinsufficiency of LIS1.

*FIELD* RF
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*FIELD* CS
INHERITANCE:
Isolated cases

HEAD AND NECK:
[Head];
Microcephaly, postnatal

NEUROLOGIC:
[Central nervous system];
Developmental delay, severe;
Mental retardation;
Axial hypotonia;
Spastic quadriparesis;
No language development;
Sleep disorders;
Seizures, refractory;
Lissencephaly (anterior to posterior increasing gradient of severity
and more prominent in posterior brain regions);
Agyria;
Pachygyria;
Subcortical band heterotopia;
Corpus callosum abnormalities;
Cerebellar hypoplasia;
Brainstem hypoplasia;
Enlarged ventricles;
White matter abnormalities;
Prominent perivascular spaces;
[Behavioral/psychiatric manifestations];
Autistic features

MISCELLANEOUS:
All reported cases have resulted from de novo mutations;
Variable severity

MOLECULAR BASIS:
Caused by mutation in the platelet-activating factor acetylhydrolase,
isoform 1B, alpha subunit gene (PAFAH1B1, 601545.0001)

*FIELD* CD
Cassandra L. Kniffin: 11/18/2009

*FIELD* ED
joanna: 12/29/2009
ckniffin: 11/18/2009

*FIELD* CN
Cassandra L. Kniffin - updated: 7/19/2010
Cassandra L. Kniffin - updated: 11/18/2009
Cassandra L. Kniffin - updated: 10/2/2008
Cassandra L. Kniffin - updated: 11/26/2007
George E. Tiller - updated: 3/3/2005
Victor A. McKusick - updated: 5/11/2004
Cassandra L. Kniffin - updated: 1/22/2004
Cassandra L. Kniffin - updated: 9/18/2003
Ada Hamosh - updated: 5/9/2003

*FIELD* CD
Cassandra L. Kniffin: 12/18/2002

*FIELD* ED
carol: 04/23/2013
ckniffin: 4/22/2013
wwang: 6/8/2011
ckniffin: 6/2/2011
carol: 3/10/2011
carol: 11/12/2010
wwang: 7/20/2010
ckniffin: 7/19/2010
wwang: 12/1/2009
ckniffin: 11/18/2009
wwang: 10/8/2008
ckniffin: 10/2/2008
wwang: 12/14/2007
ckniffin: 11/26/2007
ckniffin: 11/19/2007
alopez: 3/3/2005
tkritzer: 6/1/2004
terry: 5/11/2004
tkritzer: 2/10/2004
ckniffin: 1/22/2004
carol: 9/25/2003
ckniffin: 9/18/2003
cwells: 5/13/2003
terry: 5/9/2003
carol: 1/3/2003
ckniffin: 12/27/2002