Full text data of TUBA1A
TUBA1A
(TUBA3)
[Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Tubulin alpha-1A chain (Alpha-tubulin 3; Tubulin B-alpha-1; Tubulin alpha-3 chain)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Tubulin alpha-1A chain (Alpha-tubulin 3; Tubulin B-alpha-1; Tubulin alpha-3 chain)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
hRBCD
IPI00180675
IPI00180675 tubulin, alpha 3 tubulin, alpha 3 membrane n/a n/a n/a n/a n/a n/a n/a n/a 6 n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a cytoskeleton NLDIERPTYTNLNR, LIGQIVSSITASLR found at its expected molecular weight found at molecular weight
IPI00180675 tubulin, alpha 3 tubulin, alpha 3 membrane n/a n/a n/a n/a n/a n/a n/a n/a 6 n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a cytoskeleton NLDIERPTYTNLNR, LIGQIVSSITASLR found at its expected molecular weight found at molecular weight
UniProt
Q71U36
ID TBA1A_HUMAN Reviewed; 451 AA.
AC Q71U36; A8K0B8; G3V1U9; P04687; P05209;
DT 13-AUG-1987, integrated into UniProtKB/Swiss-Prot.
read moreDT 05-JUL-2004, sequence version 1.
DT 22-JAN-2014, entry version 106.
DE RecName: Full=Tubulin alpha-1A chain;
DE AltName: Full=Alpha-tubulin 3;
DE AltName: Full=Tubulin B-alpha-1;
DE AltName: Full=Tubulin alpha-3 chain;
GN Name=TUBA1A; Synonyms=TUBA3;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=3839072; DOI=10.1093/nar/13.1.207;
RA Hall J.L., Cowan N.J.;
RT "Structural features and restricted expression of a human alpha-
RT tubulin gene.";
RL Nucleic Acids Res. 13:207-223(1985).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Retina;
RX PubMed=11504633; DOI=10.1016/S0968-0896(01)00103-1;
RA Crabtree D.V., Ojima I., Geng X., Adler A.J.;
RT "Tubulins in the primate retina: evidence that xanthophylls may be
RT endogenous ligands for the paclitaxel-binding site.";
RL Bioorg. Med. Chem. 9:1967-1976(2001).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Cerebellum;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16541075; DOI=10.1038/nature04569;
RA Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y.,
RA Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C.,
RA Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M.,
RA Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L.,
RA Milosavljevic A., Miner G.R., Montgomery K.T., Morgan M.B.,
RA Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D.,
RA Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y., Zhang Z.,
RA Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z.,
RA Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H., Draper H.,
RA Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S., Kelly S.H.,
RA Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V.,
RA Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H., Santibanez J.,
RA Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q., Williams G.A.,
RA Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V., Bailey M.,
RA Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E., Burkett C.E.,
RA Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K.,
RA Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D.,
RA Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M.,
RA Dathorne S.R., David R., Davis C.M., Davy-Carroll L., Deshazo D.R.,
RA Donlin J.E., D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J.,
RA Escotto M., Flagg N., Forbes L.D., Gabisi A.M., Garza M., Hamilton C.,
RA Henderson N., Hernandez O., Hines S., Hogues M.E., Huang M.,
RA Idlebird D.G., Johnson R., Jolivet A., Jones S., Kagan R., King L.M.,
RA Leal B., Lebow H., Lee S., LeVan J.M., Lewis L.C., London P.,
RA Lorensuhewa L.M., Loulseged H., Lovett D.A., Lucier A., Lucier R.L.,
RA Ma J., Madu R.C., Mapua P., Martindale A.D., Martinez E., Massey E.,
RA Mawhiney S., Meador M.G., Mendez S., Mercado C., Mercado I.C.,
RA Merritt C.E., Miner Z.L., Minja E., Mitchell T., Mohabbat F.,
RA Mohabbat K., Montgomery B., Moore N., Morris S., Munidasa M.,
RA Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O., Nwokenkwo S.,
RA Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J.,
RA Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A.,
RA Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M.,
RA Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I.,
RA Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A.,
RA Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D.,
RA Trejos Z.Y., Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I.,
RA Vera V.A., Villasana D.M., Wang L., Ward-Moore S., Warren J.T.,
RA Wei X., White F., Williamson A.L., Wleczyk R., Wooden H.S.,
RA Wooden S.H., Yen J., Yoon L., Yoon V., Zorrilla S.E., Nelson D.,
RA Kucherlapati R., Weinstock G., Gibbs R.A.;
RT "The finished DNA sequence of human chromosome 12.";
RL Nature 440:346-351(2006).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Muscle, and Skin;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP PROTEIN SEQUENCE OF 41-60; 65-79; 85-105; 113-121; 157-163; 216-304;
RP 312-320; 327-336; 340-352; 374-390; 395-401 AND 403-430, AND MASS
RP SPECTROMETRY.
RC TISSUE=Brain, Cajal-Retzius cell, and Fetal brain cortex;
RA Lubec G., Afjehi-Sadat L., Chen W.-Q., Sun Y.;
RL Submitted (DEC-2008) to UniProtKB.
RN [8]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 110-451.
RC TISSUE=Fetal brain;
RX PubMed=6646120;
RA Cowan N.J., Dobner P., Fuchs E.V., Cleveland D.W.;
RT "Expression of human alpha-tubulin genes: interspecies conservation of
RT 3' untranslated regions.";
RL Mol. Cell. Biol. 3:1738-1745(1983).
RN [9]
RP TISSUE SPECIFICITY, AND VARIANTS LIS3 LEU-188; THR-263; CYS-264;
RP PHE-286; HIS-402; CYS-402 AND LEU-419.
RX PubMed=17584854; DOI=10.1002/humu.20572;
RA Poirier K., Keays D.A., Francis F., Saillour Y., Bahi N.,
RA Manouvrier S., Fallet-Bianco C., Pasquier L., Toutain A., Tuy F.P.,
RA Bienvenu T., Joriot S., Odent S., Ville D., Desguerre I.,
RA Goldenberg A., Moutard M.L., Fryns J.-P., van Esch H., Harvey R.J.,
RA Siebold C., Flint J., Beldjord C., Chelly J.;
RT "Large spectrum of lissencephaly and pachygyria phenotypes resulting
RT from de novo missense mutations in tubulin alpha 1A (TUBA1A).";
RL Hum. Mutat. 28:1055-1064(2007).
RN [10]
RP GLYCYLATION.
RX PubMed=19524510; DOI=10.1016/j.cell.2009.05.020;
RA Rogowski K., Juge F., van Dijk J., Wloga D., Strub J.-M.,
RA Levilliers N., Thomas D., Bre M.-H., Van Dorsselaer A., Gaertig J.,
RA Janke C.;
RT "Evolutionary divergence of enzymatic mechanisms for posttranslational
RT polyglycylation.";
RL Cell 137:1076-1087(2009).
CC -!- FUNCTION: Tubulin is the major constituent of microtubules. It
CC binds two moles of GTP, one at an exchangeable site on the beta
CC chain and one at a non-exchangeable site on the alpha chain.
CC -!- SUBUNIT: Dimer of alpha and beta chains. A typical microtubule is
CC a hollow water-filled tube with an outer diameter of 25 nm and an
CC inner diameter of 15 nM. Alpha-beta heterodimers associate head-
CC to-tail to form protofilaments running lengthwise along the
CC microtubule wall with the beta-tubulin subunit facing the
CC microtubule plus end conferring a structural polarity.
CC Microtubules usually have 13 protofilaments but different
CC protofilament numbers can be found in some organisms and
CC specialized cells.
CC -!- INTERACTION:
CC Q9NQC7:CYLD; NbExp=6; IntAct=EBI-302552, EBI-2117940;
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q71U36-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q71U36-2; Sequence=VSP_046782;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Expressed at a high level in fetal brain.
CC -!- PTM: Undergoes a tyrosination/detyrosination cycle, the cyclic
CC removal and re-addition of a C-terminal tyrosine residue by the
CC enzymes tubulin tyrosine carboxypeptidase (TTCP) and tubulin
CC tyrosine ligase (TTL), respectively (By similarity).
CC -!- PTM: Some glutamate residues at the C-terminus are
CC polyglutamylated. This modification occurs exclusively on
CC glutamate residues and results in polyglutamate chains on the
CC gamma-carboxyl group. Also monoglycylated but not polyglycylated
CC due to the absence of functional TTLL10 in human. Monoglycylation
CC is mainly limited to tubulin incorporated into axonemes (cilia and
CC flagella) whereas glutamylation is prevalent in neuronal cells,
CC centrioles, axonemes, and the mitotic spindle. Both modifications
CC can coexist on the same protein on adjacent residues, and lowering
CC glycylation levels increases polyglutamylation, and reciprocally.
CC The precise function of such modifications is still unclear but
CC they regulate the assembly and dynamics of axonemal microtubules
CC (Probable).
CC -!- PTM: Acetylation of alpha chains at Lys-40 stabilizes microtubules
CC and affects affinity and processivity of microtubule motors. This
CC modification has a role in multiple cellular functions, ranging
CC from cell motility, cell cycle progression or cell differentiation
CC to intracellular trafficking and signaling (By similarity).
CC -!- DISEASE: Lissencephaly 3 (LIS3) [MIM:611603]: A classic type
CC lissencephaly associated with psychomotor retardation and
CC seizures. Features include agyria or pachygyria or laminar
CC heterotopia, severe mental retardation, motor delay, variable
CC presence of seizures, and abnormalities of corpus callosum,
CC hippocampus, cerebellar vermis and brainstem. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the tubulin family.
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DR EMBL; X01703; CAA25855.1; -; Genomic_DNA.
DR EMBL; AF141347; AAD33871.1; -; mRNA.
DR EMBL; AK289483; BAF82172.1; -; mRNA.
DR EMBL; AC010173; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471111; EAW58052.1; -; Genomic_DNA.
DR EMBL; CH471111; EAW58054.1; -; Genomic_DNA.
DR EMBL; CH471111; EAW58055.1; -; Genomic_DNA.
DR EMBL; BC006468; AAH06468.1; -; mRNA.
DR EMBL; BC050637; AAH50637.1; -; mRNA.
DR EMBL; K00557; AAA91575.1; -; mRNA.
DR RefSeq; NP_001257328.1; NM_001270399.1.
DR RefSeq; NP_001257329.1; NM_001270400.1.
DR RefSeq; NP_006000.2; NM_006009.3.
DR RefSeq; XP_005269200.1; XM_005269143.1.
DR UniGene; Hs.654422; -.
DR ProteinModelPortal; Q71U36; -.
DR SMR; Q71U36; 1-440.
DR IntAct; Q71U36; 67.
DR MINT; MINT-156132; -.
DR STRING; 9606.ENSP00000301071; -.
DR BindingDB; Q71U36; -.
DR ChEMBL; CHEMBL2095182; -.
DR PhosphoSite; Q71U36; -.
DR DMDM; 55977864; -.
DR PaxDb; Q71U36; -.
DR PRIDE; Q71U36; -.
DR DNASU; 7846; -.
DR Ensembl; ENST00000295766; ENSP00000439020; ENSG00000167552.
DR Ensembl; ENST00000301071; ENSP00000301071; ENSG00000167552.
DR Ensembl; ENST00000550767; ENSP00000446637; ENSG00000167552.
DR GeneID; 7846; -.
DR KEGG; hsa:7846; -.
DR UCSC; uc001rtp.4; human.
DR CTD; 7846; -.
DR GeneCards; GC12M049578; -.
DR HGNC; HGNC:20766; TUBA1A.
DR HPA; CAB008686; -.
DR HPA; HPA039247; -.
DR HPA; HPA043684; -.
DR MIM; 602529; gene.
DR MIM; 611603; phenotype.
DR neXtProt; NX_Q71U36; -.
DR Orphanet; 171680; Lissencephaly due to TUBA1A mutation.
DR PharmGKB; PA162407319; -.
DR eggNOG; COG5023; -.
DR HOGENOM; HOG000165711; -.
DR HOVERGEN; HBG000089; -.
DR InParanoid; Q71U36; -.
DR KO; K07374; -.
DR OMA; ASRSLCM; -.
DR OrthoDB; EOG7TBC1W; -.
DR PhylomeDB; Q71U36; -.
DR Reactome; REACT_111045; Developmental Biology.
DR Reactome; REACT_11123; Membrane Trafficking.
DR Reactome; REACT_115566; Cell Cycle.
DR Reactome; REACT_17015; Metabolism of proteins.
DR Reactome; REACT_21300; Mitotic M-M/G1 phases.
DR Reactome; REACT_604; Hemostasis.
DR Reactome; REACT_6900; Immune System.
DR ChiTaRS; TUBA1A; human.
DR GeneWiki; TUBA1A; -.
DR GenomeRNAi; 7846; -.
DR NextBio; 30260; -.
DR PMAP-CutDB; Q71U36; -.
DR PRO; PR:Q71U36; -.
DR ArrayExpress; Q71U36; -.
DR Bgee; Q71U36; -.
DR CleanEx; HS_TUBA1A; -.
DR Genevestigator; Q71U36; -.
DR GO; GO:0005881; C:cytoplasmic microtubule; IEA:Ensembl.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005874; C:microtubule; IDA:UniProtKB.
DR GO; GO:0005525; F:GTP binding; IEA:UniProtKB-KW.
DR GO; GO:0003924; F:GTPase activity; IEA:InterPro.
DR GO; GO:0005200; F:structural constituent of cytoskeleton; IEA:InterPro.
DR GO; GO:0005198; F:structural molecule activity; TAS:BHF-UCL.
DR GO; GO:0051084; P:'de novo' posttranslational protein folding; TAS:Reactome.
DR GO; GO:0051301; P:cell division; TAS:BHF-UCL.
DR GO; GO:0030705; P:cytoskeleton-dependent intracellular transport; TAS:BHF-UCL.
DR GO; GO:0000086; P:G2/M transition of mitotic cell cycle; TAS:Reactome.
DR GO; GO:0007017; P:microtubule-based process; TAS:BHF-UCL.
DR GO; GO:0051258; P:protein polymerization; IEA:InterPro.
DR Gene3D; 1.10.287.600; -; 1.
DR Gene3D; 3.30.1330.20; -; 1.
DR Gene3D; 3.40.50.1440; -; 1.
DR InterPro; IPR002452; Alpha_tubulin.
DR InterPro; IPR008280; Tub_FtsZ_C.
DR InterPro; IPR000217; Tubulin.
DR InterPro; IPR018316; Tubulin/FtsZ_2-layer-sand-dom.
DR InterPro; IPR023123; Tubulin_C.
DR InterPro; IPR017975; Tubulin_CS.
DR InterPro; IPR003008; Tubulin_FtsZ_GTPase.
DR PANTHER; PTHR11588; PTHR11588; 1.
DR Pfam; PF00091; Tubulin; 1.
DR Pfam; PF03953; Tubulin_C; 1.
DR PRINTS; PR01162; ALPHATUBULIN.
DR PRINTS; PR01161; TUBULIN.
DR SMART; SM00864; Tubulin; 1.
DR SMART; SM00865; Tubulin_C; 1.
DR SUPFAM; SSF52490; SSF52490; 1.
DR SUPFAM; SSF55307; SSF55307; 1.
DR PROSITE; PS00227; TUBULIN; 1.
PE 1: Evidence at protein level;
KW Acetylation; Alternative splicing; Complete proteome; Cytoplasm;
KW Cytoskeleton; Direct protein sequencing; Disease mutation;
KW GTP-binding; Lissencephaly; Microtubule; Nitration;
KW Nucleotide-binding; Phosphoprotein; Polymorphism; Reference proteome.
FT CHAIN 1 451 Tubulin alpha-1A chain.
FT /FTId=PRO_0000048111.
FT NP_BIND 142 148 GTP (Potential).
FT SITE 451 451 Involved in polymerization (By
FT similarity).
FT MOD_RES 48 48 Phosphoserine (By similarity).
FT MOD_RES 83 83 Nitrated tyrosine (By similarity).
FT MOD_RES 282 282 Nitrated tyrosine (By similarity).
FT MOD_RES 432 432 Phosphotyrosine (By similarity).
FT MOD_RES 439 439 Phosphoserine (By similarity).
FT VAR_SEQ 1 35 Missing (in isoform 2).
FT /FTId=VSP_046782.
FT VARIANT 188 188 I -> L (in LIS3).
FT /FTId=VAR_039332.
FT VARIANT 263 263 P -> T (in LIS3).
FT /FTId=VAR_039333.
FT VARIANT 264 264 R -> C (in LIS3).
FT /FTId=VAR_039334.
FT VARIANT 286 286 L -> F (in LIS3).
FT /FTId=VAR_039335.
FT VARIANT 402 402 R -> C (in LIS3).
FT /FTId=VAR_039336.
FT VARIANT 402 402 R -> H (in LIS3).
FT /FTId=VAR_039337.
FT VARIANT 419 419 S -> L (in LIS3).
FT /FTId=VAR_039338.
FT VARIANT 447 447 E -> K (in dbSNP:rs1065730).
FT /FTId=VAR_034540.
FT CONFLICT 131 131 G -> R (in Ref. 1; CAA25855 and 8;
FT AAA91575).
FT CONFLICT 290 290 E -> D (in Ref. 8; AAA91575).
FT CONFLICT 308 308 R -> G (in Ref. 1; CAA25855 and 8;
FT AAA91575).
FT CONFLICT 438 438 D -> H (in Ref. 1; CAA25855).
SQ SEQUENCE 451 AA; 50136 MW; 00F8429A4A10E5FE CRC64;
MRECISIHVG QAGVQIGNAC WELYCLEHGI QPDGQMPSDK TIGGGDDSFN TFFSETGAGK
HVPRAVFVDL EPTVIDEVRT GTYRQLFHPE QLITGKEDAA NNYARGHYTI GKEIIDLVLD
RIRKLADQCT GLQGFLVFHS FGGGTGSGFT SLLMERLSVD YGKKSKLEFS IYPAPQVSTA
VVEPYNSILT THTTLEHSDC AFMVDNEAIY DICRRNLDIE RPTYTNLNRL IGQIVSSITA
SLRFDGALNV DLTEFQTNLV PYPRIHFPLA TYAPVISAEK AYHEQLSVAE ITNACFEPAN
QMVKCDPRHG KYMACCLLYR GDVVPKDVNA AIATIKTKRT IQFVDWCPTG FKVGINYQPP
TVVPGGDLAK VQRAVCMLSN TTAIAEAWAR LDHKFDLMYA KRAFVHWYVG EGMEEGEFSE
AREDMAALEK DYEEVGVDSV EGEGEEEGEE Y
//
ID TBA1A_HUMAN Reviewed; 451 AA.
AC Q71U36; A8K0B8; G3V1U9; P04687; P05209;
DT 13-AUG-1987, integrated into UniProtKB/Swiss-Prot.
read moreDT 05-JUL-2004, sequence version 1.
DT 22-JAN-2014, entry version 106.
DE RecName: Full=Tubulin alpha-1A chain;
DE AltName: Full=Alpha-tubulin 3;
DE AltName: Full=Tubulin B-alpha-1;
DE AltName: Full=Tubulin alpha-3 chain;
GN Name=TUBA1A; Synonyms=TUBA3;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=3839072; DOI=10.1093/nar/13.1.207;
RA Hall J.L., Cowan N.J.;
RT "Structural features and restricted expression of a human alpha-
RT tubulin gene.";
RL Nucleic Acids Res. 13:207-223(1985).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Retina;
RX PubMed=11504633; DOI=10.1016/S0968-0896(01)00103-1;
RA Crabtree D.V., Ojima I., Geng X., Adler A.J.;
RT "Tubulins in the primate retina: evidence that xanthophylls may be
RT endogenous ligands for the paclitaxel-binding site.";
RL Bioorg. Med. Chem. 9:1967-1976(2001).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Cerebellum;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16541075; DOI=10.1038/nature04569;
RA Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y.,
RA Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C.,
RA Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M.,
RA Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L.,
RA Milosavljevic A., Miner G.R., Montgomery K.T., Morgan M.B.,
RA Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D.,
RA Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y., Zhang Z.,
RA Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z.,
RA Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H., Draper H.,
RA Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S., Kelly S.H.,
RA Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V.,
RA Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H., Santibanez J.,
RA Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q., Williams G.A.,
RA Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V., Bailey M.,
RA Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E., Burkett C.E.,
RA Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K.,
RA Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D.,
RA Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M.,
RA Dathorne S.R., David R., Davis C.M., Davy-Carroll L., Deshazo D.R.,
RA Donlin J.E., D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J.,
RA Escotto M., Flagg N., Forbes L.D., Gabisi A.M., Garza M., Hamilton C.,
RA Henderson N., Hernandez O., Hines S., Hogues M.E., Huang M.,
RA Idlebird D.G., Johnson R., Jolivet A., Jones S., Kagan R., King L.M.,
RA Leal B., Lebow H., Lee S., LeVan J.M., Lewis L.C., London P.,
RA Lorensuhewa L.M., Loulseged H., Lovett D.A., Lucier A., Lucier R.L.,
RA Ma J., Madu R.C., Mapua P., Martindale A.D., Martinez E., Massey E.,
RA Mawhiney S., Meador M.G., Mendez S., Mercado C., Mercado I.C.,
RA Merritt C.E., Miner Z.L., Minja E., Mitchell T., Mohabbat F.,
RA Mohabbat K., Montgomery B., Moore N., Morris S., Munidasa M.,
RA Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O., Nwokenkwo S.,
RA Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J.,
RA Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A.,
RA Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M.,
RA Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I.,
RA Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A.,
RA Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D.,
RA Trejos Z.Y., Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I.,
RA Vera V.A., Villasana D.M., Wang L., Ward-Moore S., Warren J.T.,
RA Wei X., White F., Williamson A.L., Wleczyk R., Wooden H.S.,
RA Wooden S.H., Yen J., Yoon L., Yoon V., Zorrilla S.E., Nelson D.,
RA Kucherlapati R., Weinstock G., Gibbs R.A.;
RT "The finished DNA sequence of human chromosome 12.";
RL Nature 440:346-351(2006).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Muscle, and Skin;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP PROTEIN SEQUENCE OF 41-60; 65-79; 85-105; 113-121; 157-163; 216-304;
RP 312-320; 327-336; 340-352; 374-390; 395-401 AND 403-430, AND MASS
RP SPECTROMETRY.
RC TISSUE=Brain, Cajal-Retzius cell, and Fetal brain cortex;
RA Lubec G., Afjehi-Sadat L., Chen W.-Q., Sun Y.;
RL Submitted (DEC-2008) to UniProtKB.
RN [8]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 110-451.
RC TISSUE=Fetal brain;
RX PubMed=6646120;
RA Cowan N.J., Dobner P., Fuchs E.V., Cleveland D.W.;
RT "Expression of human alpha-tubulin genes: interspecies conservation of
RT 3' untranslated regions.";
RL Mol. Cell. Biol. 3:1738-1745(1983).
RN [9]
RP TISSUE SPECIFICITY, AND VARIANTS LIS3 LEU-188; THR-263; CYS-264;
RP PHE-286; HIS-402; CYS-402 AND LEU-419.
RX PubMed=17584854; DOI=10.1002/humu.20572;
RA Poirier K., Keays D.A., Francis F., Saillour Y., Bahi N.,
RA Manouvrier S., Fallet-Bianco C., Pasquier L., Toutain A., Tuy F.P.,
RA Bienvenu T., Joriot S., Odent S., Ville D., Desguerre I.,
RA Goldenberg A., Moutard M.L., Fryns J.-P., van Esch H., Harvey R.J.,
RA Siebold C., Flint J., Beldjord C., Chelly J.;
RT "Large spectrum of lissencephaly and pachygyria phenotypes resulting
RT from de novo missense mutations in tubulin alpha 1A (TUBA1A).";
RL Hum. Mutat. 28:1055-1064(2007).
RN [10]
RP GLYCYLATION.
RX PubMed=19524510; DOI=10.1016/j.cell.2009.05.020;
RA Rogowski K., Juge F., van Dijk J., Wloga D., Strub J.-M.,
RA Levilliers N., Thomas D., Bre M.-H., Van Dorsselaer A., Gaertig J.,
RA Janke C.;
RT "Evolutionary divergence of enzymatic mechanisms for posttranslational
RT polyglycylation.";
RL Cell 137:1076-1087(2009).
CC -!- FUNCTION: Tubulin is the major constituent of microtubules. It
CC binds two moles of GTP, one at an exchangeable site on the beta
CC chain and one at a non-exchangeable site on the alpha chain.
CC -!- SUBUNIT: Dimer of alpha and beta chains. A typical microtubule is
CC a hollow water-filled tube with an outer diameter of 25 nm and an
CC inner diameter of 15 nM. Alpha-beta heterodimers associate head-
CC to-tail to form protofilaments running lengthwise along the
CC microtubule wall with the beta-tubulin subunit facing the
CC microtubule plus end conferring a structural polarity.
CC Microtubules usually have 13 protofilaments but different
CC protofilament numbers can be found in some organisms and
CC specialized cells.
CC -!- INTERACTION:
CC Q9NQC7:CYLD; NbExp=6; IntAct=EBI-302552, EBI-2117940;
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q71U36-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q71U36-2; Sequence=VSP_046782;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Expressed at a high level in fetal brain.
CC -!- PTM: Undergoes a tyrosination/detyrosination cycle, the cyclic
CC removal and re-addition of a C-terminal tyrosine residue by the
CC enzymes tubulin tyrosine carboxypeptidase (TTCP) and tubulin
CC tyrosine ligase (TTL), respectively (By similarity).
CC -!- PTM: Some glutamate residues at the C-terminus are
CC polyglutamylated. This modification occurs exclusively on
CC glutamate residues and results in polyglutamate chains on the
CC gamma-carboxyl group. Also monoglycylated but not polyglycylated
CC due to the absence of functional TTLL10 in human. Monoglycylation
CC is mainly limited to tubulin incorporated into axonemes (cilia and
CC flagella) whereas glutamylation is prevalent in neuronal cells,
CC centrioles, axonemes, and the mitotic spindle. Both modifications
CC can coexist on the same protein on adjacent residues, and lowering
CC glycylation levels increases polyglutamylation, and reciprocally.
CC The precise function of such modifications is still unclear but
CC they regulate the assembly and dynamics of axonemal microtubules
CC (Probable).
CC -!- PTM: Acetylation of alpha chains at Lys-40 stabilizes microtubules
CC and affects affinity and processivity of microtubule motors. This
CC modification has a role in multiple cellular functions, ranging
CC from cell motility, cell cycle progression or cell differentiation
CC to intracellular trafficking and signaling (By similarity).
CC -!- DISEASE: Lissencephaly 3 (LIS3) [MIM:611603]: A classic type
CC lissencephaly associated with psychomotor retardation and
CC seizures. Features include agyria or pachygyria or laminar
CC heterotopia, severe mental retardation, motor delay, variable
CC presence of seizures, and abnormalities of corpus callosum,
CC hippocampus, cerebellar vermis and brainstem. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the tubulin family.
CC -----------------------------------------------------------------------
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DR EMBL; X01703; CAA25855.1; -; Genomic_DNA.
DR EMBL; AF141347; AAD33871.1; -; mRNA.
DR EMBL; AK289483; BAF82172.1; -; mRNA.
DR EMBL; AC010173; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471111; EAW58052.1; -; Genomic_DNA.
DR EMBL; CH471111; EAW58054.1; -; Genomic_DNA.
DR EMBL; CH471111; EAW58055.1; -; Genomic_DNA.
DR EMBL; BC006468; AAH06468.1; -; mRNA.
DR EMBL; BC050637; AAH50637.1; -; mRNA.
DR EMBL; K00557; AAA91575.1; -; mRNA.
DR RefSeq; NP_001257328.1; NM_001270399.1.
DR RefSeq; NP_001257329.1; NM_001270400.1.
DR RefSeq; NP_006000.2; NM_006009.3.
DR RefSeq; XP_005269200.1; XM_005269143.1.
DR UniGene; Hs.654422; -.
DR ProteinModelPortal; Q71U36; -.
DR SMR; Q71U36; 1-440.
DR IntAct; Q71U36; 67.
DR MINT; MINT-156132; -.
DR STRING; 9606.ENSP00000301071; -.
DR BindingDB; Q71U36; -.
DR ChEMBL; CHEMBL2095182; -.
DR PhosphoSite; Q71U36; -.
DR DMDM; 55977864; -.
DR PaxDb; Q71U36; -.
DR PRIDE; Q71U36; -.
DR DNASU; 7846; -.
DR Ensembl; ENST00000295766; ENSP00000439020; ENSG00000167552.
DR Ensembl; ENST00000301071; ENSP00000301071; ENSG00000167552.
DR Ensembl; ENST00000550767; ENSP00000446637; ENSG00000167552.
DR GeneID; 7846; -.
DR KEGG; hsa:7846; -.
DR UCSC; uc001rtp.4; human.
DR CTD; 7846; -.
DR GeneCards; GC12M049578; -.
DR HGNC; HGNC:20766; TUBA1A.
DR HPA; CAB008686; -.
DR HPA; HPA039247; -.
DR HPA; HPA043684; -.
DR MIM; 602529; gene.
DR MIM; 611603; phenotype.
DR neXtProt; NX_Q71U36; -.
DR Orphanet; 171680; Lissencephaly due to TUBA1A mutation.
DR PharmGKB; PA162407319; -.
DR eggNOG; COG5023; -.
DR HOGENOM; HOG000165711; -.
DR HOVERGEN; HBG000089; -.
DR InParanoid; Q71U36; -.
DR KO; K07374; -.
DR OMA; ASRSLCM; -.
DR OrthoDB; EOG7TBC1W; -.
DR PhylomeDB; Q71U36; -.
DR Reactome; REACT_111045; Developmental Biology.
DR Reactome; REACT_11123; Membrane Trafficking.
DR Reactome; REACT_115566; Cell Cycle.
DR Reactome; REACT_17015; Metabolism of proteins.
DR Reactome; REACT_21300; Mitotic M-M/G1 phases.
DR Reactome; REACT_604; Hemostasis.
DR Reactome; REACT_6900; Immune System.
DR ChiTaRS; TUBA1A; human.
DR GeneWiki; TUBA1A; -.
DR GenomeRNAi; 7846; -.
DR NextBio; 30260; -.
DR PMAP-CutDB; Q71U36; -.
DR PRO; PR:Q71U36; -.
DR ArrayExpress; Q71U36; -.
DR Bgee; Q71U36; -.
DR CleanEx; HS_TUBA1A; -.
DR Genevestigator; Q71U36; -.
DR GO; GO:0005881; C:cytoplasmic microtubule; IEA:Ensembl.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005874; C:microtubule; IDA:UniProtKB.
DR GO; GO:0005525; F:GTP binding; IEA:UniProtKB-KW.
DR GO; GO:0003924; F:GTPase activity; IEA:InterPro.
DR GO; GO:0005200; F:structural constituent of cytoskeleton; IEA:InterPro.
DR GO; GO:0005198; F:structural molecule activity; TAS:BHF-UCL.
DR GO; GO:0051084; P:'de novo' posttranslational protein folding; TAS:Reactome.
DR GO; GO:0051301; P:cell division; TAS:BHF-UCL.
DR GO; GO:0030705; P:cytoskeleton-dependent intracellular transport; TAS:BHF-UCL.
DR GO; GO:0000086; P:G2/M transition of mitotic cell cycle; TAS:Reactome.
DR GO; GO:0007017; P:microtubule-based process; TAS:BHF-UCL.
DR GO; GO:0051258; P:protein polymerization; IEA:InterPro.
DR Gene3D; 1.10.287.600; -; 1.
DR Gene3D; 3.30.1330.20; -; 1.
DR Gene3D; 3.40.50.1440; -; 1.
DR InterPro; IPR002452; Alpha_tubulin.
DR InterPro; IPR008280; Tub_FtsZ_C.
DR InterPro; IPR000217; Tubulin.
DR InterPro; IPR018316; Tubulin/FtsZ_2-layer-sand-dom.
DR InterPro; IPR023123; Tubulin_C.
DR InterPro; IPR017975; Tubulin_CS.
DR InterPro; IPR003008; Tubulin_FtsZ_GTPase.
DR PANTHER; PTHR11588; PTHR11588; 1.
DR Pfam; PF00091; Tubulin; 1.
DR Pfam; PF03953; Tubulin_C; 1.
DR PRINTS; PR01162; ALPHATUBULIN.
DR PRINTS; PR01161; TUBULIN.
DR SMART; SM00864; Tubulin; 1.
DR SMART; SM00865; Tubulin_C; 1.
DR SUPFAM; SSF52490; SSF52490; 1.
DR SUPFAM; SSF55307; SSF55307; 1.
DR PROSITE; PS00227; TUBULIN; 1.
PE 1: Evidence at protein level;
KW Acetylation; Alternative splicing; Complete proteome; Cytoplasm;
KW Cytoskeleton; Direct protein sequencing; Disease mutation;
KW GTP-binding; Lissencephaly; Microtubule; Nitration;
KW Nucleotide-binding; Phosphoprotein; Polymorphism; Reference proteome.
FT CHAIN 1 451 Tubulin alpha-1A chain.
FT /FTId=PRO_0000048111.
FT NP_BIND 142 148 GTP (Potential).
FT SITE 451 451 Involved in polymerization (By
FT similarity).
FT MOD_RES 48 48 Phosphoserine (By similarity).
FT MOD_RES 83 83 Nitrated tyrosine (By similarity).
FT MOD_RES 282 282 Nitrated tyrosine (By similarity).
FT MOD_RES 432 432 Phosphotyrosine (By similarity).
FT MOD_RES 439 439 Phosphoserine (By similarity).
FT VAR_SEQ 1 35 Missing (in isoform 2).
FT /FTId=VSP_046782.
FT VARIANT 188 188 I -> L (in LIS3).
FT /FTId=VAR_039332.
FT VARIANT 263 263 P -> T (in LIS3).
FT /FTId=VAR_039333.
FT VARIANT 264 264 R -> C (in LIS3).
FT /FTId=VAR_039334.
FT VARIANT 286 286 L -> F (in LIS3).
FT /FTId=VAR_039335.
FT VARIANT 402 402 R -> C (in LIS3).
FT /FTId=VAR_039336.
FT VARIANT 402 402 R -> H (in LIS3).
FT /FTId=VAR_039337.
FT VARIANT 419 419 S -> L (in LIS3).
FT /FTId=VAR_039338.
FT VARIANT 447 447 E -> K (in dbSNP:rs1065730).
FT /FTId=VAR_034540.
FT CONFLICT 131 131 G -> R (in Ref. 1; CAA25855 and 8;
FT AAA91575).
FT CONFLICT 290 290 E -> D (in Ref. 8; AAA91575).
FT CONFLICT 308 308 R -> G (in Ref. 1; CAA25855 and 8;
FT AAA91575).
FT CONFLICT 438 438 D -> H (in Ref. 1; CAA25855).
SQ SEQUENCE 451 AA; 50136 MW; 00F8429A4A10E5FE CRC64;
MRECISIHVG QAGVQIGNAC WELYCLEHGI QPDGQMPSDK TIGGGDDSFN TFFSETGAGK
HVPRAVFVDL EPTVIDEVRT GTYRQLFHPE QLITGKEDAA NNYARGHYTI GKEIIDLVLD
RIRKLADQCT GLQGFLVFHS FGGGTGSGFT SLLMERLSVD YGKKSKLEFS IYPAPQVSTA
VVEPYNSILT THTTLEHSDC AFMVDNEAIY DICRRNLDIE RPTYTNLNRL IGQIVSSITA
SLRFDGALNV DLTEFQTNLV PYPRIHFPLA TYAPVISAEK AYHEQLSVAE ITNACFEPAN
QMVKCDPRHG KYMACCLLYR GDVVPKDVNA AIATIKTKRT IQFVDWCPTG FKVGINYQPP
TVVPGGDLAK VQRAVCMLSN TTAIAEAWAR LDHKFDLMYA KRAFVHWYVG EGMEEGEFSE
AREDMAALEK DYEEVGVDSV EGEGEEEGEE Y
//
MIM
602529
*RECORD*
*FIELD* NO
602529
*FIELD* TI
*602529 TUBULIN, ALPHA-1A; TUBA1A
;;TUBULIN, ALPHA, BRAIN-SPECIFIC;;
B-ALPHA-1;;
TUBA3
read more*FIELD* TX
GENE FAMILY
Microtubules tend to be functionally distinct and are involved in
mitosis, cell movement, intracellular movement, and other biologic
processes. The main components of microtubules are different isoforms of
alpha and beta tubulins, which are often cell-type specific.
Lewis and Cowan (1990) reviewed the alpha-tubulin gene family. In
humans, this family consists of 15 to 20 dispersed genes, many of which
are processed pseudogenes. The positions of the first 3 introns are
identical between members of the human and rat gene families; in
addition, some human alpha-tubulin genes have a fourth intron, also at
an identical position. Within a vertebrate species, the genes can be
distinguished by their 3-prime untranslated regions (UTRs). Since a
large proportion of the diversity of alpha-tubulins is clustered at the
C-terminal region and is conserved across species, alpha-tubulin genes
can be classified based on homology of their encoded C-terminal motifs
to those of mouse alpha-tubulin genes.
NOMENCLATURE
See Khodiyar et al. (2007) for a revised nomenclature of the
alpha-tubulin gene family.
CLONING
The b-alpha-1 gene, cloned from a human fetal brain cDNA library by
Cowan et al. (1983), is the human counterpart of mouse M-alpha-1. By
Northern blot analysis, Cowan et al. (1983) showed that b-alpha-1 mRNA
is expressed only in brain. They found that the 3-prime UTR of b-alpha-1
is more than 80% homologous to the UTR of the rat brain alpha-tubulin
gene, IL-alpha-T1.
Hall and Cowan (1985) screened a human genomic library with the 3-prime
UTR of b-alpha-1 and isolated the b-alpha-1 gene and a pseudogene.
B-alpha-1 encodes a predicted 451-amino acid protein that is 100%
identical to the rat homolog and differs by only 2 and 3 amino acids
from the pig and chicken homologs, respectively. Furthermore, they
observed that the first and largest intron of the b-alpha-1 gene is
homologous to that of the rat gene. Northern blotting showed that
b-alpha-1 expression was restricted to morphologically differentiated
neurologic cells.
By Northern blot analysis and in situ hybridization, Miller et al.
(1987) found that the rat homolog of b-alpha-1, which they called
T-alpha-1, is expressed at high levels during the extension of neuronal
processes.
Crabtree et al. (2001) cloned alpha-tubulin variants from a human retina
cDNA library. One variant had the same sequence as the clone isolated by
Cowan et al. (1983) from fetal brain, and the other had the same
sequence as the brain-specific alpha-tubulin clone isolated by Hall and
Cowan (1985), suggesting that this alpha-tubulin gene is expressed in
both brain and retina.
Poirier et al. (2007) detected high expression of the TUBA1A gene in
human fetal brain. Detailed study of mouse embryos showed expression in
the cortex, hippocampus, cerebellum, brainstem, and rostral migratory
stream. Tuba1a expression was decreased in most neurons at later
postnatal stages and in adulthood.
GENE STRUCTURE
Hall and Cowan (1985) determined that the b-alpha-1 gene contains 4
exons and spans less than 4 kb.
MAPPING
Scott (2001) mapped the TUBA1A gene to human chromosome 12 based on
sequence similarity between the TUBA1A sequence (GenBank GENBANK
AF141347) and chromosome 12 clones RP11-234P5 and RP11-977B10, (GenBank
GENBANK AC016125 and GenBank GENBANK AC010173).
Khodiyar et al. (2007) stated that the TUBA1A gene maps to human
chromosome 12q13.12 and mouse chromosome 15F1.
MOLECULAR GENETICS
In 2 unrelated patients with lissencephaly (LIS3; 611603), Keays et al.
(2007) and Poirier et al. (2007) identified 2 different de novo
heterozygous mutations in the TUBA1A gene (602529.0001; 602529.0002).
Poirier et al. (2007) identified de novo heterozygous TUBA1A mutations
(see, e.g., 602529.0003-602529.0005) in 6 additional patients with a
wide spectrum of brain dysgenesis, ranging from agyria to laminar
heterotopia. Retrospective examination of brain MRI showed defects in
the cerebellum, hippocampus, corpus callosum, and brainstem. Patients
who survived showed mental retardation, seizures, motor delay, and
microcephaly. In general, gyral malformations were more severe in the
posterior than anterior brain regions.
Bahi-Buisson et al. (2008) identified 6 de novo mutations in the TUBA1A
gene (see, e.g., 602529.0006; 602529.0007) in 6 of 100 patients with
lissencephaly who were negative for mutations in other known
lissencephaly-associated genes. The phenotype ranged from the less
severe perisylvian pachygyria to the more severe posteriorly predominant
pachygyria, which was associated with dysgenesis of the anterior limb of
the internal capsule and mild to severe cerebellar hypoplasia. Patients
with TUBA1A mutations shared a common clinical phenotype consisting of
congenital microcephaly, mental retardation and diplegia/tetraplegia.
Morris-Rosendahl et al. (2008) identified 4 different TUBA1A mutations
(see, e.g., 602529.0008) in 5 of 46 patients with variable patterns of
lissencephaly on brain MRI and no DCX (300121) or PAFAH1B1 (601545)
mutation. Four of the 5 patients had congenital microcephaly, and all
had dysgenesis of the corpus callosum, cerebellar hypoplasia, and
variable cortical malformations, including subtle subcortical band
heterotopia and absence or hypoplasia of the anterior limb of the
internal capsule.
Kumar et al. (2010) screened a cohort of 125 lissencephaly patients in
whom mutations in DCX and PAFAH1B1 had been excluded and identified
novel and recurrent TUBA1A mutations in 1% of children with classic
lissencephaly and in 30% of children with lissencephaly with cerebellar
hypoplasia. A TUBA1A mutation was also found in 1 child with agenesis of
the corpus callosum and cerebellar hypoplasia without lissencephaly. The
authors demonstrated a wider spectrum of phenotypes than had been
reported and suggested that lissencephaly-associated mutations of TUBA1A
may operate via diverse mechanisms that include disruption of binding
sites for microtubule-associated proteins.
Tian et al. (2010) studied the effects of 9 disease-associated TUBA1A
mutations on tubulin folding, heterodimer assembly, microtubule
dynamics, and stability. The translational yield of each mutant protein
varied across a continuum from an amount similar to that of wildtype for
mutant L286F, to slightly reduced formation for mutants I188L
(602529.0003), I238V, P263T (602529.0004), R402H (602529.0002) and S419L
(602529.0005), to significantly diminished amounts for mutants V303G,
L397P, and R402C. Studies of GTP-dependent polymerization and
depolymerization indicated that all the disease-causing TUBA1A mutations
were competent for assembly into microtubules in vitro. However, some of
the mutant proteins showed defects in the tubulin heterodimer assembly
pathway, with deficiencies in the production of intermediates. Mutants
I188L, I238V, L397P and R402C all generated lower yields of
intermediates compared to control TUBA1A; in addition, R402C showed a
time-dependent decay of intermediates, indicating instability. Some of
the mutant proteins (R264C, V303G, and L397P) also showed defective
interaction with assembly chaperone protein TBCB (see, e.g., TBCA,
610058). Tests of heterodimer stability showed that P263T and V303G had
reduced stability, whereas L397P and R402C were highly unstable. P263T
expression resulted in the assembly of heterodimers with a deleterious
effect on microtubule dynamics, whereas the other mutant proteins did
not show defects in microtubule growth. The findings demonstrated that
different TUBA1A mutations result in a variety of tubulin defects, but
also suggested that the mutations may cause compromised interactions
with other interacting proteins essential for proper neuronal migration.
ANIMAL MODEL
Keays et al. (2007) reported a hyperactive N-ethyl-N-nitrosourea
(ENU)-induced mouse mutant with abnormalities in the laminar
architecture of the hippocampus and cortex accompanied by impaired
neuronal migration. Fine mapping and genomic screening identified an
S140G mutation in the Tuba1a gene. Functional studies showed that the
mutation resulted in decreased GTP binding and impaired tubulin
heterodimer formation. However, heterodimers that did form were able to
polymerize and were incorporated into the microtubule network of
cultured cells. Abnormal neuronal migration was manifest as
perturbations in layers II/III and IV of the visual, auditory, and
somatosensory cortices, and a fractured pyramidal cell layer in the
hippocampus. Behavioral studies showed that the mutant mice had impaired
spatial working memory, reduced anxiety, and abnormal nesting,
consistent with a hippocampal deficit. Keays et al. (2007) concluded
that pathogenic mutations in the TUBA1A gene interferes with microtubule
function, thus impairing neuronal migration.
*FIELD* AV
.0001
LISSENCEPHALY 3
TUBA1A, ARG264CYS
In a patient with lissencephaly (LIS3; 611603), Keays et al. (2007) and
Poirier et al. (2007) identified a heterozygous de novo 790C-T
transition in exon 4 of the TUBA1A gene, resulting in an arg264-to-cys
(R264C) substitution in a loop between H8 and S7. The patient had
microcephaly, pachygyria, an abnormally shaped corpus callosum, and
hypoplasia of the cerebellar vermis and brainstem. Clinical features
included severe mental retardation, mild motor delay, and absence of
seizures. Poirier et al. (2007) reported another unrelated patient with
a similar phenotype who carried the R264C mutation.
Bahi-Buisson et al. (2008) identified the R264C mutation in 2 additional
unrelated patients with LIS3.
.0002
LISSENCEPHALY 3
TUBA1A, ARG402HIS
In a patient with lissencephaly (LIS3; 611603), Keays et al. (2007) and
Poirier et al. (2007) identified a heterozygous de novo 1205G-A
transition in exon 4 of the TUBA1A gene, resulting in an arg402-to-his
(R402H) substitution at the beginning of the H11-H12 loop near the
interface with beta-tubulin (191130). The patient had microcephaly,
agyria, thin corpus callosum, abnormal hippocampus, and hypoplasia of
the cerebellar vermis and brainstem, and severe ventricular dilatation.
Clinical features included profound mental retardation, spastic
tetraplegia, and intractable tonic-clonic seizures.
By extensive in vitro functional expression assays, Tian et al. (2010)
found that mutant R402H performed like wildtype, although there was a
slight reduction in the amount of protein translated and a slight
reduction in the formation of tubulin assembly intermediates. There were
no obvious effects on de novo heterodimer assembly or microtubule
dynamics, suggesting that the disease phenotype is likely to be caused
by an effect on other microtubule-dependent processes such as the
binding of associated proteins.
.0003
LISSENCEPHALY 3
TUBA1A, ILE188LEU
In a female patient with lissencephaly (LIS3; 611603), Poirier et al.
(2007) identified a heterozygous de novo 562A-C transversion in the
TUBA1A gene, resulting in an ile188-to-leu (I188L) substitution. She had
microcephaly, laminar heterotopia, thin corpus callosum with partial
agenesis, and hypoplasia of the brainstem and cerebellar vermis.
By extensive in vitro functional expression assays, Tian et al. (2010)
found that mutant I188L performed like wildtype, although there was a
slight reduction in the amount of protein translated and a slight
reduction in the formation of tubulin assembly intermediates. There were
no obvious effects on de novo heterodimer assembly or microtubule
dynamics, suggesting that the disease phenotype is likely to be caused
by an effect on other microtubule-dependent processes such as the
binding of associated proteins.
.0004
LISSENCEPHALY 3
TUBA1A, PRO263THR
In a 26-week-old fetus with lissencephaly (LIS3; 611603), Poirier et al.
(2007) identified a de novo heterozygous 787C-A transversion in the
TUBA1A gene, resulting in a pro263-to-thr (P263T) substitution.
Postmortem examination showed agyria, agenesis of the corpus callosum,
abnormal hippocampus, hypoplasia of the cerebellar vermis and brainstem,
and severe ventricular dilatation.
By extensive in vitro functional expression assays, Tian et al. (2010)
found that mutant P263T showed reduced stability and resulted in the
assembly of heterodimers with a deleterious effect on microtubule
dynamics, with a damping of the microtubule growth rate.
.0005
LISSENCEPHALY 3
TUBA1A, SER419LEU
In an 18-year-old man with lissencephaly (LIS3; 611603), Poirier et al.
(2007) identified a de novo heterozygous 1256C-T transition in the
TUBA1A gene, resulting in a ser419-to-leu (S419L) substitution. He had
profound mental retardation, spastic tetraplegia, intractable seizures,
and pachygyria.
By extensive in vitro functional expression assays, Tian et al. (2010)
found that mutant S419L performed like wildtype, although there was a
slight reduction in the amount of protein translated and a slight
reduction in the formation of tubulin assembly intermediates. There were
no obvious effects on de novo heterodimer assembly or microtubule
dynamics, suggesting that the disease phenotype is likely to be caused
by an effect on other microtubule-dependent processes such as the
binding of associated proteins.
.0006
LISSENCEPHALY 3
TUBA1A, LEU397PRO
In a 5.5-year-old boy with lissencephaly (LIS3; 611603), Bahi-Buisson et
al. (2008) identified a de novo heterozygous 1190T-C transition in the
TUBA1A gene, resulting in a leu397-to-pro (L397P) substitution. The
patient had microcephaly, spastic diplegia, and cognitive delay with few
words acquired. MRI scan showed perisylvian pachygyria with dysgenesis
of the internal capsule and posterior agenesis of the corpus callosum.
There was also severe vermian dysplasia of the cerebellum. The mutation
was not identified in 360 control individuals.
.0007
LISSENCEPHALY 3
TUBA1A, ARG422CYS
In a 4.5-year-old girl with lissencephaly (LIS3; 611603), Bahi-Buisson
et al. (2008) identified a de novo heterozygous 1264C-T transition in
the TUBA1A gene, resulting in an arg422-to-cys (R422C) substitution. The
patient had microcephaly, spastic diplegia, and could speak only in
short sentences. MRI scan showed perisylvian pachygyria with dysgenesis
of the internal capsule and mild hypoplasia of the corpus callosum.
There was also mild vermian hypoplasia of the cerebellum. The mutation
was not identified in 360 control individuals.
.0008
LISSENCEPHALY 3
TUBA1A, ARG422HIS
In 2 unrelated patients with lissencephaly (LIS3; 611603),
Morris-Rosendahl et al. (2008) identified a heterozygous 1265G-A
transition in exon 4 of the TUBA1A gene, resulting in an arg422-to-his
(R422H) substitution. In addition to the classic features of
microcephaly, seizure, pachygyria, and hypoplasia of the corpus callosum
and cerebellum, both patients had subtle evidence of subcortical band
heterotopia.
.0009
LISSENCEPHALY 3
TUBA1A, ILE5LEU
In 2 sisters, born of consanguineous Moroccan parents, with LIS3
(611603), Jansen et al. (2011) identified a heterozygous 13A-C
transition in exon 2 of the TUBA1A gene, resulting in an ile5-to-leu
(I5L) substitution. The girls had developmental delay, spastic diplegia,
and ataxia; 1 had seizures. Brain MRI showed perisylvian polymicrogyria,
gray matter heterotopia, enlarged lateral ventricle with a hooked aspect
of the right frontal horn due to abnormally shaped basal ganglia, thin
corpus callosum, and hypoplasia of the pons. One girl had optic nerve
hypoplasia and mild vermian hypoplasia. The clinically asymptomatic
mother was found to be somatic mosaic for the mutation, which was
detected in 5.6% of DNA in peripheral blood. Her brain MRI showed a thin
corpus callosum, hypoplasia of the superior vermis, and a thin medulla.
The report indicated that rare familial recurrence of LIS3 can occur.
*FIELD* RF
1. Bahi-Buisson, N.; Poirier, K.; Boddaert, N.; Saillour, Y.; Castelnau,
L.; Philip, N.; Buyse, G.; Villard, L.; Joriot, S.; Marret, S.; Bourgeois,
M.; Van Esch, H.; Lagae, L.; Amiel, J.; Hertz-Pannier, L.; Roubertie,
A.; Rivier, F.; Pinard, J. M.; Beldjord, C.; Chelly, J.: Refinement
of cortical dysgeneses spectrum associated with TUBA1A mutations. J.
Med. Genet. 45: 647-653, 2008.
2. Cowan, N. J.; Dobner, P. R.; Fuchs, E. V.; Cleveland, D. W.: Expression
of human alpha-tubulin genes: interspecies conservation of 3-prime
untranslated regions. Molec. Cell. Biol. 3: 1738-1745, 1983.
3. Crabtree, D. V.; Ojima, I.; Geng, X.; Adler, A. J.: Tubulins in
the primate retina: evidence that xanthophylls may be endogenous ligands
for the paclitaxel-binding site. Bioorganic Medicinal Chemistry 9:
1967-1976, 2001.
4. Hall, J. L.; Cowan, N. J.: Structural features and restricted
expression of a human alpha-tubulin gene. Nucleic Acids Res. 13:
207-223, 1985.
5. Jansen, A. C.; Oostra, A.; Desprechins, B.; De Vlaeminck, Y.; Verhelst,
H.; Regal, L.; Verloo, P.; Bockaert, N.; Keymolen, K.; Seneca, S.;
De Meirleir, L.; Lissens, W.: TUBA1A mutations: from isolated lissencephaly
to familial polymicrogyria. Neurology 76: 988-992, 2011.
6. Keays, D. A.; Tian, G.; Poirier, K.; Huang, G.-J.; Siebold, C.;
Cleak, J.; Oliver, P. L.; Fray, M.; Harvey, R. J.; Molnar, Z.; Pinon,
M. C.; Dear, N.; Valdar, W.; Brown, S. D. M.; Davies, K. E.; Rawlins,
J. N. P.; Cowan, N. J.; Nolan, P.; Chelly, J.; Flint, J.: Mutations
in alpha-tubulin cause abnormal neuronal migration in mice and lissencephaly
in humans. Cell 128: 45-57, 2007.
7. Khodiyar, V. K.; Maltais, L. J.; Ruef, B. J.; Sneddon, K. M. B.;
Smith, J. R.; Shimoyama, M.; Cabral, F.; Dumontet, C.; Dutcher, S.
K.; Harvey, R. J.; Lafanechere, L.; Murray, J. M.; Nogales, E.; Piquemal,
D.; Stanchi, F.; Povey, S.; Lovering, R. C.: A revised nomenclature
for the human and rodent alpha-tubulin gene family. Genomics 90:
285-289, 2007. Note: Erratum: Genomics 93: 397 only, 2009.
8. Kumar, R. A.; Pilz, D. T.; Babatz, T. D.; Cushion, T. D.; Harvey,
K.; Topf, M.; Yates, L.; Robb, S.; Uyanik, G.; Mancini, G. M. S.;
Rees, M. I.; Harvey, R. J.; Dobyns, W. B.: TUBA1A mutations cause
wide spectrum lissencephaly (smooth brain) and suggest that multiple
neuronal migration pathways converge on alpha tubulins. Hum. Molec.
Genet. 19: 2817-2827, 2010.
9. Lewis, S. A.; Cowan, N. J.: Tubulin genes: structure, expression,
and regulation.In: Avila, J. (ed.): Microtubule proteins. Boca
Raton: CRC Press, Inc. 1990. Pp. 37-66.
10. Miller, F. D.; Naus, C. C. G.; Durand, M.; Bloom, F. E.; Milner,
R. J.: Isotypes of alpha-tubulin are differentially regulated during
neuronal maturation. J. Cell Biol. 105: 3065-3073, 1987.
11. Morris-Rosendahl, D. J.; Najm, J.; Lachmeijer, A. M. A.; Sztriha,
L.; Martins, M.; Kuechler, A.; Haug, V.; Zeschnigk, C.; Martin, P.;
Santos, M.; Vasconcelos, C.; Omran, H.; Kraus, U.; Van der Knaap,
M. S.; Schuierer, G.; Kutsche, K.; Uyanik, G.: Refining the phenotype
of alpha-1a tubulin (TUBA1A) mutation in patients with classical lissencephaly. Clin.
Genet. 74: 425-433, 2008.
12. Poirier, K.; Keays, D. A.; Francis, F.; Saillour, Y.; Bahi, N.;
Manouvrier, S.; Fallet-Bianco, C.; Pasquier, L.; Toutain, A.; Tuy,
F. P. D.; Bienvenu, T.; Joriot, S.; and 12 others: Large spectrum
of lissencephaly and pachygyria phenotypes resulting from de novo
missense mutations in tubulin alpha 1A (TUBA1A). Hum. Mutat. 28:
1055-1064, 2007.
13. Scott, A. F.: Personal Communication. Baltimore, Md. 10/3/2001.
14. Tian, G.; Jaglin, X. H.; Keays, D. A.; Francis, F.; Chelly, J.;
Cowan, N. J.: Disease-associated mutations in TUBA1A result in a
spectrum of defects in the tubulin folding and heterodimer assembly
pathway. Hum. Molec. Genet. 19: 3599-3613, 2010.
*FIELD* CN
George E. Tiller - updated: 09/05/2013
Cassandra L. Kniffin - updated: 4/18/2012
Cassandra L. Kniffin - updated: 3/3/2009
Cassandra L. Kniffin - updated: 2/12/2009
Cassandra L. Kniffin - updated: 11/19/2007
Patricia A. Hartz - updated: 12/21/2004
Alan F. Scott - updated: 10/3/2001
*FIELD* CD
Rebekah S. Rasooly: 4/16/1998
*FIELD* ED
alopez: 09/05/2013
terry: 11/28/2012
carol: 5/3/2012
ckniffin: 4/18/2012
alopez: 8/18/2011
ckniffin: 8/3/2011
wwang: 3/6/2009
ckniffin: 3/3/2009
wwang: 2/20/2009
ckniffin: 2/12/2009
wwang: 12/14/2007
ckniffin: 11/19/2007
carol: 9/13/2007
carol: 9/11/2007
alopez: 2/8/2007
mgross: 1/12/2005
terry: 12/21/2004
joanna: 10/3/2001
alopez: 6/18/1999
psherman: 4/20/1998
psherman: 4/16/1998
*RECORD*
*FIELD* NO
602529
*FIELD* TI
*602529 TUBULIN, ALPHA-1A; TUBA1A
;;TUBULIN, ALPHA, BRAIN-SPECIFIC;;
B-ALPHA-1;;
TUBA3
read more*FIELD* TX
GENE FAMILY
Microtubules tend to be functionally distinct and are involved in
mitosis, cell movement, intracellular movement, and other biologic
processes. The main components of microtubules are different isoforms of
alpha and beta tubulins, which are often cell-type specific.
Lewis and Cowan (1990) reviewed the alpha-tubulin gene family. In
humans, this family consists of 15 to 20 dispersed genes, many of which
are processed pseudogenes. The positions of the first 3 introns are
identical between members of the human and rat gene families; in
addition, some human alpha-tubulin genes have a fourth intron, also at
an identical position. Within a vertebrate species, the genes can be
distinguished by their 3-prime untranslated regions (UTRs). Since a
large proportion of the diversity of alpha-tubulins is clustered at the
C-terminal region and is conserved across species, alpha-tubulin genes
can be classified based on homology of their encoded C-terminal motifs
to those of mouse alpha-tubulin genes.
NOMENCLATURE
See Khodiyar et al. (2007) for a revised nomenclature of the
alpha-tubulin gene family.
CLONING
The b-alpha-1 gene, cloned from a human fetal brain cDNA library by
Cowan et al. (1983), is the human counterpart of mouse M-alpha-1. By
Northern blot analysis, Cowan et al. (1983) showed that b-alpha-1 mRNA
is expressed only in brain. They found that the 3-prime UTR of b-alpha-1
is more than 80% homologous to the UTR of the rat brain alpha-tubulin
gene, IL-alpha-T1.
Hall and Cowan (1985) screened a human genomic library with the 3-prime
UTR of b-alpha-1 and isolated the b-alpha-1 gene and a pseudogene.
B-alpha-1 encodes a predicted 451-amino acid protein that is 100%
identical to the rat homolog and differs by only 2 and 3 amino acids
from the pig and chicken homologs, respectively. Furthermore, they
observed that the first and largest intron of the b-alpha-1 gene is
homologous to that of the rat gene. Northern blotting showed that
b-alpha-1 expression was restricted to morphologically differentiated
neurologic cells.
By Northern blot analysis and in situ hybridization, Miller et al.
(1987) found that the rat homolog of b-alpha-1, which they called
T-alpha-1, is expressed at high levels during the extension of neuronal
processes.
Crabtree et al. (2001) cloned alpha-tubulin variants from a human retina
cDNA library. One variant had the same sequence as the clone isolated by
Cowan et al. (1983) from fetal brain, and the other had the same
sequence as the brain-specific alpha-tubulin clone isolated by Hall and
Cowan (1985), suggesting that this alpha-tubulin gene is expressed in
both brain and retina.
Poirier et al. (2007) detected high expression of the TUBA1A gene in
human fetal brain. Detailed study of mouse embryos showed expression in
the cortex, hippocampus, cerebellum, brainstem, and rostral migratory
stream. Tuba1a expression was decreased in most neurons at later
postnatal stages and in adulthood.
GENE STRUCTURE
Hall and Cowan (1985) determined that the b-alpha-1 gene contains 4
exons and spans less than 4 kb.
MAPPING
Scott (2001) mapped the TUBA1A gene to human chromosome 12 based on
sequence similarity between the TUBA1A sequence (GenBank GENBANK
AF141347) and chromosome 12 clones RP11-234P5 and RP11-977B10, (GenBank
GENBANK AC016125 and GenBank GENBANK AC010173).
Khodiyar et al. (2007) stated that the TUBA1A gene maps to human
chromosome 12q13.12 and mouse chromosome 15F1.
MOLECULAR GENETICS
In 2 unrelated patients with lissencephaly (LIS3; 611603), Keays et al.
(2007) and Poirier et al. (2007) identified 2 different de novo
heterozygous mutations in the TUBA1A gene (602529.0001; 602529.0002).
Poirier et al. (2007) identified de novo heterozygous TUBA1A mutations
(see, e.g., 602529.0003-602529.0005) in 6 additional patients with a
wide spectrum of brain dysgenesis, ranging from agyria to laminar
heterotopia. Retrospective examination of brain MRI showed defects in
the cerebellum, hippocampus, corpus callosum, and brainstem. Patients
who survived showed mental retardation, seizures, motor delay, and
microcephaly. In general, gyral malformations were more severe in the
posterior than anterior brain regions.
Bahi-Buisson et al. (2008) identified 6 de novo mutations in the TUBA1A
gene (see, e.g., 602529.0006; 602529.0007) in 6 of 100 patients with
lissencephaly who were negative for mutations in other known
lissencephaly-associated genes. The phenotype ranged from the less
severe perisylvian pachygyria to the more severe posteriorly predominant
pachygyria, which was associated with dysgenesis of the anterior limb of
the internal capsule and mild to severe cerebellar hypoplasia. Patients
with TUBA1A mutations shared a common clinical phenotype consisting of
congenital microcephaly, mental retardation and diplegia/tetraplegia.
Morris-Rosendahl et al. (2008) identified 4 different TUBA1A mutations
(see, e.g., 602529.0008) in 5 of 46 patients with variable patterns of
lissencephaly on brain MRI and no DCX (300121) or PAFAH1B1 (601545)
mutation. Four of the 5 patients had congenital microcephaly, and all
had dysgenesis of the corpus callosum, cerebellar hypoplasia, and
variable cortical malformations, including subtle subcortical band
heterotopia and absence or hypoplasia of the anterior limb of the
internal capsule.
Kumar et al. (2010) screened a cohort of 125 lissencephaly patients in
whom mutations in DCX and PAFAH1B1 had been excluded and identified
novel and recurrent TUBA1A mutations in 1% of children with classic
lissencephaly and in 30% of children with lissencephaly with cerebellar
hypoplasia. A TUBA1A mutation was also found in 1 child with agenesis of
the corpus callosum and cerebellar hypoplasia without lissencephaly. The
authors demonstrated a wider spectrum of phenotypes than had been
reported and suggested that lissencephaly-associated mutations of TUBA1A
may operate via diverse mechanisms that include disruption of binding
sites for microtubule-associated proteins.
Tian et al. (2010) studied the effects of 9 disease-associated TUBA1A
mutations on tubulin folding, heterodimer assembly, microtubule
dynamics, and stability. The translational yield of each mutant protein
varied across a continuum from an amount similar to that of wildtype for
mutant L286F, to slightly reduced formation for mutants I188L
(602529.0003), I238V, P263T (602529.0004), R402H (602529.0002) and S419L
(602529.0005), to significantly diminished amounts for mutants V303G,
L397P, and R402C. Studies of GTP-dependent polymerization and
depolymerization indicated that all the disease-causing TUBA1A mutations
were competent for assembly into microtubules in vitro. However, some of
the mutant proteins showed defects in the tubulin heterodimer assembly
pathway, with deficiencies in the production of intermediates. Mutants
I188L, I238V, L397P and R402C all generated lower yields of
intermediates compared to control TUBA1A; in addition, R402C showed a
time-dependent decay of intermediates, indicating instability. Some of
the mutant proteins (R264C, V303G, and L397P) also showed defective
interaction with assembly chaperone protein TBCB (see, e.g., TBCA,
610058). Tests of heterodimer stability showed that P263T and V303G had
reduced stability, whereas L397P and R402C were highly unstable. P263T
expression resulted in the assembly of heterodimers with a deleterious
effect on microtubule dynamics, whereas the other mutant proteins did
not show defects in microtubule growth. The findings demonstrated that
different TUBA1A mutations result in a variety of tubulin defects, but
also suggested that the mutations may cause compromised interactions
with other interacting proteins essential for proper neuronal migration.
ANIMAL MODEL
Keays et al. (2007) reported a hyperactive N-ethyl-N-nitrosourea
(ENU)-induced mouse mutant with abnormalities in the laminar
architecture of the hippocampus and cortex accompanied by impaired
neuronal migration. Fine mapping and genomic screening identified an
S140G mutation in the Tuba1a gene. Functional studies showed that the
mutation resulted in decreased GTP binding and impaired tubulin
heterodimer formation. However, heterodimers that did form were able to
polymerize and were incorporated into the microtubule network of
cultured cells. Abnormal neuronal migration was manifest as
perturbations in layers II/III and IV of the visual, auditory, and
somatosensory cortices, and a fractured pyramidal cell layer in the
hippocampus. Behavioral studies showed that the mutant mice had impaired
spatial working memory, reduced anxiety, and abnormal nesting,
consistent with a hippocampal deficit. Keays et al. (2007) concluded
that pathogenic mutations in the TUBA1A gene interferes with microtubule
function, thus impairing neuronal migration.
*FIELD* AV
.0001
LISSENCEPHALY 3
TUBA1A, ARG264CYS
In a patient with lissencephaly (LIS3; 611603), Keays et al. (2007) and
Poirier et al. (2007) identified a heterozygous de novo 790C-T
transition in exon 4 of the TUBA1A gene, resulting in an arg264-to-cys
(R264C) substitution in a loop between H8 and S7. The patient had
microcephaly, pachygyria, an abnormally shaped corpus callosum, and
hypoplasia of the cerebellar vermis and brainstem. Clinical features
included severe mental retardation, mild motor delay, and absence of
seizures. Poirier et al. (2007) reported another unrelated patient with
a similar phenotype who carried the R264C mutation.
Bahi-Buisson et al. (2008) identified the R264C mutation in 2 additional
unrelated patients with LIS3.
.0002
LISSENCEPHALY 3
TUBA1A, ARG402HIS
In a patient with lissencephaly (LIS3; 611603), Keays et al. (2007) and
Poirier et al. (2007) identified a heterozygous de novo 1205G-A
transition in exon 4 of the TUBA1A gene, resulting in an arg402-to-his
(R402H) substitution at the beginning of the H11-H12 loop near the
interface with beta-tubulin (191130). The patient had microcephaly,
agyria, thin corpus callosum, abnormal hippocampus, and hypoplasia of
the cerebellar vermis and brainstem, and severe ventricular dilatation.
Clinical features included profound mental retardation, spastic
tetraplegia, and intractable tonic-clonic seizures.
By extensive in vitro functional expression assays, Tian et al. (2010)
found that mutant R402H performed like wildtype, although there was a
slight reduction in the amount of protein translated and a slight
reduction in the formation of tubulin assembly intermediates. There were
no obvious effects on de novo heterodimer assembly or microtubule
dynamics, suggesting that the disease phenotype is likely to be caused
by an effect on other microtubule-dependent processes such as the
binding of associated proteins.
.0003
LISSENCEPHALY 3
TUBA1A, ILE188LEU
In a female patient with lissencephaly (LIS3; 611603), Poirier et al.
(2007) identified a heterozygous de novo 562A-C transversion in the
TUBA1A gene, resulting in an ile188-to-leu (I188L) substitution. She had
microcephaly, laminar heterotopia, thin corpus callosum with partial
agenesis, and hypoplasia of the brainstem and cerebellar vermis.
By extensive in vitro functional expression assays, Tian et al. (2010)
found that mutant I188L performed like wildtype, although there was a
slight reduction in the amount of protein translated and a slight
reduction in the formation of tubulin assembly intermediates. There were
no obvious effects on de novo heterodimer assembly or microtubule
dynamics, suggesting that the disease phenotype is likely to be caused
by an effect on other microtubule-dependent processes such as the
binding of associated proteins.
.0004
LISSENCEPHALY 3
TUBA1A, PRO263THR
In a 26-week-old fetus with lissencephaly (LIS3; 611603), Poirier et al.
(2007) identified a de novo heterozygous 787C-A transversion in the
TUBA1A gene, resulting in a pro263-to-thr (P263T) substitution.
Postmortem examination showed agyria, agenesis of the corpus callosum,
abnormal hippocampus, hypoplasia of the cerebellar vermis and brainstem,
and severe ventricular dilatation.
By extensive in vitro functional expression assays, Tian et al. (2010)
found that mutant P263T showed reduced stability and resulted in the
assembly of heterodimers with a deleterious effect on microtubule
dynamics, with a damping of the microtubule growth rate.
.0005
LISSENCEPHALY 3
TUBA1A, SER419LEU
In an 18-year-old man with lissencephaly (LIS3; 611603), Poirier et al.
(2007) identified a de novo heterozygous 1256C-T transition in the
TUBA1A gene, resulting in a ser419-to-leu (S419L) substitution. He had
profound mental retardation, spastic tetraplegia, intractable seizures,
and pachygyria.
By extensive in vitro functional expression assays, Tian et al. (2010)
found that mutant S419L performed like wildtype, although there was a
slight reduction in the amount of protein translated and a slight
reduction in the formation of tubulin assembly intermediates. There were
no obvious effects on de novo heterodimer assembly or microtubule
dynamics, suggesting that the disease phenotype is likely to be caused
by an effect on other microtubule-dependent processes such as the
binding of associated proteins.
.0006
LISSENCEPHALY 3
TUBA1A, LEU397PRO
In a 5.5-year-old boy with lissencephaly (LIS3; 611603), Bahi-Buisson et
al. (2008) identified a de novo heterozygous 1190T-C transition in the
TUBA1A gene, resulting in a leu397-to-pro (L397P) substitution. The
patient had microcephaly, spastic diplegia, and cognitive delay with few
words acquired. MRI scan showed perisylvian pachygyria with dysgenesis
of the internal capsule and posterior agenesis of the corpus callosum.
There was also severe vermian dysplasia of the cerebellum. The mutation
was not identified in 360 control individuals.
.0007
LISSENCEPHALY 3
TUBA1A, ARG422CYS
In a 4.5-year-old girl with lissencephaly (LIS3; 611603), Bahi-Buisson
et al. (2008) identified a de novo heterozygous 1264C-T transition in
the TUBA1A gene, resulting in an arg422-to-cys (R422C) substitution. The
patient had microcephaly, spastic diplegia, and could speak only in
short sentences. MRI scan showed perisylvian pachygyria with dysgenesis
of the internal capsule and mild hypoplasia of the corpus callosum.
There was also mild vermian hypoplasia of the cerebellum. The mutation
was not identified in 360 control individuals.
.0008
LISSENCEPHALY 3
TUBA1A, ARG422HIS
In 2 unrelated patients with lissencephaly (LIS3; 611603),
Morris-Rosendahl et al. (2008) identified a heterozygous 1265G-A
transition in exon 4 of the TUBA1A gene, resulting in an arg422-to-his
(R422H) substitution. In addition to the classic features of
microcephaly, seizure, pachygyria, and hypoplasia of the corpus callosum
and cerebellum, both patients had subtle evidence of subcortical band
heterotopia.
.0009
LISSENCEPHALY 3
TUBA1A, ILE5LEU
In 2 sisters, born of consanguineous Moroccan parents, with LIS3
(611603), Jansen et al. (2011) identified a heterozygous 13A-C
transition in exon 2 of the TUBA1A gene, resulting in an ile5-to-leu
(I5L) substitution. The girls had developmental delay, spastic diplegia,
and ataxia; 1 had seizures. Brain MRI showed perisylvian polymicrogyria,
gray matter heterotopia, enlarged lateral ventricle with a hooked aspect
of the right frontal horn due to abnormally shaped basal ganglia, thin
corpus callosum, and hypoplasia of the pons. One girl had optic nerve
hypoplasia and mild vermian hypoplasia. The clinically asymptomatic
mother was found to be somatic mosaic for the mutation, which was
detected in 5.6% of DNA in peripheral blood. Her brain MRI showed a thin
corpus callosum, hypoplasia of the superior vermis, and a thin medulla.
The report indicated that rare familial recurrence of LIS3 can occur.
*FIELD* RF
1. Bahi-Buisson, N.; Poirier, K.; Boddaert, N.; Saillour, Y.; Castelnau,
L.; Philip, N.; Buyse, G.; Villard, L.; Joriot, S.; Marret, S.; Bourgeois,
M.; Van Esch, H.; Lagae, L.; Amiel, J.; Hertz-Pannier, L.; Roubertie,
A.; Rivier, F.; Pinard, J. M.; Beldjord, C.; Chelly, J.: Refinement
of cortical dysgeneses spectrum associated with TUBA1A mutations. J.
Med. Genet. 45: 647-653, 2008.
2. Cowan, N. J.; Dobner, P. R.; Fuchs, E. V.; Cleveland, D. W.: Expression
of human alpha-tubulin genes: interspecies conservation of 3-prime
untranslated regions. Molec. Cell. Biol. 3: 1738-1745, 1983.
3. Crabtree, D. V.; Ojima, I.; Geng, X.; Adler, A. J.: Tubulins in
the primate retina: evidence that xanthophylls may be endogenous ligands
for the paclitaxel-binding site. Bioorganic Medicinal Chemistry 9:
1967-1976, 2001.
4. Hall, J. L.; Cowan, N. J.: Structural features and restricted
expression of a human alpha-tubulin gene. Nucleic Acids Res. 13:
207-223, 1985.
5. Jansen, A. C.; Oostra, A.; Desprechins, B.; De Vlaeminck, Y.; Verhelst,
H.; Regal, L.; Verloo, P.; Bockaert, N.; Keymolen, K.; Seneca, S.;
De Meirleir, L.; Lissens, W.: TUBA1A mutations: from isolated lissencephaly
to familial polymicrogyria. Neurology 76: 988-992, 2011.
6. Keays, D. A.; Tian, G.; Poirier, K.; Huang, G.-J.; Siebold, C.;
Cleak, J.; Oliver, P. L.; Fray, M.; Harvey, R. J.; Molnar, Z.; Pinon,
M. C.; Dear, N.; Valdar, W.; Brown, S. D. M.; Davies, K. E.; Rawlins,
J. N. P.; Cowan, N. J.; Nolan, P.; Chelly, J.; Flint, J.: Mutations
in alpha-tubulin cause abnormal neuronal migration in mice and lissencephaly
in humans. Cell 128: 45-57, 2007.
7. Khodiyar, V. K.; Maltais, L. J.; Ruef, B. J.; Sneddon, K. M. B.;
Smith, J. R.; Shimoyama, M.; Cabral, F.; Dumontet, C.; Dutcher, S.
K.; Harvey, R. J.; Lafanechere, L.; Murray, J. M.; Nogales, E.; Piquemal,
D.; Stanchi, F.; Povey, S.; Lovering, R. C.: A revised nomenclature
for the human and rodent alpha-tubulin gene family. Genomics 90:
285-289, 2007. Note: Erratum: Genomics 93: 397 only, 2009.
8. Kumar, R. A.; Pilz, D. T.; Babatz, T. D.; Cushion, T. D.; Harvey,
K.; Topf, M.; Yates, L.; Robb, S.; Uyanik, G.; Mancini, G. M. S.;
Rees, M. I.; Harvey, R. J.; Dobyns, W. B.: TUBA1A mutations cause
wide spectrum lissencephaly (smooth brain) and suggest that multiple
neuronal migration pathways converge on alpha tubulins. Hum. Molec.
Genet. 19: 2817-2827, 2010.
9. Lewis, S. A.; Cowan, N. J.: Tubulin genes: structure, expression,
and regulation.In: Avila, J. (ed.): Microtubule proteins. Boca
Raton: CRC Press, Inc. 1990. Pp. 37-66.
10. Miller, F. D.; Naus, C. C. G.; Durand, M.; Bloom, F. E.; Milner,
R. J.: Isotypes of alpha-tubulin are differentially regulated during
neuronal maturation. J. Cell Biol. 105: 3065-3073, 1987.
11. Morris-Rosendahl, D. J.; Najm, J.; Lachmeijer, A. M. A.; Sztriha,
L.; Martins, M.; Kuechler, A.; Haug, V.; Zeschnigk, C.; Martin, P.;
Santos, M.; Vasconcelos, C.; Omran, H.; Kraus, U.; Van der Knaap,
M. S.; Schuierer, G.; Kutsche, K.; Uyanik, G.: Refining the phenotype
of alpha-1a tubulin (TUBA1A) mutation in patients with classical lissencephaly. Clin.
Genet. 74: 425-433, 2008.
12. Poirier, K.; Keays, D. A.; Francis, F.; Saillour, Y.; Bahi, N.;
Manouvrier, S.; Fallet-Bianco, C.; Pasquier, L.; Toutain, A.; Tuy,
F. P. D.; Bienvenu, T.; Joriot, S.; and 12 others: Large spectrum
of lissencephaly and pachygyria phenotypes resulting from de novo
missense mutations in tubulin alpha 1A (TUBA1A). Hum. Mutat. 28:
1055-1064, 2007.
13. Scott, A. F.: Personal Communication. Baltimore, Md. 10/3/2001.
14. Tian, G.; Jaglin, X. H.; Keays, D. A.; Francis, F.; Chelly, J.;
Cowan, N. J.: Disease-associated mutations in TUBA1A result in a
spectrum of defects in the tubulin folding and heterodimer assembly
pathway. Hum. Molec. Genet. 19: 3599-3613, 2010.
*FIELD* CN
George E. Tiller - updated: 09/05/2013
Cassandra L. Kniffin - updated: 4/18/2012
Cassandra L. Kniffin - updated: 3/3/2009
Cassandra L. Kniffin - updated: 2/12/2009
Cassandra L. Kniffin - updated: 11/19/2007
Patricia A. Hartz - updated: 12/21/2004
Alan F. Scott - updated: 10/3/2001
*FIELD* CD
Rebekah S. Rasooly: 4/16/1998
*FIELD* ED
alopez: 09/05/2013
terry: 11/28/2012
carol: 5/3/2012
ckniffin: 4/18/2012
alopez: 8/18/2011
ckniffin: 8/3/2011
wwang: 3/6/2009
ckniffin: 3/3/2009
wwang: 2/20/2009
ckniffin: 2/12/2009
wwang: 12/14/2007
ckniffin: 11/19/2007
carol: 9/13/2007
carol: 9/11/2007
alopez: 2/8/2007
mgross: 1/12/2005
terry: 12/21/2004
joanna: 10/3/2001
alopez: 6/18/1999
psherman: 4/20/1998
psherman: 4/16/1998
MIM
611603
*RECORD*
*FIELD* NO
611603
*FIELD* TI
#611603 LISSENCEPHALY 3; LIS3
*FIELD* TX
A number sign (#) is used with this entry because lissencephaly-3 is
read morecaused by heterozygous mutation in the TUBA1A gene (602529) on
chromosome 12q13.
For a general description and a discussion of genetic heterogeneity of
lissencephaly, see LIS1 (607432).
CLINICAL FEATURES
Keays et al. (2007) and Poirier et al. (2007) reported 2 unrelated
children with lissencephaly. One patient had microcephaly, pachygyria,
an abnormally shaped corpus callosum, and hypoplasia of the cerebellar
vermis and brainstem. Clinical features included severe mental
retardation, mild motor delay, and absence of seizures. The second
patient had a more severe phenotype, with microcephaly, agyria, thin
corpus callosum, abnormal hippocampus, hypoplasia of the cerebellar
vermis and brainstem, and severe ventricular dilatation. Clinical
features included profound mental retardation, spastic tetraplegia, and
intractable tonic-clonic seizures.
Poirier et al. (2007) reported 6 additional patients with a wide
spectrum of brain dysgenesis, ranging from agyria to laminar
heterotopia. Retrospective examination of brain MRI showed defects in
the cerebellum, hippocampus, corpus callosum, and brainstem. Patients
who survived showed mental retardation, seizures, motor delay, and
microcephaly. The brain anomalies were consistent with a neuronal
migration disorder.
Bahi-Buisson et al. (2008) reported 6 patients with LIS3 confirmed by
genetic analysis. The phenotype ranged from the less severe perisylvian
pachygyria to the more severe posteriorly predominant pachygyria, which
was associated with dysgenesis of the anterior limb of the internal
capsule and mild to severe cerebellar hypoplasia. Patients with TUBA1A
mutations shared a common clinical phenotype consisting of congenital
microcephaly, mental retardation, lack of language development, and
diplegia/tetraplegia.
Jansen et al. (2011) reported a boy with genetically confirmed LIS3. He
had microcephaly at birth, and presented with severe hypotonia and
feeding difficulties. He developed refractory focal seizures soon after
birth. At age 18 months, he had axial hypotonia with peripheral
hypertonia and essentially no psychomotor development. Brain MRI showed
grade 2 lissencephaly with an anterior-to-posterior gradient, enlarged
ventricles, thin corpus callosum, and cerebellar hypoplasia. The TUBA1A
mutation occurred de novo.
Poirier et al. (2013) reported 3 unrelated patients with polymicrogyria
(PMG) associated with 3 different heterozygous de novo missense
mutations in the TUBA1A gene. The first patient, a 7.5-year-old boy, had
mildly delayed development with autistic features, refractory focal
seizures, poor language, and right hemiparesis with hemianopsia. Brain
MRI showed perisylvian PMG more prominent in the right perisylvian
region and frontal region, dysmorphic basal ganglia, and hypoplasia of
the corpus callosum. The second patient was an 11-year-old girl with
microcephaly, hypotonia, refractory occipital seizures, left
hemiparesis, lack of speech, and cortical blindness. Brain MRI showed
PMG more localized in right perisylvian region, dysmorphic basal
ganglia, dysplastic cerebellar vermis, hypoplastic pons, and hypoplasia
of the corpus callosum. The third patient was a 12-month-old boy with
microcephaly, hypotonia, convergent strabismus, and pyramidal signs. MRI
showed asymmetrical perisylvian PMG that was localized on the left but
extended to the parietal region on the right. There was also dysmorphic
basal ganglia, dysplastic cerebellar vermis, severe brainstem
hypoplasia, and hypoplasia of the corpus callosum. Protein structural
data suggested that the mutations may specifically affect microtubule
dynamics or stability, or local interactions with partner proteins. The
patients were ascertained from a larger cohort of 95 patients with
bilateral PMG and thus accounted for 3.1% of the total group. The report
broadened the phenotypic spectrum associated with TUBA1A mutations to
include PMG as well as additional brain abnormalities, including
dysmorphic basal ganglia, hypoplastic pons, and cerebellar dysplasia.
INHERITANCE
Most cases of LIS3 occur de novo. However, Jansen et al. (2011) reported
2 sisters with LIS3, born of consanguineous Moroccan parents, who each
had the same heterozygous mutation in the TUBA1A gene (I5L; 602529.0009)
inherited from their mother who was somatic mosaic for the mutation,
which was found in 5.6% of her peripheral blood. The girls, ages 7 and 3
years, respectively, had global developmental delay, pyramidal signs,
and limb ataxia. One had seizures. Brain MRI showed perisylvian
polymicrogyria, gray matter heterotopia, enlarged lateral ventricle with
a hooked aspect of the right frontal horn due to abnormally shaped basal
ganglia, thin corpus callosum, and hypoplasia of the pons. One girl had
optic nerve hypoplasia and mild vermian hypoplasia. Brain MRI of the
clinically asymptomatic mother showed a thin corpus callosum, hypoplasia
of the superior vermis, and a thin medulla. The report indicated that
rare familial recurrence of LIS3 can occur.
MOLECULAR GENETICS
In 2 unrelated patients with LIS3, Keays et al. (2007) and Poirier et
al. (2007) identified 2 different de novo heterozygous mutations in the
TUBA1A gene (602529.0001; 602529.0002).
Poirier et al. (2007) identified de novo heterozygous TUBA1A mutations
(see, e.g., 602529.0003-602529.0005) in 6 additional patients with LIS3.
Bahi-Buisson et al. (2008) identified 6 de novo mutations in the TUBA1A
gene (see, e.g., 602529.0006; 602529.0007) in 6 of 100 patients with
lissencephaly who were negative for mutations in other known
lissencephaly-associated genes.
Morris-Rosendahl et al. (2008) identified 4 different TUBA1A mutations
(see, e.g., 602529.0008) in 5 of 46 patients with variable patterns of
lissencephaly on brain MRI and no DCX (300121) or PAFAH1B1 (601545)
mutation. Four of the 5 patients had congenital microcephaly, and all
had dysgenesis of the corpus callosum, cerebellar hypoplasia, and
variable cortical malformations, including subtle subcortical band
heterotopia and absence or hypoplasia of the anterior limb of the
internal capsule. Morris-Rosendahl et al. (2008) estimated that TUBA1A
mutation is a rare cause of classic lissencephaly comprising a maximum
of 4% of patients including those with DCX and PAFAH1B1 mutations.
Kumar et al. (2010) screened a cohort of 125 lissencephaly patients in
whom mutations in DCX and PAFAH1B1 had been excluded and identified
novel and recurrent TUBA1A mutations in 1% of children with classic
lissencephaly and in 30% of children with lissencephaly with cerebellar
hypoplasia. A TUBA1A mutation was also found in 1 child with agenesis of
the corpus callosum and cerebellar hypoplasia without lissencephaly. The
authors demonstrated a wider spectrum of phenotypes than had been
reported and suggested that lissencephaly-associated mutations of TUBA1A
may operate via diverse mechanisms that include disruption of binding
sites for microtubule-associated proteins.
*FIELD* RF
1. Bahi-Buisson, N.; Poirier, K.; Boddaert, N.; Saillour, Y.; Castelnau,
L.; Philip, N.; Buyse, G.; Villard, L.; Joriot, S.; Marret, S.; Bourgeois,
M.; Van Esch, H.; Lagae, L.; Amiel, J.; Hertz-Pannier, L.; Roubertie,
A.; Rivier, F.; Pinard, J. M.; Beldjord, C.; Chelly, J.: Refinement
of cortical dysgeneses spectrum associated with TUBA1A mutations. J.
Med. Genet. 45: 647-653, 2008.
2. Jansen, A. C.; Oostra, A.; Desprechins, B.; De Vlaeminck, Y.; Verhelst,
H.; Regal, L.; Verloo, P.; Bockaert, N.; Keymolen, K.; Seneca, S.;
De Meirleir, L.; Lissens, W.: TUBA1A mutations: from isolated lissencephaly
to familial polymicrogyria. Neurology 76: 988-992, 2011.
3. Keays, D. A.; Tian, G.; Poirier, K.; Huang, G.-J.; Siebold, C.;
Cleak, J.; Oliver, P. L.; Fray, M.; Harvey, R. J.; Molnar, Z.; Pinon,
M. C.; Dear, N.; Valdar, W.; Brown, S. D. M.; Davies, K. E.; Rawlins,
J. N. P.; Cowan, N. J.; Nolan, P.; Chelly, J.; Flint, J.: Mutations
in alpha-tubulin cause abnormal neuronal migration in mice and lissencephaly
in humans. Cell 128: 45-57, 2007.
4. Kumar, R. A.; Pilz, D. T.; Babatz, T. D.; Cushion, T. D.; Harvey,
K.; Topf, M.; Yates, L.; Robb, S.; Uyanik, G.; Mancini, G. M. S.;
Rees, M. I.; Harvey, R. J.; Dobyns, W. B.: TUBA1A mutations cause
wide spectrum lissencephaly (smooth brain) and suggest that multiple
neuronal migration pathways converge on alpha tubulins. Hum. Molec.
Genet. 19: 2817-2827, 2010.
5. Morris-Rosendahl, D. J.; Najm, J.; Lachmeijer, A. M. A.; Sztriha,
L.; Martins, M.; Kuechler, A.; Haug, V.; Zeschnigk, C.; Martin, P.;
Santos, M.; Vasconcelos, C.; Omran, H.; Kraus, U.; Van der Knaap,
M. S.; Schuierer, G.; Kutsche, K.; Uyanik, G.: Refining the phenotype
of alpha-1a tubulin (TUBA1A) mutation in patients with classical lissencephaly. Clin.
Genet. 74: 425-433, 2008.
6. Poirier, K.; Keays, D. A.; Francis, F.; Saillour, Y.; Bahi, N.;
Manouvrier, S.; Fallet-Bianco, C.; Pasquier, L.; Toutain, A.; Tuy,
F. P. D.; Bienvenu, T.; Joriot, S.; and 12 others: Large spectrum
of lissencephaly and pachygyria phenotypes resulting from de novo
missense mutations in tubulin alpha 1A (TUBA1A). Hum. Mutat. 28:
1055-1064, 2007.
7. Poirier, K.; Saillour, Y.; Fourniol, F.; Francis, F.; Souville,
I.; Valence, S.; Desguerre, I.; Lepage, J. M.; Boddaert, N.; Jacquemont,
M. L.; Beldjord, C.; Chelly, J.; Bahi-Buisson, N.: Expanding the
spectrum of TUBA1A-related cortical dysgenesis to polymicrogyria. Europ.
J. Hum. Genet. 21: 381-385, 2013.
*FIELD* CS
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Head];
Microcephaly
NEUROLOGIC:
[Central nervous system];
Mental retardation, severe to profound;
Delayed motor development;
Hypotonia;
Spastic tetraplegia;
Ataxia;
Seizures;
Lissencephaly;
Agyria (posterior-to-anterior gradient);
Pachygyria (posterior-to-anterior gradient);
Polymicrogyria;
Subcortical laminar heterotopia;
Hooked aspect of the frontal horn of the lateral ventricles due to
abnormally shaped basal ganglia;
Ventricular dilatation;
Thin corpus callosum;
Abnormal hippocampus;
Agenesis of the corpus callosum;
Absence or hypoplasia of the anterior limb of the internal capsule;
Hypoplasia of the cerebellar vermis;
Hypoplasia of the brainstem
MISCELLANEOUS:
Most cases occur de novo
MOLECULAR BASIS:
Caused by mutation in the alpha-tubulin 1A gene (TUBA1A, 602529.0001)
*FIELD* CN
Cassandra L. Kniffin - updated: 8/3/2011
Cassandra L. Kniffin - updated: 2/16/2009
*FIELD* CD
Cassandra L. Kniffin: 11/19/2007
*FIELD* ED
joanna: 12/29/2011
ckniffin: 8/3/2011
joanna: 5/14/2009
ckniffin: 2/16/2009
joanna: 3/19/2008
ckniffin: 11/19/2007
*FIELD* CN
George E. Tiller - updated: 09/05/2013
Cassandra L. Kniffin - updated: 5/8/2013
Cassandra L. Kniffin - updated: 3/3/2009
Cassandra L. Kniffin - updated: 2/12/2009
*FIELD* CD
Cassandra L. Kniffin: 11/19/2007
*FIELD* ED
alopez: 09/05/2013
carol: 5/20/2013
ckniffin: 5/8/2013
terry: 1/17/2012
alopez: 8/18/2011
ckniffin: 8/3/2011
carol: 6/2/2011
wwang: 3/6/2009
ckniffin: 3/3/2009
wwang: 2/20/2009
ckniffin: 2/12/2009
wwang: 12/14/2007
ckniffin: 11/19/2007
*RECORD*
*FIELD* NO
611603
*FIELD* TI
#611603 LISSENCEPHALY 3; LIS3
*FIELD* TX
A number sign (#) is used with this entry because lissencephaly-3 is
read morecaused by heterozygous mutation in the TUBA1A gene (602529) on
chromosome 12q13.
For a general description and a discussion of genetic heterogeneity of
lissencephaly, see LIS1 (607432).
CLINICAL FEATURES
Keays et al. (2007) and Poirier et al. (2007) reported 2 unrelated
children with lissencephaly. One patient had microcephaly, pachygyria,
an abnormally shaped corpus callosum, and hypoplasia of the cerebellar
vermis and brainstem. Clinical features included severe mental
retardation, mild motor delay, and absence of seizures. The second
patient had a more severe phenotype, with microcephaly, agyria, thin
corpus callosum, abnormal hippocampus, hypoplasia of the cerebellar
vermis and brainstem, and severe ventricular dilatation. Clinical
features included profound mental retardation, spastic tetraplegia, and
intractable tonic-clonic seizures.
Poirier et al. (2007) reported 6 additional patients with a wide
spectrum of brain dysgenesis, ranging from agyria to laminar
heterotopia. Retrospective examination of brain MRI showed defects in
the cerebellum, hippocampus, corpus callosum, and brainstem. Patients
who survived showed mental retardation, seizures, motor delay, and
microcephaly. The brain anomalies were consistent with a neuronal
migration disorder.
Bahi-Buisson et al. (2008) reported 6 patients with LIS3 confirmed by
genetic analysis. The phenotype ranged from the less severe perisylvian
pachygyria to the more severe posteriorly predominant pachygyria, which
was associated with dysgenesis of the anterior limb of the internal
capsule and mild to severe cerebellar hypoplasia. Patients with TUBA1A
mutations shared a common clinical phenotype consisting of congenital
microcephaly, mental retardation, lack of language development, and
diplegia/tetraplegia.
Jansen et al. (2011) reported a boy with genetically confirmed LIS3. He
had microcephaly at birth, and presented with severe hypotonia and
feeding difficulties. He developed refractory focal seizures soon after
birth. At age 18 months, he had axial hypotonia with peripheral
hypertonia and essentially no psychomotor development. Brain MRI showed
grade 2 lissencephaly with an anterior-to-posterior gradient, enlarged
ventricles, thin corpus callosum, and cerebellar hypoplasia. The TUBA1A
mutation occurred de novo.
Poirier et al. (2013) reported 3 unrelated patients with polymicrogyria
(PMG) associated with 3 different heterozygous de novo missense
mutations in the TUBA1A gene. The first patient, a 7.5-year-old boy, had
mildly delayed development with autistic features, refractory focal
seizures, poor language, and right hemiparesis with hemianopsia. Brain
MRI showed perisylvian PMG more prominent in the right perisylvian
region and frontal region, dysmorphic basal ganglia, and hypoplasia of
the corpus callosum. The second patient was an 11-year-old girl with
microcephaly, hypotonia, refractory occipital seizures, left
hemiparesis, lack of speech, and cortical blindness. Brain MRI showed
PMG more localized in right perisylvian region, dysmorphic basal
ganglia, dysplastic cerebellar vermis, hypoplastic pons, and hypoplasia
of the corpus callosum. The third patient was a 12-month-old boy with
microcephaly, hypotonia, convergent strabismus, and pyramidal signs. MRI
showed asymmetrical perisylvian PMG that was localized on the left but
extended to the parietal region on the right. There was also dysmorphic
basal ganglia, dysplastic cerebellar vermis, severe brainstem
hypoplasia, and hypoplasia of the corpus callosum. Protein structural
data suggested that the mutations may specifically affect microtubule
dynamics or stability, or local interactions with partner proteins. The
patients were ascertained from a larger cohort of 95 patients with
bilateral PMG and thus accounted for 3.1% of the total group. The report
broadened the phenotypic spectrum associated with TUBA1A mutations to
include PMG as well as additional brain abnormalities, including
dysmorphic basal ganglia, hypoplastic pons, and cerebellar dysplasia.
INHERITANCE
Most cases of LIS3 occur de novo. However, Jansen et al. (2011) reported
2 sisters with LIS3, born of consanguineous Moroccan parents, who each
had the same heterozygous mutation in the TUBA1A gene (I5L; 602529.0009)
inherited from their mother who was somatic mosaic for the mutation,
which was found in 5.6% of her peripheral blood. The girls, ages 7 and 3
years, respectively, had global developmental delay, pyramidal signs,
and limb ataxia. One had seizures. Brain MRI showed perisylvian
polymicrogyria, gray matter heterotopia, enlarged lateral ventricle with
a hooked aspect of the right frontal horn due to abnormally shaped basal
ganglia, thin corpus callosum, and hypoplasia of the pons. One girl had
optic nerve hypoplasia and mild vermian hypoplasia. Brain MRI of the
clinically asymptomatic mother showed a thin corpus callosum, hypoplasia
of the superior vermis, and a thin medulla. The report indicated that
rare familial recurrence of LIS3 can occur.
MOLECULAR GENETICS
In 2 unrelated patients with LIS3, Keays et al. (2007) and Poirier et
al. (2007) identified 2 different de novo heterozygous mutations in the
TUBA1A gene (602529.0001; 602529.0002).
Poirier et al. (2007) identified de novo heterozygous TUBA1A mutations
(see, e.g., 602529.0003-602529.0005) in 6 additional patients with LIS3.
Bahi-Buisson et al. (2008) identified 6 de novo mutations in the TUBA1A
gene (see, e.g., 602529.0006; 602529.0007) in 6 of 100 patients with
lissencephaly who were negative for mutations in other known
lissencephaly-associated genes.
Morris-Rosendahl et al. (2008) identified 4 different TUBA1A mutations
(see, e.g., 602529.0008) in 5 of 46 patients with variable patterns of
lissencephaly on brain MRI and no DCX (300121) or PAFAH1B1 (601545)
mutation. Four of the 5 patients had congenital microcephaly, and all
had dysgenesis of the corpus callosum, cerebellar hypoplasia, and
variable cortical malformations, including subtle subcortical band
heterotopia and absence or hypoplasia of the anterior limb of the
internal capsule. Morris-Rosendahl et al. (2008) estimated that TUBA1A
mutation is a rare cause of classic lissencephaly comprising a maximum
of 4% of patients including those with DCX and PAFAH1B1 mutations.
Kumar et al. (2010) screened a cohort of 125 lissencephaly patients in
whom mutations in DCX and PAFAH1B1 had been excluded and identified
novel and recurrent TUBA1A mutations in 1% of children with classic
lissencephaly and in 30% of children with lissencephaly with cerebellar
hypoplasia. A TUBA1A mutation was also found in 1 child with agenesis of
the corpus callosum and cerebellar hypoplasia without lissencephaly. The
authors demonstrated a wider spectrum of phenotypes than had been
reported and suggested that lissencephaly-associated mutations of TUBA1A
may operate via diverse mechanisms that include disruption of binding
sites for microtubule-associated proteins.
*FIELD* RF
1. Bahi-Buisson, N.; Poirier, K.; Boddaert, N.; Saillour, Y.; Castelnau,
L.; Philip, N.; Buyse, G.; Villard, L.; Joriot, S.; Marret, S.; Bourgeois,
M.; Van Esch, H.; Lagae, L.; Amiel, J.; Hertz-Pannier, L.; Roubertie,
A.; Rivier, F.; Pinard, J. M.; Beldjord, C.; Chelly, J.: Refinement
of cortical dysgeneses spectrum associated with TUBA1A mutations. J.
Med. Genet. 45: 647-653, 2008.
2. Jansen, A. C.; Oostra, A.; Desprechins, B.; De Vlaeminck, Y.; Verhelst,
H.; Regal, L.; Verloo, P.; Bockaert, N.; Keymolen, K.; Seneca, S.;
De Meirleir, L.; Lissens, W.: TUBA1A mutations: from isolated lissencephaly
to familial polymicrogyria. Neurology 76: 988-992, 2011.
3. Keays, D. A.; Tian, G.; Poirier, K.; Huang, G.-J.; Siebold, C.;
Cleak, J.; Oliver, P. L.; Fray, M.; Harvey, R. J.; Molnar, Z.; Pinon,
M. C.; Dear, N.; Valdar, W.; Brown, S. D. M.; Davies, K. E.; Rawlins,
J. N. P.; Cowan, N. J.; Nolan, P.; Chelly, J.; Flint, J.: Mutations
in alpha-tubulin cause abnormal neuronal migration in mice and lissencephaly
in humans. Cell 128: 45-57, 2007.
4. Kumar, R. A.; Pilz, D. T.; Babatz, T. D.; Cushion, T. D.; Harvey,
K.; Topf, M.; Yates, L.; Robb, S.; Uyanik, G.; Mancini, G. M. S.;
Rees, M. I.; Harvey, R. J.; Dobyns, W. B.: TUBA1A mutations cause
wide spectrum lissencephaly (smooth brain) and suggest that multiple
neuronal migration pathways converge on alpha tubulins. Hum. Molec.
Genet. 19: 2817-2827, 2010.
5. Morris-Rosendahl, D. J.; Najm, J.; Lachmeijer, A. M. A.; Sztriha,
L.; Martins, M.; Kuechler, A.; Haug, V.; Zeschnigk, C.; Martin, P.;
Santos, M.; Vasconcelos, C.; Omran, H.; Kraus, U.; Van der Knaap,
M. S.; Schuierer, G.; Kutsche, K.; Uyanik, G.: Refining the phenotype
of alpha-1a tubulin (TUBA1A) mutation in patients with classical lissencephaly. Clin.
Genet. 74: 425-433, 2008.
6. Poirier, K.; Keays, D. A.; Francis, F.; Saillour, Y.; Bahi, N.;
Manouvrier, S.; Fallet-Bianco, C.; Pasquier, L.; Toutain, A.; Tuy,
F. P. D.; Bienvenu, T.; Joriot, S.; and 12 others: Large spectrum
of lissencephaly and pachygyria phenotypes resulting from de novo
missense mutations in tubulin alpha 1A (TUBA1A). Hum. Mutat. 28:
1055-1064, 2007.
7. Poirier, K.; Saillour, Y.; Fourniol, F.; Francis, F.; Souville,
I.; Valence, S.; Desguerre, I.; Lepage, J. M.; Boddaert, N.; Jacquemont,
M. L.; Beldjord, C.; Chelly, J.; Bahi-Buisson, N.: Expanding the
spectrum of TUBA1A-related cortical dysgenesis to polymicrogyria. Europ.
J. Hum. Genet. 21: 381-385, 2013.
*FIELD* CS
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Head];
Microcephaly
NEUROLOGIC:
[Central nervous system];
Mental retardation, severe to profound;
Delayed motor development;
Hypotonia;
Spastic tetraplegia;
Ataxia;
Seizures;
Lissencephaly;
Agyria (posterior-to-anterior gradient);
Pachygyria (posterior-to-anterior gradient);
Polymicrogyria;
Subcortical laminar heterotopia;
Hooked aspect of the frontal horn of the lateral ventricles due to
abnormally shaped basal ganglia;
Ventricular dilatation;
Thin corpus callosum;
Abnormal hippocampus;
Agenesis of the corpus callosum;
Absence or hypoplasia of the anterior limb of the internal capsule;
Hypoplasia of the cerebellar vermis;
Hypoplasia of the brainstem
MISCELLANEOUS:
Most cases occur de novo
MOLECULAR BASIS:
Caused by mutation in the alpha-tubulin 1A gene (TUBA1A, 602529.0001)
*FIELD* CN
Cassandra L. Kniffin - updated: 8/3/2011
Cassandra L. Kniffin - updated: 2/16/2009
*FIELD* CD
Cassandra L. Kniffin: 11/19/2007
*FIELD* ED
joanna: 12/29/2011
ckniffin: 8/3/2011
joanna: 5/14/2009
ckniffin: 2/16/2009
joanna: 3/19/2008
ckniffin: 11/19/2007
*FIELD* CN
George E. Tiller - updated: 09/05/2013
Cassandra L. Kniffin - updated: 5/8/2013
Cassandra L. Kniffin - updated: 3/3/2009
Cassandra L. Kniffin - updated: 2/12/2009
*FIELD* CD
Cassandra L. Kniffin: 11/19/2007
*FIELD* ED
alopez: 09/05/2013
carol: 5/20/2013
ckniffin: 5/8/2013
terry: 1/17/2012
alopez: 8/18/2011
ckniffin: 8/3/2011
carol: 6/2/2011
wwang: 3/6/2009
ckniffin: 3/3/2009
wwang: 2/20/2009
ckniffin: 2/12/2009
wwang: 12/14/2007
ckniffin: 11/19/2007