Full text data of WDR81
WDR81
[Confidence: low (only semi-automatic identification from reviews)]
WD repeat-containing protein 81
Note: presumably soluble (membrane word is not in UniProt keywords or features)
WD repeat-containing protein 81
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
Q562E7
ID WDR81_HUMAN Reviewed; 1941 AA.
AC Q562E7; B3KW16; B3KXU1; B7Z579; E9PHG7; Q24JP6; Q8N277; Q8N3F3;
read moreAC Q8TEL1;
DT 25-JUL-2006, integrated into UniProtKB/Swiss-Prot.
DT 05-SEP-2012, sequence version 2.
DT 22-JAN-2014, entry version 81.
DE RecName: Full=WD repeat-containing protein 81;
GN Name=WDR81;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 3 AND 5), NUCLEOTIDE
RP SEQUENCE [LARGE SCALE MRNA] OF 873-1941 (ISOFORM 4), AND VARIANT
RP VAL-1535.
RC TISSUE=Mesangial cell, Spleen, Synovium, and Tongue;
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 [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16625196; DOI=10.1038/nature04689;
RA Zody M.C., Garber M., Adams D.J., Sharpe T., Harrow J., Lupski J.R.,
RA Nicholson C., Searle S.M., Wilming L., Young S.K., Abouelleil A.,
RA Allen N.R., Bi W., Bloom T., Borowsky M.L., Bugalter B.E., Butler J.,
RA Chang J.L., Chen C.-K., Cook A., Corum B., Cuomo C.A., de Jong P.J.,
RA DeCaprio D., Dewar K., FitzGerald M., Gilbert J., Gibson R.,
RA Gnerre S., Goldstein S., Grafham D.V., Grocock R., Hafez N.,
RA Hagopian D.S., Hart E., Norman C.H., Humphray S., Jaffe D.B.,
RA Jones M., Kamal M., Khodiyar V.K., LaButti K., Laird G., Lehoczky J.,
RA Liu X., Lokyitsang T., Loveland J., Lui A., Macdonald P., Major J.E.,
RA Matthews L., Mauceli E., McCarroll S.A., Mihalev A.H., Mudge J.,
RA Nguyen C., Nicol R., O'Leary S.B., Osoegawa K., Schwartz D.C.,
RA Shaw-Smith C., Stankiewicz P., Steward C., Swarbreck D.,
RA Venkataraman V., Whittaker C.A., Yang X., Zimmer A.R., Bradley A.,
RA Hubbard T., Birren B.W., Rogers J., Lander E.S., Nusbaum C.;
RT "DNA sequence of human chromosome 17 and analysis of rearrangement in
RT the human lineage.";
RL Nature 440:1045-1049(2006).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), AND NUCLEOTIDE
RP SEQUENCE [LARGE SCALE MRNA] OF 1049-1941 (ISOFORM 3).
RC TISSUE=Lymph;
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 [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1033-1941.
RC TISSUE=Melanoma;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [5]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [6]
RP VARIANT CAMRQ2 LEU-856, AND TISSUE SPECIFICITY.
RX PubMed=21885617; DOI=10.1101/gr.126110.111;
RA Gulsuner S., Tekinay A.B., Doerschner K., Boyaci H., Bilguvar K.,
RA Unal H., Ors A., Onat O.E., Atalar E., Basak A.N., Topaloglu H.,
RA Kansu T., Tan M., Tan U., Gunel M., Ozcelik T.;
RT "Homozygosity mapping and targeted genomic sequencing reveal the gene
RT responsible for cerebellar hypoplasia and quadrupedal locomotion in a
RT consanguineous kindred.";
RL Genome Res. 21:1995-2003(2011).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=6;
CC Name=1;
CC IsoId=Q562E7-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q562E7-2; Sequence=VSP_044065, VSP_019955;
CC Note=No experimental confirmation available;
CC Name=3;
CC IsoId=Q562E7-3; Sequence=VSP_044065;
CC Note=No experimental confirmation available;
CC Name=4;
CC IsoId=Q562E7-4; Sequence=VSP_044067;
CC Note=No experimental confirmation available;
CC Name=5;
CC IsoId=Q562E7-5; Sequence=VSP_044064, VSP_044066;
CC Note=No experimental confirmation available;
CC Name=6;
CC IsoId=Q562E7-6; Sequence=VSP_044063;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Widely expressed. In the brain, highest levels
CC in cerebellum and corpus callosum.
CC -!- DISEASE: Cerebellar ataxia, mental retardation, and dysequilibrium
CC syndrome 2 (CAMRQ2) [MIM:610185]: A congenital cerebellar ataxia
CC associated with cerebellar hypoplasia, mental retardation, and
CC inability to walk bipedally, resulting in quadrupedal locomotion
CC as a functional adaptation. Additional findings include
CC generalized brain atrophy and mild hypoplasia of the corpus
CC callosum. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- SIMILARITY: Contains 1 BEACH domain.
CC -!- SIMILARITY: Contains 5 WD repeats.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAG53978.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
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DR EMBL; AK074111; BAB84937.1; -; mRNA.
DR EMBL; AK091136; BAC03593.1; -; mRNA.
DR EMBL; AK123896; BAG53978.1; ALT_INIT; mRNA.
DR EMBL; AK127946; BAG54603.1; -; mRNA.
DR EMBL; AK298567; BAH12815.1; -; mRNA.
DR EMBL; AC130343; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC092513; AAH92513.1; -; mRNA.
DR EMBL; BC114568; AAI14569.1; -; mRNA.
DR EMBL; AL834379; CAD39042.1; -; mRNA.
DR RefSeq; NP_001157145.1; NM_001163673.1.
DR RefSeq; NP_001157281.1; NM_001163809.1.
DR RefSeq; NP_001157283.1; NM_001163811.1.
DR RefSeq; NP_689561.2; NM_152348.3.
DR RefSeq; XP_005256513.1; XM_005256456.1.
DR UniGene; Hs.234572; -.
DR ProteinModelPortal; Q562E7; -.
DR SMR; Q562E7; 352-591, 1589-1864.
DR IntAct; Q562E7; 2.
DR STRING; 9606.ENSP00000386609; -.
DR DMDM; 74755061; -.
DR PaxDb; Q562E7; -.
DR PRIDE; Q562E7; -.
DR Ensembl; ENST00000309182; ENSP00000312074; ENSG00000167716.
DR Ensembl; ENST00000409644; ENSP00000386609; ENSG00000167716.
DR Ensembl; ENST00000419248; ENSP00000407845; ENSG00000167716.
DR Ensembl; ENST00000437219; ENSP00000391074; ENSG00000167716.
DR GeneID; 124997; -.
DR KEGG; hsa:124997; -.
DR UCSC; uc002ftj.2; human.
DR CTD; 124997; -.
DR GeneCards; GC17P001567; -.
DR HGNC; HGNC:26600; WDR81.
DR HPA; HPA023044; -.
DR MIM; 610185; phenotype.
DR MIM; 614218; gene.
DR neXtProt; NX_Q562E7; -.
DR Orphanet; 1766; Dysequilibrium syndrome.
DR PharmGKB; PA142670584; -.
DR eggNOG; NOG241991; -.
DR HOGENOM; HOG000154851; -.
DR HOVERGEN; HBG083542; -.
DR InParanoid; Q562E7; -.
DR KO; K17601; -.
DR OMA; KNVCLHL; -.
DR OrthoDB; EOG7CVPWV; -.
DR SignaLink; Q562E7; -.
DR GenomeRNAi; 124997; -.
DR NextBio; 81466; -.
DR PRO; PR:Q562E7; -.
DR ArrayExpress; Q562E7; -.
DR Bgee; Q562E7; -.
DR CleanEx; HS_WDR81; -.
DR Genevestigator; Q562E7; -.
DR GO; GO:0016772; F:transferase activity, transferring phosphorus-containing groups; IEA:InterPro.
DR GO; GO:0010923; P:negative regulation of phosphatase activity; IDA:UniProtKB.
DR Gene3D; 1.10.1540.10; -; 1.
DR Gene3D; 2.130.10.10; -; 1.
DR InterPro; IPR000409; BEACH_dom.
DR InterPro; IPR011009; Kinase-like_dom.
DR InterPro; IPR015943; WD40/YVTN_repeat-like_dom.
DR InterPro; IPR001680; WD40_repeat.
DR InterPro; IPR017986; WD40_repeat_dom.
DR Pfam; PF02138; Beach; 1.
DR Pfam; PF00400; WD40; 2.
DR SMART; SM01026; Beach; 1.
DR SMART; SM00320; WD40; 6.
DR SUPFAM; SSF50978; SSF50978; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR SUPFAM; SSF81837; SSF81837; 1.
DR PROSITE; PS50197; BEACH; 1.
DR PROSITE; PS00678; WD_REPEATS_1; FALSE_NEG.
DR PROSITE; PS50082; WD_REPEATS_2; 1.
DR PROSITE; PS50294; WD_REPEATS_REGION; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Complete proteome; Disease mutation;
KW Mental retardation; Phosphoprotein; Polymorphism; Reference proteome;
KW Repeat; WD repeat.
FT CHAIN 1 1941 WD repeat-containing protein 81.
FT /FTId=PRO_0000247244.
FT DOMAIN 337 614 BEACH.
FT REPEAT 1646 1685 WD 1.
FT REPEAT 1692 1732 WD 2.
FT REPEAT 1784 1823 WD 3.
FT REPEAT 1826 1864 WD 4.
FT REPEAT 1911 1941 WD 5.
FT COMPBIAS 1150 1217 Glu-rich.
FT COMPBIAS 1587 1596 Poly-Gly.
FT MOD_RES 1136 1136 Phosphoserine (By similarity).
FT VAR_SEQ 1 1227 Missing (in isoform 6).
FT /FTId=VSP_044063.
FT VAR_SEQ 1 1203 Missing (in isoform 5).
FT /FTId=VSP_044064.
FT VAR_SEQ 1 1051 Missing (in isoform 2 and isoform 3).
FT /FTId=VSP_044065.
FT VAR_SEQ 1115 1312 Missing (in isoform 2).
FT /FTId=VSP_019955.
FT VAR_SEQ 1204 1223 EEEEALPEQSEGKEQKILLD -> MLVRVVLSLTPSFPEPS
FT ALY (in isoform 5).
FT /FTId=VSP_044066.
FT VAR_SEQ 1776 1941 HEFRLGGGLNPGLVRALAISPSGRSVVAGFSSGFMVLLDTR
FT TGLVLRGWPAHEGDILQIKAVEGSVLVSSSSDHSLTVWKEL
FT EQKPTHHYKSASDPIHTFDLYGSEVVTGTVSNKIGVCSLLE
FT PPSQATTKLSSENFRGTLTSLALLPTKRHLLLGSDNGVIRL
FT LA -> VRGVQFPEHSPGSLGTWQGGETPQKQKARMLFWGP
FT S (in isoform 4).
FT /FTId=VSP_044067.
FT VARIANT 856 856 P -> L (in CAMRQ2).
FT /FTId=VAR_068220.
FT VARIANT 1535 1535 M -> V (in dbSNP:rs3809870).
FT /FTId=VAR_062107.
FT CONFLICT 1033 1033 Missing (in Ref. 1; BAB84937).
FT CONFLICT 1051 1051 P -> L (in Ref. 4; CAD39042).
FT CONFLICT 1298 1298 C -> Y (in Ref. 1; BAC03593).
FT CONFLICT 1540 1540 P -> H (in Ref. 1; BAB84937).
FT CONFLICT 1573 1573 D -> G (in Ref. 1; BAG53978).
FT CONFLICT 1744 1744 A -> V (in Ref. 1; BAG54603).
FT CONFLICT 1760 1760 S -> T (in Ref. 1; BAC03593).
FT CONFLICT 1776 1776 H -> Y (in Ref. 1; BAC03593).
SQ SEQUENCE 1941 AA; 211697 MW; F6E62BC07FAAE8DB CRC64;
MAQGSGGREG ALRTPAGGWH SPPSPDMQEL LRSVERDLSI DPRQLAPAPG GTHVVALVPA
RWLASLRDRR LPLGPCPRAE GLGEAEVRTL LQRSVQRLPA GWTRVEVHGL RKRRLSYPLG
GGLPFEDGSC GPETLTRFMQ EVAAQNYRNL WRHAYHTYGQ PYSHSPAPSA VPALDSVRQA
LQRVYGCSFL PVGETTQCPS YAREGPCPPR GSPACPSLLR AEALLESPEM LYVVHPYVQF
SLHDVVTFSP AKLTNSQAKV LFILFRVLRA MDACHRQGLA CGALSLYHIA VDEKLCSELR
LDLSAYERPE EDENEEAPVA RDEAGIVSQE EQGGQPGQPT GQEELRSLVL DWVHGRISNF
HYLMQLNRLA GRRQGDPNYH PVLPWVVDFT TPHGRFRDLR KSKFRLNKGD KQLDFTYEMT
RQAFVAGGAG GGEPPHVPHH ISDVLSDITY YVYKARRTPR SVLCGHVRAQ WEPHEYPASM
ERMQNWTPDE CIPEFYTDPS IFRSIHPDMP DLDVPAWCSS SQEFVAAHRA LLESREVSRD
LHHWIDLTFG YKLQGKEAVK EKNVCLHLVD AHTHLASYGV VQLFDQPHPQ RLAGAPALAP
EPPLIPKLLV QTIQETTGRE DFTENPGQLP NGVGRPVLEA TPCEASWTRD RPVAGEDDLE
QATEALDSIS LAGKAGDQLG SSSQASPGLL SFSVASASRP GRRNKAAGAD PGEGEEGRIL
LPEGFNPMQA LEELEKTGNF LAKGLGGLLE VPEQPRVQPA VPLQCLLHRD MQALGVLLAE
MVFATRVRTL QPDAPLWVRF QAVRGLCTRH PKEVPVSLQP VLDTLLQMSG PEVPMGAERG
KLDQLFEYRP VSQGLPPPCP SQLLSPFSSV VPFPPYFPAL HRFILLYQAR RVEDEAQGRE
LVFALWQQLG AVLKDITPEG LEILLPFVLS LMSEEHTAVY TAWYLFEPVA KALGPKNANK
YLLKPLIGAY ESPCQLHGRF YLYTDCFVAQ LMVRLGLQAF LTHLLPHVLQ VLAGAEASQE
ESKDLAGAAE EEESGLPGAG PGSCAFGEEI PMDGEPPASS GLGLPDYTSG VSFHDQADLP
ETEDFQAGLY VTESPQPQEA EAVSLGRLSD KSSTSETSLG EERAPDEGGA PVDKSSLRSG
DSSQDLKQSE GSEEEEEEED SCVVLEEEEG EQEEVTGASE LTLSDTVLSM ETVVAGGSGG
DGEEEEEALP EQSEGKEQKI LLDTACKMVR WLSAKLGPTV ASRHVARNLL RLLTSCYVGP
TRQQFTVSSG ESPPLSAGNI YQKRPVLGDI VSGPVLSCLL HIARLYGEPV LTYQYLPYIS
YLVAPGSASG PSRLNSRKEA GLLAAVTLTQ KIIVYLSDTT LMDILPRISH EVLLPVLSFL
TSLVTGFPSG AQARTILCVK TISLIALICL RIGQEMVQQH LSEPVATFFQ VFSQLHELRQ
QDLKLDPAGR GEGQLPQVVF SDGQQRPVDP ALLDELQKVF TLEMAYTIYV PFSCLLGDII
RKIIPNHELV GELAALYLES ISPSSRNPAS VEPTMPGTGP EWDPHGGGCP QDDGHSGTFG
SVLVGNRIQI PNDSRPENPG PLGPISGVGG GGLGSGSDDN ALKQELPRSV HGLSGNWLAY
WQYEIGVSQQ DAHFHFHQIR LQSFPGHSGA VKCVAPLSSE DFFLSGSKDR TVRLWPLYNY
GDGTSETAPR LVYTQHRKSV FFVGQLEAPQ HVVSCDGAVH VWDPFTGKTL RTVEPLDSRV
PLTAVAVMPA PHTSITMASS DSTLRFVDCR KPGLQHEFRL GGGLNPGLVR ALAISPSGRS
VVAGFSSGFM VLLDTRTGLV LRGWPAHEGD ILQIKAVEGS VLVSSSSDHS LTVWKELEQK
PTHHYKSASD PIHTFDLYGS EVVTGTVSNK IGVCSLLEPP SQATTKLSSE NFRGTLTSLA
LLPTKRHLLL GSDNGVIRLL A
//
ID WDR81_HUMAN Reviewed; 1941 AA.
AC Q562E7; B3KW16; B3KXU1; B7Z579; E9PHG7; Q24JP6; Q8N277; Q8N3F3;
read moreAC Q8TEL1;
DT 25-JUL-2006, integrated into UniProtKB/Swiss-Prot.
DT 05-SEP-2012, sequence version 2.
DT 22-JAN-2014, entry version 81.
DE RecName: Full=WD repeat-containing protein 81;
GN Name=WDR81;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 3 AND 5), NUCLEOTIDE
RP SEQUENCE [LARGE SCALE MRNA] OF 873-1941 (ISOFORM 4), AND VARIANT
RP VAL-1535.
RC TISSUE=Mesangial cell, Spleen, Synovium, and Tongue;
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 [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16625196; DOI=10.1038/nature04689;
RA Zody M.C., Garber M., Adams D.J., Sharpe T., Harrow J., Lupski J.R.,
RA Nicholson C., Searle S.M., Wilming L., Young S.K., Abouelleil A.,
RA Allen N.R., Bi W., Bloom T., Borowsky M.L., Bugalter B.E., Butler J.,
RA Chang J.L., Chen C.-K., Cook A., Corum B., Cuomo C.A., de Jong P.J.,
RA DeCaprio D., Dewar K., FitzGerald M., Gilbert J., Gibson R.,
RA Gnerre S., Goldstein S., Grafham D.V., Grocock R., Hafez N.,
RA Hagopian D.S., Hart E., Norman C.H., Humphray S., Jaffe D.B.,
RA Jones M., Kamal M., Khodiyar V.K., LaButti K., Laird G., Lehoczky J.,
RA Liu X., Lokyitsang T., Loveland J., Lui A., Macdonald P., Major J.E.,
RA Matthews L., Mauceli E., McCarroll S.A., Mihalev A.H., Mudge J.,
RA Nguyen C., Nicol R., O'Leary S.B., Osoegawa K., Schwartz D.C.,
RA Shaw-Smith C., Stankiewicz P., Steward C., Swarbreck D.,
RA Venkataraman V., Whittaker C.A., Yang X., Zimmer A.R., Bradley A.,
RA Hubbard T., Birren B.W., Rogers J., Lander E.S., Nusbaum C.;
RT "DNA sequence of human chromosome 17 and analysis of rearrangement in
RT the human lineage.";
RL Nature 440:1045-1049(2006).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), AND NUCLEOTIDE
RP SEQUENCE [LARGE SCALE MRNA] OF 1049-1941 (ISOFORM 3).
RC TISSUE=Lymph;
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 [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1033-1941.
RC TISSUE=Melanoma;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [5]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [6]
RP VARIANT CAMRQ2 LEU-856, AND TISSUE SPECIFICITY.
RX PubMed=21885617; DOI=10.1101/gr.126110.111;
RA Gulsuner S., Tekinay A.B., Doerschner K., Boyaci H., Bilguvar K.,
RA Unal H., Ors A., Onat O.E., Atalar E., Basak A.N., Topaloglu H.,
RA Kansu T., Tan M., Tan U., Gunel M., Ozcelik T.;
RT "Homozygosity mapping and targeted genomic sequencing reveal the gene
RT responsible for cerebellar hypoplasia and quadrupedal locomotion in a
RT consanguineous kindred.";
RL Genome Res. 21:1995-2003(2011).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=6;
CC Name=1;
CC IsoId=Q562E7-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q562E7-2; Sequence=VSP_044065, VSP_019955;
CC Note=No experimental confirmation available;
CC Name=3;
CC IsoId=Q562E7-3; Sequence=VSP_044065;
CC Note=No experimental confirmation available;
CC Name=4;
CC IsoId=Q562E7-4; Sequence=VSP_044067;
CC Note=No experimental confirmation available;
CC Name=5;
CC IsoId=Q562E7-5; Sequence=VSP_044064, VSP_044066;
CC Note=No experimental confirmation available;
CC Name=6;
CC IsoId=Q562E7-6; Sequence=VSP_044063;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Widely expressed. In the brain, highest levels
CC in cerebellum and corpus callosum.
CC -!- DISEASE: Cerebellar ataxia, mental retardation, and dysequilibrium
CC syndrome 2 (CAMRQ2) [MIM:610185]: A congenital cerebellar ataxia
CC associated with cerebellar hypoplasia, mental retardation, and
CC inability to walk bipedally, resulting in quadrupedal locomotion
CC as a functional adaptation. Additional findings include
CC generalized brain atrophy and mild hypoplasia of the corpus
CC callosum. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- SIMILARITY: Contains 1 BEACH domain.
CC -!- SIMILARITY: Contains 5 WD repeats.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAG53978.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
CC -----------------------------------------------------------------------
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CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; AK074111; BAB84937.1; -; mRNA.
DR EMBL; AK091136; BAC03593.1; -; mRNA.
DR EMBL; AK123896; BAG53978.1; ALT_INIT; mRNA.
DR EMBL; AK127946; BAG54603.1; -; mRNA.
DR EMBL; AK298567; BAH12815.1; -; mRNA.
DR EMBL; AC130343; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC092513; AAH92513.1; -; mRNA.
DR EMBL; BC114568; AAI14569.1; -; mRNA.
DR EMBL; AL834379; CAD39042.1; -; mRNA.
DR RefSeq; NP_001157145.1; NM_001163673.1.
DR RefSeq; NP_001157281.1; NM_001163809.1.
DR RefSeq; NP_001157283.1; NM_001163811.1.
DR RefSeq; NP_689561.2; NM_152348.3.
DR RefSeq; XP_005256513.1; XM_005256456.1.
DR UniGene; Hs.234572; -.
DR ProteinModelPortal; Q562E7; -.
DR SMR; Q562E7; 352-591, 1589-1864.
DR IntAct; Q562E7; 2.
DR STRING; 9606.ENSP00000386609; -.
DR DMDM; 74755061; -.
DR PaxDb; Q562E7; -.
DR PRIDE; Q562E7; -.
DR Ensembl; ENST00000309182; ENSP00000312074; ENSG00000167716.
DR Ensembl; ENST00000409644; ENSP00000386609; ENSG00000167716.
DR Ensembl; ENST00000419248; ENSP00000407845; ENSG00000167716.
DR Ensembl; ENST00000437219; ENSP00000391074; ENSG00000167716.
DR GeneID; 124997; -.
DR KEGG; hsa:124997; -.
DR UCSC; uc002ftj.2; human.
DR CTD; 124997; -.
DR GeneCards; GC17P001567; -.
DR HGNC; HGNC:26600; WDR81.
DR HPA; HPA023044; -.
DR MIM; 610185; phenotype.
DR MIM; 614218; gene.
DR neXtProt; NX_Q562E7; -.
DR Orphanet; 1766; Dysequilibrium syndrome.
DR PharmGKB; PA142670584; -.
DR eggNOG; NOG241991; -.
DR HOGENOM; HOG000154851; -.
DR HOVERGEN; HBG083542; -.
DR InParanoid; Q562E7; -.
DR KO; K17601; -.
DR OMA; KNVCLHL; -.
DR OrthoDB; EOG7CVPWV; -.
DR SignaLink; Q562E7; -.
DR GenomeRNAi; 124997; -.
DR NextBio; 81466; -.
DR PRO; PR:Q562E7; -.
DR ArrayExpress; Q562E7; -.
DR Bgee; Q562E7; -.
DR CleanEx; HS_WDR81; -.
DR Genevestigator; Q562E7; -.
DR GO; GO:0016772; F:transferase activity, transferring phosphorus-containing groups; IEA:InterPro.
DR GO; GO:0010923; P:negative regulation of phosphatase activity; IDA:UniProtKB.
DR Gene3D; 1.10.1540.10; -; 1.
DR Gene3D; 2.130.10.10; -; 1.
DR InterPro; IPR000409; BEACH_dom.
DR InterPro; IPR011009; Kinase-like_dom.
DR InterPro; IPR015943; WD40/YVTN_repeat-like_dom.
DR InterPro; IPR001680; WD40_repeat.
DR InterPro; IPR017986; WD40_repeat_dom.
DR Pfam; PF02138; Beach; 1.
DR Pfam; PF00400; WD40; 2.
DR SMART; SM01026; Beach; 1.
DR SMART; SM00320; WD40; 6.
DR SUPFAM; SSF50978; SSF50978; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR SUPFAM; SSF81837; SSF81837; 1.
DR PROSITE; PS50197; BEACH; 1.
DR PROSITE; PS00678; WD_REPEATS_1; FALSE_NEG.
DR PROSITE; PS50082; WD_REPEATS_2; 1.
DR PROSITE; PS50294; WD_REPEATS_REGION; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Complete proteome; Disease mutation;
KW Mental retardation; Phosphoprotein; Polymorphism; Reference proteome;
KW Repeat; WD repeat.
FT CHAIN 1 1941 WD repeat-containing protein 81.
FT /FTId=PRO_0000247244.
FT DOMAIN 337 614 BEACH.
FT REPEAT 1646 1685 WD 1.
FT REPEAT 1692 1732 WD 2.
FT REPEAT 1784 1823 WD 3.
FT REPEAT 1826 1864 WD 4.
FT REPEAT 1911 1941 WD 5.
FT COMPBIAS 1150 1217 Glu-rich.
FT COMPBIAS 1587 1596 Poly-Gly.
FT MOD_RES 1136 1136 Phosphoserine (By similarity).
FT VAR_SEQ 1 1227 Missing (in isoform 6).
FT /FTId=VSP_044063.
FT VAR_SEQ 1 1203 Missing (in isoform 5).
FT /FTId=VSP_044064.
FT VAR_SEQ 1 1051 Missing (in isoform 2 and isoform 3).
FT /FTId=VSP_044065.
FT VAR_SEQ 1115 1312 Missing (in isoform 2).
FT /FTId=VSP_019955.
FT VAR_SEQ 1204 1223 EEEEALPEQSEGKEQKILLD -> MLVRVVLSLTPSFPEPS
FT ALY (in isoform 5).
FT /FTId=VSP_044066.
FT VAR_SEQ 1776 1941 HEFRLGGGLNPGLVRALAISPSGRSVVAGFSSGFMVLLDTR
FT TGLVLRGWPAHEGDILQIKAVEGSVLVSSSSDHSLTVWKEL
FT EQKPTHHYKSASDPIHTFDLYGSEVVTGTVSNKIGVCSLLE
FT PPSQATTKLSSENFRGTLTSLALLPTKRHLLLGSDNGVIRL
FT LA -> VRGVQFPEHSPGSLGTWQGGETPQKQKARMLFWGP
FT S (in isoform 4).
FT /FTId=VSP_044067.
FT VARIANT 856 856 P -> L (in CAMRQ2).
FT /FTId=VAR_068220.
FT VARIANT 1535 1535 M -> V (in dbSNP:rs3809870).
FT /FTId=VAR_062107.
FT CONFLICT 1033 1033 Missing (in Ref. 1; BAB84937).
FT CONFLICT 1051 1051 P -> L (in Ref. 4; CAD39042).
FT CONFLICT 1298 1298 C -> Y (in Ref. 1; BAC03593).
FT CONFLICT 1540 1540 P -> H (in Ref. 1; BAB84937).
FT CONFLICT 1573 1573 D -> G (in Ref. 1; BAG53978).
FT CONFLICT 1744 1744 A -> V (in Ref. 1; BAG54603).
FT CONFLICT 1760 1760 S -> T (in Ref. 1; BAC03593).
FT CONFLICT 1776 1776 H -> Y (in Ref. 1; BAC03593).
SQ SEQUENCE 1941 AA; 211697 MW; F6E62BC07FAAE8DB CRC64;
MAQGSGGREG ALRTPAGGWH SPPSPDMQEL LRSVERDLSI DPRQLAPAPG GTHVVALVPA
RWLASLRDRR LPLGPCPRAE GLGEAEVRTL LQRSVQRLPA GWTRVEVHGL RKRRLSYPLG
GGLPFEDGSC GPETLTRFMQ EVAAQNYRNL WRHAYHTYGQ PYSHSPAPSA VPALDSVRQA
LQRVYGCSFL PVGETTQCPS YAREGPCPPR GSPACPSLLR AEALLESPEM LYVVHPYVQF
SLHDVVTFSP AKLTNSQAKV LFILFRVLRA MDACHRQGLA CGALSLYHIA VDEKLCSELR
LDLSAYERPE EDENEEAPVA RDEAGIVSQE EQGGQPGQPT GQEELRSLVL DWVHGRISNF
HYLMQLNRLA GRRQGDPNYH PVLPWVVDFT TPHGRFRDLR KSKFRLNKGD KQLDFTYEMT
RQAFVAGGAG GGEPPHVPHH ISDVLSDITY YVYKARRTPR SVLCGHVRAQ WEPHEYPASM
ERMQNWTPDE CIPEFYTDPS IFRSIHPDMP DLDVPAWCSS SQEFVAAHRA LLESREVSRD
LHHWIDLTFG YKLQGKEAVK EKNVCLHLVD AHTHLASYGV VQLFDQPHPQ RLAGAPALAP
EPPLIPKLLV QTIQETTGRE DFTENPGQLP NGVGRPVLEA TPCEASWTRD RPVAGEDDLE
QATEALDSIS LAGKAGDQLG SSSQASPGLL SFSVASASRP GRRNKAAGAD PGEGEEGRIL
LPEGFNPMQA LEELEKTGNF LAKGLGGLLE VPEQPRVQPA VPLQCLLHRD MQALGVLLAE
MVFATRVRTL QPDAPLWVRF QAVRGLCTRH PKEVPVSLQP VLDTLLQMSG PEVPMGAERG
KLDQLFEYRP VSQGLPPPCP SQLLSPFSSV VPFPPYFPAL HRFILLYQAR RVEDEAQGRE
LVFALWQQLG AVLKDITPEG LEILLPFVLS LMSEEHTAVY TAWYLFEPVA KALGPKNANK
YLLKPLIGAY ESPCQLHGRF YLYTDCFVAQ LMVRLGLQAF LTHLLPHVLQ VLAGAEASQE
ESKDLAGAAE EEESGLPGAG PGSCAFGEEI PMDGEPPASS GLGLPDYTSG VSFHDQADLP
ETEDFQAGLY VTESPQPQEA EAVSLGRLSD KSSTSETSLG EERAPDEGGA PVDKSSLRSG
DSSQDLKQSE GSEEEEEEED SCVVLEEEEG EQEEVTGASE LTLSDTVLSM ETVVAGGSGG
DGEEEEEALP EQSEGKEQKI LLDTACKMVR WLSAKLGPTV ASRHVARNLL RLLTSCYVGP
TRQQFTVSSG ESPPLSAGNI YQKRPVLGDI VSGPVLSCLL HIARLYGEPV LTYQYLPYIS
YLVAPGSASG PSRLNSRKEA GLLAAVTLTQ KIIVYLSDTT LMDILPRISH EVLLPVLSFL
TSLVTGFPSG AQARTILCVK TISLIALICL RIGQEMVQQH LSEPVATFFQ VFSQLHELRQ
QDLKLDPAGR GEGQLPQVVF SDGQQRPVDP ALLDELQKVF TLEMAYTIYV PFSCLLGDII
RKIIPNHELV GELAALYLES ISPSSRNPAS VEPTMPGTGP EWDPHGGGCP QDDGHSGTFG
SVLVGNRIQI PNDSRPENPG PLGPISGVGG GGLGSGSDDN ALKQELPRSV HGLSGNWLAY
WQYEIGVSQQ DAHFHFHQIR LQSFPGHSGA VKCVAPLSSE DFFLSGSKDR TVRLWPLYNY
GDGTSETAPR LVYTQHRKSV FFVGQLEAPQ HVVSCDGAVH VWDPFTGKTL RTVEPLDSRV
PLTAVAVMPA PHTSITMASS DSTLRFVDCR KPGLQHEFRL GGGLNPGLVR ALAISPSGRS
VVAGFSSGFM VLLDTRTGLV LRGWPAHEGD ILQIKAVEGS VLVSSSSDHS LTVWKELEQK
PTHHYKSASD PIHTFDLYGS EVVTGTVSNK IGVCSLLEPP SQATTKLSSE NFRGTLTSLA
LLPTKRHLLL GSDNGVIRLL A
//
MIM
610185
*RECORD*
*FIELD* NO
610185
*FIELD* TI
#610185 CEREBELLAR ATAXIA, MENTAL RETARDATION, AND DYSEQUILIBRIUM SYNDROME
2; CAMRQ2
read more;;CEREBELLAR ATAXIA AND MENTAL RETARDATION WITH OR WITHOUT QUADRUPEDAL
LOCOMOTION 2
*FIELD* TX
A number sign (#) is used with this entry because cerebellar ataxia,
mental retardation, and dysequilibrium syndrome-2 (CAMRQ2) is caused by
homozygous mutation in the WDR81 gene (614218) on chromosome 17p.
DESCRIPTION
Cerebellar ataxia, mental retardation, and dysequilibrium syndrome
(CAMRQ) is a genetically heterogeneous disorder characterized by
congenital cerebellar ataxia and mental retardation (summary by Gulsuner
et al., 2011).
For a discussion of genetic heterogeneity of CAMRQ, see CAMRQ1 (224050).
CLINICAL FEATURES
Turkmen et al. (2006) reported a consanguineous Turkish family of
Kurdish origin in which 5 sibs had cerebellar hypoplasia, mental
retardation, and an inability to walk bipedally, resulting in
quadrupedal locomotion as a functional adaptation. An affected brother
and sister were bipedal but had similar neurologic features and a lesser
degree of cognitive impairment. One of the quadrupedal sibs died at age
26 years of unknown causes. Detailed examination of the 28-year-old male
proband showed moderate thoracic kyphosis, short stature, cerebellar
ataxia, dysarthria, dysmetria, and dysdiadochokinesia without pyramidal
signs. He preferred to walk on his extremities with entire hands and
feet touching the ground (palmigrade walking) and fully stretched knee
and elbow joints. All 4 affected individuals moved about freely and
participated most of the time in the family's daily work in the fields.
They could understand and communicate basic words, but cognitive
abilities were severely impaired. Brain MRI of affected individuals
showed hypogenesis and midline clefting of the cerebellar vermis. In all
cases the superior half of the vermis was formed, whereas the inferior
section was not. The dentate nucleus was atrophic. Other findings
included generalized brain atrophy and mild hypoplasia of the corpus
callosum. Cortical dysplasia, lissencephaly, and gray matter heterotopia
were not observed. Individuals who demonstrated quadrupedal locomotion
did so effectively and without discomfort. As they moved, their knee and
elbow joints showed almost no flexion, and their hands touched the
ground mainly on their palms, distinct from knuckle walking of great
apes.
Tan (2006) provided a report of the same family. He noted that the
affected individuals demonstrated diagonal walking seen in many animals,
such as dogs, horses, and chimpanzees. Tan (2006) suggested that this
syndrome may represent a live model for human evolution from quadrupedal
to bipedal gait.
Gulsuner et al. (2011) reported detailed neuroradiologic studies of the
patients reported by Turkmen et al. (2006). Brain MRI of affected
individuals showed morphologic abnormalities in the cerebellum and
corpus callosum, in particular atrophy of superior, middle, and inferior
peduncles of the cerebellum. Structural MRI showed additional
morphometric abnormalities in several cortical areas, including the
corpus callosum, precentral gyrus, and several Brodmann areas.
Garcias and Roth (2007) reported 4 Brazilian sibs, 2 males and 2
females, born of consanguineous parents, with a clinically homogeneous
syndrome in which the predominant characteristic was a quadrupedal gait.
All had a normal neonatal period but did not learn to crawl normally on
4 limbs. When they learned to 'walk,' they assumed a quadrupedal
position leaning on the hands and feet with erect lower limbs.
Radiographic exams showed no osteoarticular changes that could justify
the quadrupedal gait. All sibs had mental retardation with absent
speech, short stature, coarse facial features, hirsutism, strabismus,
wide and short nape of the neck, and small hands and feet. Secondary
sexual characteristics were normal, except that the males had small
penis. One sib had convulsions around puberty.
- Etiology of Quadrupedal Locomotion
Ozcelik et al. (2008) maintained that quadrupedal locomotion in the
affected individuals results from abnormal function of brain structures
that are critical for gait. Humphrey et al. (2008) concluded that the
tendency toward quadrupedal locomotion in affected individuals is an
adaptive and effective compensation for problems with balance caused by
congenital cerebellar hypoplasia. Thus, the unusual gait could be
attributed to the local cultural environment. Herz et al. (2008) also
concluded that quadrupedal locomotion is more likely an adaptation to
severe truncal ataxia, resulting from a combination of uneven, rough
surfaces in rural areas, imitation of affected sibs, and lack of
supportive therapy. Ozcelik et al. (2008) responded and defended their
position.
MAPPING
By genomewide linkage analysis of the affected Turkish family, Turkmen
et al. (2006) identified a candidate disease locus on chromosome 17p
between markers D17S1866 and D17S690 (peak multipoint lod score of 5.37
was calculated between D17S831 and D17S1298).
Ozcelik et al. (2008) confirmed linkage to chromosome 17p13 in the
family previously reported by Turkmen et al. (2006). They reported 1
unrelated Turkish family that showed no evidence of linkage to 17p13 and
9p24.
MOLECULAR GENETICS
In affected members of a consanguineous Turkish family with autosomal
recessive cerebellar ataxia, mental retardation, and dysequilibrium
syndrome-2 (Turkmen et al., 2006), Gulsuner et al. (2011) identified a
homozygous mutation in the WDR81 gene (P856L; 614218). Homozygosity for
the mutation segregated with the phenotype. The mutation occurred in a
highly conserved residue, and was not found in 549 controls. The
mutation was found by targeted sequencing of the candidate disease
region identified by linkage analysis. WDR81 was expressed in the
cerebellum and corpus callosum.
*FIELD* RF
1. Garcias, G. de L.; Roth, M. da G. M.: A Brazilian family with
quadrupedal gait, severe mental retardation, coarse facial characteristics,
and hirsutism. Int. J. Neurosci. 117: 927-933, 2007.
2. Gulsuner, S.; Tekinay, A. B.; Doerschner, K.; Boyaci, H.; Bilguvar,
K.; Unal, H.; Ors, A.; Onat, O. E.; Atalar, E.; Basak, A. N.; Topaloglu,
H.; Kansu, T.; Tan, M.; Tan, U.; Gunel, M.; Ozcelik, T.: Homozygosity
mapping and targeted genomic sequencing reveal the gene responsible
for cerebellar hypoplasia and quadrupedal locomotion in a consanguineous
kindred. Genome Res. 21: 1995-2003, 2011.
3. Herz, J.; Boycott, K. M.; Parboosingh, J. S.: 'Devolution' of
bipedality. (Letter) Proc. Nat. Acad. Sci. 105: E25 only, 2008.
Note: Electronic Article.
4. Humphrey, N.; Mundlos, S.; Turkmen, S.: Genes and quadrupedal
locomotion in humans. (Letter) Proc. Nat. Acad. Sci. 105: E26 only,
2008. Note: Electronic Article.
5. Ozcelik, T.; Akarsu, N.; Uz, E.; Caglayan, S.; Gulsuner, S.; Onat,
O. E.; Tan, M.: Mutations in the very low-density lipoprotein receptor
VLDLR cause cerebellar hypoplasia and quadrupedal locomotion in humans. Proc.
Nat. Acad. Sci. 105: 4232-4236, 2008.
6. Ozcelik, T.; Akarsu, N.; Uz, E.; Caglayan, S.; Gulsuner, S.; Onat,
O. E.; Tan, M.; Tan, U.: Reply to Herz et al. and Humphrey et al.:
Genetic heterogeneity of cerebellar hypoplasia with quadrupedal locomotion.
(Letter) Proc. Nat. Acad. Sci. 105: E32-E33, 2008. Note: Electronic
Article.
7. Tan, U.: A new syndrome with quadrupedal gait, primitive speech,
and severe mental retardation as a live model for human evolution. Int.
J. Neurosci. 116: 361-369, 2006.
8. Turkmen, S.; Demirhan, O.; Hoffmann, K.; Diers, A.; Zimmer, C.;
Sperling, K.; Mundlos, S.: Cerebellar hypoplasia and quadrupedal
locomotion in humans as a recessive trait mapping to chromosome 17p.
(Letter) J. Med. Genet. 43: 461-464, 2006.
*FIELD* CS
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Short stature
HEAD AND NECK:
[Head];
Head is flexed forward;
[Face];
Coarse facial features;
[Eyes];
Strabismus;
[Neck];
Wide and short nape of the neck
SKELETAL:
[Spine];
Thoracic kyphosis;
Thoracic scoliosis;
Skull is flexed forward on the spine;
[Hands];
Small hands;
[Feet];
Small feet
SKIN, NAILS, HAIR:
[Hair];
Hirsutism
NEUROLOGIC:
[Central nervous system];
Mental retardation, severe;
Cerebellar ataxia;
Delayed psychomotor development;
Poor language development;
Absence of language development;
Quadrupedal gait (palm of hands, legs straight) with diagonal walking;
Truncal ataxia, severe;
Tremor;
Dysmetria;
Dysarthria;
Dysdiadochokinesis;
Hyporeflexia;
Cerebellar hypoplasia;
Aplasia of the inferior half of the cerebellar vermis;
Atrophy of the dentate nucleus;
Generalized cerebral atrophy;
Hypoplasia of the corpus callosum;
Cerebellar atrophy
MISCELLANEOUS:
Onset in infancy
MOLECULAR BASIS:
Caused by mutation in the WD repeat-containing protein 81 gene (WDR81,
614218.0001)
*FIELD* CN
Cassandra L. Kniffin - updated: 5/24/2012
Cassandra L. Kniffin - updated: 6/19/2008
Cassandra L. Kniffin - updated: 1/30/2008
*FIELD* CD
Cassandra L. Kniffin: 6/13/2006
*FIELD* ED
joanna: 06/04/2012
ckniffin: 5/24/2012
ckniffin: 2/18/2010
ckniffin: 2/3/2010
ckniffin: 7/15/2008
ckniffin: 6/19/2008
ckniffin: 1/30/2008
joanna: 10/27/2006
joanna: 10/26/2006
ckniffin: 6/13/2006
*FIELD* CN
Cassandra L. Kniffin - updated: 5/24/2012
Cassandra L. Kniffin - updated: 2/3/2010
Cassandra L. Kniffin - updated: 7/16/2008
Cassandra L. Kniffin - updated: 6/19/2008
Cassandra L. Kniffin - updated: 1/30/2008
*FIELD* CD
Cassandra L. Kniffin: 6/13/2006
*FIELD* ED
alopez: 06/11/2013
alopez: 5/25/2012
ckniffin: 5/24/2012
carol: 11/12/2010
joanna: 3/25/2010
joanna: 3/10/2010
carol: 2/22/2010
carol: 2/4/2010
ckniffin: 2/3/2010
joanna: 9/8/2008
ckniffin: 9/8/2008
wwang: 7/16/2008
ckniffin: 7/15/2008
ckniffin: 6/19/2008
wwang: 2/1/2008
ckniffin: 1/30/2008
wwang: 1/7/2008
wwang: 6/16/2006
ckniffin: 6/13/2006
*RECORD*
*FIELD* NO
610185
*FIELD* TI
#610185 CEREBELLAR ATAXIA, MENTAL RETARDATION, AND DYSEQUILIBRIUM SYNDROME
2; CAMRQ2
read more;;CEREBELLAR ATAXIA AND MENTAL RETARDATION WITH OR WITHOUT QUADRUPEDAL
LOCOMOTION 2
*FIELD* TX
A number sign (#) is used with this entry because cerebellar ataxia,
mental retardation, and dysequilibrium syndrome-2 (CAMRQ2) is caused by
homozygous mutation in the WDR81 gene (614218) on chromosome 17p.
DESCRIPTION
Cerebellar ataxia, mental retardation, and dysequilibrium syndrome
(CAMRQ) is a genetically heterogeneous disorder characterized by
congenital cerebellar ataxia and mental retardation (summary by Gulsuner
et al., 2011).
For a discussion of genetic heterogeneity of CAMRQ, see CAMRQ1 (224050).
CLINICAL FEATURES
Turkmen et al. (2006) reported a consanguineous Turkish family of
Kurdish origin in which 5 sibs had cerebellar hypoplasia, mental
retardation, and an inability to walk bipedally, resulting in
quadrupedal locomotion as a functional adaptation. An affected brother
and sister were bipedal but had similar neurologic features and a lesser
degree of cognitive impairment. One of the quadrupedal sibs died at age
26 years of unknown causes. Detailed examination of the 28-year-old male
proband showed moderate thoracic kyphosis, short stature, cerebellar
ataxia, dysarthria, dysmetria, and dysdiadochokinesia without pyramidal
signs. He preferred to walk on his extremities with entire hands and
feet touching the ground (palmigrade walking) and fully stretched knee
and elbow joints. All 4 affected individuals moved about freely and
participated most of the time in the family's daily work in the fields.
They could understand and communicate basic words, but cognitive
abilities were severely impaired. Brain MRI of affected individuals
showed hypogenesis and midline clefting of the cerebellar vermis. In all
cases the superior half of the vermis was formed, whereas the inferior
section was not. The dentate nucleus was atrophic. Other findings
included generalized brain atrophy and mild hypoplasia of the corpus
callosum. Cortical dysplasia, lissencephaly, and gray matter heterotopia
were not observed. Individuals who demonstrated quadrupedal locomotion
did so effectively and without discomfort. As they moved, their knee and
elbow joints showed almost no flexion, and their hands touched the
ground mainly on their palms, distinct from knuckle walking of great
apes.
Tan (2006) provided a report of the same family. He noted that the
affected individuals demonstrated diagonal walking seen in many animals,
such as dogs, horses, and chimpanzees. Tan (2006) suggested that this
syndrome may represent a live model for human evolution from quadrupedal
to bipedal gait.
Gulsuner et al. (2011) reported detailed neuroradiologic studies of the
patients reported by Turkmen et al. (2006). Brain MRI of affected
individuals showed morphologic abnormalities in the cerebellum and
corpus callosum, in particular atrophy of superior, middle, and inferior
peduncles of the cerebellum. Structural MRI showed additional
morphometric abnormalities in several cortical areas, including the
corpus callosum, precentral gyrus, and several Brodmann areas.
Garcias and Roth (2007) reported 4 Brazilian sibs, 2 males and 2
females, born of consanguineous parents, with a clinically homogeneous
syndrome in which the predominant characteristic was a quadrupedal gait.
All had a normal neonatal period but did not learn to crawl normally on
4 limbs. When they learned to 'walk,' they assumed a quadrupedal
position leaning on the hands and feet with erect lower limbs.
Radiographic exams showed no osteoarticular changes that could justify
the quadrupedal gait. All sibs had mental retardation with absent
speech, short stature, coarse facial features, hirsutism, strabismus,
wide and short nape of the neck, and small hands and feet. Secondary
sexual characteristics were normal, except that the males had small
penis. One sib had convulsions around puberty.
- Etiology of Quadrupedal Locomotion
Ozcelik et al. (2008) maintained that quadrupedal locomotion in the
affected individuals results from abnormal function of brain structures
that are critical for gait. Humphrey et al. (2008) concluded that the
tendency toward quadrupedal locomotion in affected individuals is an
adaptive and effective compensation for problems with balance caused by
congenital cerebellar hypoplasia. Thus, the unusual gait could be
attributed to the local cultural environment. Herz et al. (2008) also
concluded that quadrupedal locomotion is more likely an adaptation to
severe truncal ataxia, resulting from a combination of uneven, rough
surfaces in rural areas, imitation of affected sibs, and lack of
supportive therapy. Ozcelik et al. (2008) responded and defended their
position.
MAPPING
By genomewide linkage analysis of the affected Turkish family, Turkmen
et al. (2006) identified a candidate disease locus on chromosome 17p
between markers D17S1866 and D17S690 (peak multipoint lod score of 5.37
was calculated between D17S831 and D17S1298).
Ozcelik et al. (2008) confirmed linkage to chromosome 17p13 in the
family previously reported by Turkmen et al. (2006). They reported 1
unrelated Turkish family that showed no evidence of linkage to 17p13 and
9p24.
MOLECULAR GENETICS
In affected members of a consanguineous Turkish family with autosomal
recessive cerebellar ataxia, mental retardation, and dysequilibrium
syndrome-2 (Turkmen et al., 2006), Gulsuner et al. (2011) identified a
homozygous mutation in the WDR81 gene (P856L; 614218). Homozygosity for
the mutation segregated with the phenotype. The mutation occurred in a
highly conserved residue, and was not found in 549 controls. The
mutation was found by targeted sequencing of the candidate disease
region identified by linkage analysis. WDR81 was expressed in the
cerebellum and corpus callosum.
*FIELD* RF
1. Garcias, G. de L.; Roth, M. da G. M.: A Brazilian family with
quadrupedal gait, severe mental retardation, coarse facial characteristics,
and hirsutism. Int. J. Neurosci. 117: 927-933, 2007.
2. Gulsuner, S.; Tekinay, A. B.; Doerschner, K.; Boyaci, H.; Bilguvar,
K.; Unal, H.; Ors, A.; Onat, O. E.; Atalar, E.; Basak, A. N.; Topaloglu,
H.; Kansu, T.; Tan, M.; Tan, U.; Gunel, M.; Ozcelik, T.: Homozygosity
mapping and targeted genomic sequencing reveal the gene responsible
for cerebellar hypoplasia and quadrupedal locomotion in a consanguineous
kindred. Genome Res. 21: 1995-2003, 2011.
3. Herz, J.; Boycott, K. M.; Parboosingh, J. S.: 'Devolution' of
bipedality. (Letter) Proc. Nat. Acad. Sci. 105: E25 only, 2008.
Note: Electronic Article.
4. Humphrey, N.; Mundlos, S.; Turkmen, S.: Genes and quadrupedal
locomotion in humans. (Letter) Proc. Nat. Acad. Sci. 105: E26 only,
2008. Note: Electronic Article.
5. Ozcelik, T.; Akarsu, N.; Uz, E.; Caglayan, S.; Gulsuner, S.; Onat,
O. E.; Tan, M.: Mutations in the very low-density lipoprotein receptor
VLDLR cause cerebellar hypoplasia and quadrupedal locomotion in humans. Proc.
Nat. Acad. Sci. 105: 4232-4236, 2008.
6. Ozcelik, T.; Akarsu, N.; Uz, E.; Caglayan, S.; Gulsuner, S.; Onat,
O. E.; Tan, M.; Tan, U.: Reply to Herz et al. and Humphrey et al.:
Genetic heterogeneity of cerebellar hypoplasia with quadrupedal locomotion.
(Letter) Proc. Nat. Acad. Sci. 105: E32-E33, 2008. Note: Electronic
Article.
7. Tan, U.: A new syndrome with quadrupedal gait, primitive speech,
and severe mental retardation as a live model for human evolution. Int.
J. Neurosci. 116: 361-369, 2006.
8. Turkmen, S.; Demirhan, O.; Hoffmann, K.; Diers, A.; Zimmer, C.;
Sperling, K.; Mundlos, S.: Cerebellar hypoplasia and quadrupedal
locomotion in humans as a recessive trait mapping to chromosome 17p.
(Letter) J. Med. Genet. 43: 461-464, 2006.
*FIELD* CS
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Short stature
HEAD AND NECK:
[Head];
Head is flexed forward;
[Face];
Coarse facial features;
[Eyes];
Strabismus;
[Neck];
Wide and short nape of the neck
SKELETAL:
[Spine];
Thoracic kyphosis;
Thoracic scoliosis;
Skull is flexed forward on the spine;
[Hands];
Small hands;
[Feet];
Small feet
SKIN, NAILS, HAIR:
[Hair];
Hirsutism
NEUROLOGIC:
[Central nervous system];
Mental retardation, severe;
Cerebellar ataxia;
Delayed psychomotor development;
Poor language development;
Absence of language development;
Quadrupedal gait (palm of hands, legs straight) with diagonal walking;
Truncal ataxia, severe;
Tremor;
Dysmetria;
Dysarthria;
Dysdiadochokinesis;
Hyporeflexia;
Cerebellar hypoplasia;
Aplasia of the inferior half of the cerebellar vermis;
Atrophy of the dentate nucleus;
Generalized cerebral atrophy;
Hypoplasia of the corpus callosum;
Cerebellar atrophy
MISCELLANEOUS:
Onset in infancy
MOLECULAR BASIS:
Caused by mutation in the WD repeat-containing protein 81 gene (WDR81,
614218.0001)
*FIELD* CN
Cassandra L. Kniffin - updated: 5/24/2012
Cassandra L. Kniffin - updated: 6/19/2008
Cassandra L. Kniffin - updated: 1/30/2008
*FIELD* CD
Cassandra L. Kniffin: 6/13/2006
*FIELD* ED
joanna: 06/04/2012
ckniffin: 5/24/2012
ckniffin: 2/18/2010
ckniffin: 2/3/2010
ckniffin: 7/15/2008
ckniffin: 6/19/2008
ckniffin: 1/30/2008
joanna: 10/27/2006
joanna: 10/26/2006
ckniffin: 6/13/2006
*FIELD* CN
Cassandra L. Kniffin - updated: 5/24/2012
Cassandra L. Kniffin - updated: 2/3/2010
Cassandra L. Kniffin - updated: 7/16/2008
Cassandra L. Kniffin - updated: 6/19/2008
Cassandra L. Kniffin - updated: 1/30/2008
*FIELD* CD
Cassandra L. Kniffin: 6/13/2006
*FIELD* ED
alopez: 06/11/2013
alopez: 5/25/2012
ckniffin: 5/24/2012
carol: 11/12/2010
joanna: 3/25/2010
joanna: 3/10/2010
carol: 2/22/2010
carol: 2/4/2010
ckniffin: 2/3/2010
joanna: 9/8/2008
ckniffin: 9/8/2008
wwang: 7/16/2008
ckniffin: 7/15/2008
ckniffin: 6/19/2008
wwang: 2/1/2008
ckniffin: 1/30/2008
wwang: 1/7/2008
wwang: 6/16/2006
ckniffin: 6/13/2006
MIM
614218
*RECORD*
*FIELD* NO
614218
*FIELD* TI
*614218 WD REPEAT-CONTAINING PROTEIN 81; WDR81
*FIELD* TX
CLONING
Okazaki et al. (2004) cloned mouse Wdr81, which they designated
read moreFLJ00182. The deduced protein contains 693 amino acids.
Gulsuner et al. (2011) stated that the longest isoform of the human
WDR81 gene, isoform-1, contains 1,941 amino acids. The protein contains
an N-terminal BEACH (Beige and Chediak-Higashi) domain, a MFS (major
facilitator superfamily) domain, and 6 C-terminal WD40 repeats. The
protein is predicted to be a transmembrane protein with 6
membrane-spanning domains. Human WDR81 was expressed in all brain
regions analyzed, with highest levels of expression in the cerebellum
and corpus callosum. Wdr81 was detected in Purkinje cells in the
cerebellum of mouse embryos, and was coexpressed with genes involved in
neuronal differentiation and projection, axonogenesis, and cell
morphogenesis, suggesting a role in development.
Traka et al. (2013) stated that mouse Wdr81 isoform-1, which is
orthologous to human isoform-1, contains 1,934 amino acids and has a
calculated molecular mass of approximately 211 kD. RT-PCR detected
variable Wdr81 expression in all 11 mouse tissues examined. Western blot
analysis detected Wdr81 isoforms of approximately 90 and 80 kD in mouse
cerebellum, brain, and spinal cord, but not in thymus, suggesting that
isoform-1 is not expressed in these tissues or undergoes proteolytic
processing. Immunohistochemical analysis revealed Wdr81 expression in
central nervous system neurons, including Purkinje cells and neurons of
deep cerebellar nuclei, and in photoreceptor cells. Wdr81 localized to
mitochondria.
GENE STRUCTURE
Gulsuner et al. (2011) stated that the human WDR81 gene contains 10
exons.
MAPPING
Hartz (2011) mapped the WDR81 gene to chromosome 17p13.3 based on an
alignment of the WDR81 sequence (GenBank GENBANK AK091136) with the
genomic sequence (GRCh37).
Okazaki et al. (2004) mapped the mouse Wdr81 gene to chromosome 11.
MOLECULAR GENETICS
In affected members of a consanguineous Turkish family with autosomal
recessive cerebellar ataxia, mental retardation, and dysequilibrium
syndrome-2 (CAMRQ2; 610185), Gulsuner et al. (2011) identified a
homozygous mutation in the WDR81 gene (P856L; 614218.0001). Homozygosity
for the mutation segregated with the phenotype. The mutation occurred in
a highly conserved residue and was not found in 549 controls. The
mutation was found by targeted sequencing of the candidate disease
region identified by linkage analysis. The family had originally been
reported by Turkmen et al. (2006) as having cerebellar hypoplasia,
mental retardation, and an inability to walk bipedally, resulting in
quadrupedal locomotion as a functional adaptation. Brain MRI of affected
individuals by Gulsuner et al. (2011) showed morphologic abnormalities
in the cerebellum and corpus callosum, in particular atrophy of
superior, middle, and inferior peduncles of the cerebellum. Structural
MRI showed additional morphometric abnormalities in several cortical
areas, including the corpus callosum, precentral gyrus, and several
Brodmann areas.
ANIMAL MODEL
Homozygous mice from the N-ethyl-N-nitrosourea-induced mutant line nur5
appear normal at birth, but they develop tremor and an abnormal gait as
adults. Traka et al. (2013) found that Purkinje cells developed normally
in nur5/nur5 animals before postnatal day 21, but that they began dying
soon afterwards. Purkinje cell loss correlated with progressive ataxia
in nur5/nur5 mice. Nur5/nur5 animals also developed noticeable shrinkage
of the eye, concomitant with loss of photoreceptor cells and thinning of
the retina. Traka et al. (2013) identified the nur5 mutation as a
leu1349-to-pro (L1349P) substitution within the MFS domain of Wdr81.
Quantitative RT-PCR detected expression of Wdr81 with L1349P at a level
comparable to that of wildtype Wdr81 in cerebellum, and Wdr81 with
L1349P localized normally to mitochondria. However, a significant subset
of nur5/nur5 mitochondria were substantially larger and more spherical
than wildtype mitochondria and showed disrupted cristae and outer
membranes.
*FIELD* AV
.0001
CEREBELLAR ATAXIA, MENTAL RETARDATION, AND DYSEQUILIBRIUM SYNDROME
2
WDR81, PRO856LEU
In affected members of a consanguineous Turkish family with autosomal
recessive cerebellar ataxia, mental retardation, and dysequilibrium
syndrome-2 (CAMRQ2; 610185) (Turkmen et al., 2006), Gulsuner et al.
(2011) identified a homozygous C-to-T transition at cDNA position 2567
(2567C-T) in exon 1 of the WDR81 gene, resulting in a pro856-to-leu
(P856L) substitution in a highly conserved residue in the MFS domain of
isoform-1. The mutation was not found in 549 controls.
*FIELD* RF
1. Gulsuner, S.; Tekinay, A. B.; Doerschner, K.; Boyaci, H.; Bilguvar,
K.; Unal, H.; Ors, A.; Onat, O. E.; Atalar, E.; Basak, A. N.; Topaloglu,
H.; Kansu, T.; Tan, M.; Tan, U.; Gunel, M.; Ozcelik, T.: Homozygosity
mapping and targeted genomic sequencing reveal the gene responsible
for cerebellar hypoplasia and quadrupedal locomotion in a consanguineous
kindred. Genome Res. 21: 1995-2003, 2011.
2. Hartz, P. A.: Personal Communication. Baltimore, Md. 9/8/2011.
3. Okazaki, N.; Kikuno, R.; Ohara, R.; Inamoto, S.; Koseki, H.; Hiraoka,
S.; Saga, Y.; Kitamura, H.; Nakagawa, T.; Nagase, T.; Ohara, O.; Koga,
H.: Prediction of the coding sequences of mouse homologues of FLJ
genes: the complete nucleotide sequences of 110 mouse FLJ-homologous
cDNAs identified by screening of terminal sequences of cDNA clones
randomly sampled from size-fractionated libraries. DNA Res. 11:
127-135, 2004.
4. Traka, M.; Millen, K. J.; Collins, D.; Elbaz, B.; Kidd, G. J.;
Gomez, C. M.; Popko, B.: WDR81 is necessary for Purkinje and photoreceptor
cell survival. J. Neurosci. 33: 6834-6844, 2013.
5. Turkmen, S.; Demirhan, O.; Hoffmann, K.; Diers, A.; Zimmer, C.;
Sperling, K.; Mundlos, S.: Cerebellar hypoplasia and quadrupedal
locomotion in humans as a recessive trait mapping to chromosome 17p.
(Letter) J. Med. Genet. 43: 461-464, 2006.
*FIELD* CN
Patricia A. Hartz - updated: 1/9/2014
Cassandra L. Kniffin - updated: 5/24/2012
*FIELD* CD
Patricia A. Hartz: 9/8/2011
*FIELD* ED
mgross: 01/09/2014
mcolton: 1/9/2014
terry: 6/11/2012
alopez: 5/25/2012
ckniffin: 5/24/2012
mgross: 5/23/2012
*RECORD*
*FIELD* NO
614218
*FIELD* TI
*614218 WD REPEAT-CONTAINING PROTEIN 81; WDR81
*FIELD* TX
CLONING
Okazaki et al. (2004) cloned mouse Wdr81, which they designated
read moreFLJ00182. The deduced protein contains 693 amino acids.
Gulsuner et al. (2011) stated that the longest isoform of the human
WDR81 gene, isoform-1, contains 1,941 amino acids. The protein contains
an N-terminal BEACH (Beige and Chediak-Higashi) domain, a MFS (major
facilitator superfamily) domain, and 6 C-terminal WD40 repeats. The
protein is predicted to be a transmembrane protein with 6
membrane-spanning domains. Human WDR81 was expressed in all brain
regions analyzed, with highest levels of expression in the cerebellum
and corpus callosum. Wdr81 was detected in Purkinje cells in the
cerebellum of mouse embryos, and was coexpressed with genes involved in
neuronal differentiation and projection, axonogenesis, and cell
morphogenesis, suggesting a role in development.
Traka et al. (2013) stated that mouse Wdr81 isoform-1, which is
orthologous to human isoform-1, contains 1,934 amino acids and has a
calculated molecular mass of approximately 211 kD. RT-PCR detected
variable Wdr81 expression in all 11 mouse tissues examined. Western blot
analysis detected Wdr81 isoforms of approximately 90 and 80 kD in mouse
cerebellum, brain, and spinal cord, but not in thymus, suggesting that
isoform-1 is not expressed in these tissues or undergoes proteolytic
processing. Immunohistochemical analysis revealed Wdr81 expression in
central nervous system neurons, including Purkinje cells and neurons of
deep cerebellar nuclei, and in photoreceptor cells. Wdr81 localized to
mitochondria.
GENE STRUCTURE
Gulsuner et al. (2011) stated that the human WDR81 gene contains 10
exons.
MAPPING
Hartz (2011) mapped the WDR81 gene to chromosome 17p13.3 based on an
alignment of the WDR81 sequence (GenBank GENBANK AK091136) with the
genomic sequence (GRCh37).
Okazaki et al. (2004) mapped the mouse Wdr81 gene to chromosome 11.
MOLECULAR GENETICS
In affected members of a consanguineous Turkish family with autosomal
recessive cerebellar ataxia, mental retardation, and dysequilibrium
syndrome-2 (CAMRQ2; 610185), Gulsuner et al. (2011) identified a
homozygous mutation in the WDR81 gene (P856L; 614218.0001). Homozygosity
for the mutation segregated with the phenotype. The mutation occurred in
a highly conserved residue and was not found in 549 controls. The
mutation was found by targeted sequencing of the candidate disease
region identified by linkage analysis. The family had originally been
reported by Turkmen et al. (2006) as having cerebellar hypoplasia,
mental retardation, and an inability to walk bipedally, resulting in
quadrupedal locomotion as a functional adaptation. Brain MRI of affected
individuals by Gulsuner et al. (2011) showed morphologic abnormalities
in the cerebellum and corpus callosum, in particular atrophy of
superior, middle, and inferior peduncles of the cerebellum. Structural
MRI showed additional morphometric abnormalities in several cortical
areas, including the corpus callosum, precentral gyrus, and several
Brodmann areas.
ANIMAL MODEL
Homozygous mice from the N-ethyl-N-nitrosourea-induced mutant line nur5
appear normal at birth, but they develop tremor and an abnormal gait as
adults. Traka et al. (2013) found that Purkinje cells developed normally
in nur5/nur5 animals before postnatal day 21, but that they began dying
soon afterwards. Purkinje cell loss correlated with progressive ataxia
in nur5/nur5 mice. Nur5/nur5 animals also developed noticeable shrinkage
of the eye, concomitant with loss of photoreceptor cells and thinning of
the retina. Traka et al. (2013) identified the nur5 mutation as a
leu1349-to-pro (L1349P) substitution within the MFS domain of Wdr81.
Quantitative RT-PCR detected expression of Wdr81 with L1349P at a level
comparable to that of wildtype Wdr81 in cerebellum, and Wdr81 with
L1349P localized normally to mitochondria. However, a significant subset
of nur5/nur5 mitochondria were substantially larger and more spherical
than wildtype mitochondria and showed disrupted cristae and outer
membranes.
*FIELD* AV
.0001
CEREBELLAR ATAXIA, MENTAL RETARDATION, AND DYSEQUILIBRIUM SYNDROME
2
WDR81, PRO856LEU
In affected members of a consanguineous Turkish family with autosomal
recessive cerebellar ataxia, mental retardation, and dysequilibrium
syndrome-2 (CAMRQ2; 610185) (Turkmen et al., 2006), Gulsuner et al.
(2011) identified a homozygous C-to-T transition at cDNA position 2567
(2567C-T) in exon 1 of the WDR81 gene, resulting in a pro856-to-leu
(P856L) substitution in a highly conserved residue in the MFS domain of
isoform-1. The mutation was not found in 549 controls.
*FIELD* RF
1. Gulsuner, S.; Tekinay, A. B.; Doerschner, K.; Boyaci, H.; Bilguvar,
K.; Unal, H.; Ors, A.; Onat, O. E.; Atalar, E.; Basak, A. N.; Topaloglu,
H.; Kansu, T.; Tan, M.; Tan, U.; Gunel, M.; Ozcelik, T.: Homozygosity
mapping and targeted genomic sequencing reveal the gene responsible
for cerebellar hypoplasia and quadrupedal locomotion in a consanguineous
kindred. Genome Res. 21: 1995-2003, 2011.
2. Hartz, P. A.: Personal Communication. Baltimore, Md. 9/8/2011.
3. Okazaki, N.; Kikuno, R.; Ohara, R.; Inamoto, S.; Koseki, H.; Hiraoka,
S.; Saga, Y.; Kitamura, H.; Nakagawa, T.; Nagase, T.; Ohara, O.; Koga,
H.: Prediction of the coding sequences of mouse homologues of FLJ
genes: the complete nucleotide sequences of 110 mouse FLJ-homologous
cDNAs identified by screening of terminal sequences of cDNA clones
randomly sampled from size-fractionated libraries. DNA Res. 11:
127-135, 2004.
4. Traka, M.; Millen, K. J.; Collins, D.; Elbaz, B.; Kidd, G. J.;
Gomez, C. M.; Popko, B.: WDR81 is necessary for Purkinje and photoreceptor
cell survival. J. Neurosci. 33: 6834-6844, 2013.
5. Turkmen, S.; Demirhan, O.; Hoffmann, K.; Diers, A.; Zimmer, C.;
Sperling, K.; Mundlos, S.: Cerebellar hypoplasia and quadrupedal
locomotion in humans as a recessive trait mapping to chromosome 17p.
(Letter) J. Med. Genet. 43: 461-464, 2006.
*FIELD* CN
Patricia A. Hartz - updated: 1/9/2014
Cassandra L. Kniffin - updated: 5/24/2012
*FIELD* CD
Patricia A. Hartz: 9/8/2011
*FIELD* ED
mgross: 01/09/2014
mcolton: 1/9/2014
terry: 6/11/2012
alopez: 5/25/2012
ckniffin: 5/24/2012
mgross: 5/23/2012