Full text data of WDR45
WDR45
(WDRX1, WDRXI4, WIPI4)
[Confidence: low (only semi-automatic identification from reviews)]
WD repeat domain phosphoinositide-interacting protein 4; WIPI-4 (WD repeat-containing protein 45)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
WD repeat domain phosphoinositide-interacting protein 4; WIPI-4 (WD repeat-containing protein 45)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
Q9Y484
ID WIPI4_HUMAN Reviewed; 360 AA.
AC Q9Y484; A6NGH5; B7WPI2; Q5MNZ5; Q6IBS7; Q6NT94; Q96H03;
DT 10-JAN-2006, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-NOV-1999, sequence version 1.
DT 22-JAN-2014, entry version 106.
DE RecName: Full=WD repeat domain phosphoinositide-interacting protein 4;
DE Short=WIPI-4;
DE AltName: Full=WD repeat-containing protein 45;
GN Name=WDR45; Synonyms=WDRX1, WDRXI4, WIPI4; ORFNames=JM5;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND TISSUE SPECIFICITY.
RC TISSUE=Testis;
RX PubMed=15602573; DOI=10.1038/sj.onc.1208331;
RA Proikas-Cezanne T., Waddell S., Gaugel A., Frickey T., Lupas A.,
RA Nordheim A.;
RT "WIPI-1alpha (WIPI49), a member of the novel 7-bladed WIPI protein
RT family, is aberrantly expressed in human cancer and is linked to
RT starvation-induced autophagy.";
RL Oncogene 23:9314-9325(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA Strom T.M., Nyakatura G., Hellebrand H., Drescher B., Rosenthal A.,
RA Meindl A.;
RT "Transcription map in Xp11.23.";
RL Submitted (APR-1998) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15772651; DOI=10.1038/nature03440;
RA Ross M.T., Grafham D.V., Coffey A.J., Scherer S., McLay K., Muzny D.,
RA Platzer M., Howell G.R., Burrows C., Bird C.P., Frankish A.,
RA Lovell F.L., Howe K.L., Ashurst J.L., Fulton R.S., Sudbrak R., Wen G.,
RA Jones M.C., Hurles M.E., Andrews T.D., Scott C.E., Searle S.,
RA Ramser J., Whittaker A., Deadman R., Carter N.P., Hunt S.E., Chen R.,
RA Cree A., Gunaratne P., Havlak P., Hodgson A., Metzker M.L.,
RA Richards S., Scott G., Steffen D., Sodergren E., Wheeler D.A.,
RA Worley K.C., Ainscough R., Ambrose K.D., Ansari-Lari M.A., Aradhya S.,
RA Ashwell R.I., Babbage A.K., Bagguley C.L., Ballabio A., Banerjee R.,
RA Barker G.E., Barlow K.F., Barrett I.P., Bates K.N., Beare D.M.,
RA Beasley H., Beasley O., Beck A., Bethel G., Blechschmidt K., Brady N.,
RA Bray-Allen S., Bridgeman A.M., Brown A.J., Brown M.J., Bonnin D.,
RA Bruford E.A., Buhay C., Burch P., Burford D., Burgess J., Burrill W.,
RA Burton J., Bye J.M., Carder C., Carrel L., Chako J., Chapman J.C.,
RA Chavez D., Chen E., Chen G., Chen Y., Chen Z., Chinault C.,
RA Ciccodicola A., Clark S.Y., Clarke G., Clee C.M., Clegg S.,
RA Clerc-Blankenburg K., Clifford K., Cobley V., Cole C.G., Conquer J.S.,
RA Corby N., Connor R.E., David R., Davies J., Davis C., Davis J.,
RA Delgado O., Deshazo D., Dhami P., Ding Y., Dinh H., Dodsworth S.,
RA Draper H., Dugan-Rocha S., Dunham A., Dunn M., Durbin K.J., Dutta I.,
RA Eades T., Ellwood M., Emery-Cohen A., Errington H., Evans K.L.,
RA Faulkner L., Francis F., Frankland J., Fraser A.E., Galgoczy P.,
RA Gilbert J., Gill R., Gloeckner G., Gregory S.G., Gribble S.,
RA Griffiths C., Grocock R., Gu Y., Gwilliam R., Hamilton C., Hart E.A.,
RA Hawes A., Heath P.D., Heitmann K., Hennig S., Hernandez J.,
RA Hinzmann B., Ho S., Hoffs M., Howden P.J., Huckle E.J., Hume J.,
RA Hunt P.J., Hunt A.R., Isherwood J., Jacob L., Johnson D., Jones S.,
RA de Jong P.J., Joseph S.S., Keenan S., Kelly S., Kershaw J.K., Khan Z.,
RA Kioschis P., Klages S., Knights A.J., Kosiura A., Kovar-Smith C.,
RA Laird G.K., Langford C., Lawlor S., Leversha M., Lewis L., Liu W.,
RA Lloyd C., Lloyd D.M., Loulseged H., Loveland J.E., Lovell J.D.,
RA Lozado R., Lu J., Lyne R., Ma J., Maheshwari M., Matthews L.H.,
RA McDowall J., McLaren S., McMurray A., Meidl P., Meitinger T.,
RA Milne S., Miner G., Mistry S.L., Morgan M., Morris S., Mueller I.,
RA Mullikin J.C., Nguyen N., Nordsiek G., Nyakatura G., O'dell C.N.,
RA Okwuonu G., Palmer S., Pandian R., Parker D., Parrish J.,
RA Pasternak S., Patel D., Pearce A.V., Pearson D.M., Pelan S.E.,
RA Perez L., Porter K.M., Ramsey Y., Reichwald K., Rhodes S.,
RA Ridler K.A., Schlessinger D., Schueler M.G., Sehra H.K.,
RA Shaw-Smith C., Shen H., Sheridan E.M., Shownkeen R., Skuce C.D.,
RA Smith M.L., Sotheran E.C., Steingruber H.E., Steward C.A., Storey R.,
RA Swann R.M., Swarbreck D., Tabor P.E., Taudien S., Taylor T.,
RA Teague B., Thomas K., Thorpe A., Timms K., Tracey A., Trevanion S.,
RA Tromans A.C., d'Urso M., Verduzco D., Villasana D., Waldron L.,
RA Wall M., Wang Q., Warren J., Warry G.L., Wei X., West A.,
RA Whitehead S.L., Whiteley M.N., Wilkinson J.E., Willey D.L.,
RA Williams G., Williams L., Williamson A., Williamson H., Wilming L.,
RA Woodmansey R.L., Wray P.W., Yen J., Zhang J., Zhou J., Zoghbi H.,
RA Zorilla S., Buck D., Reinhardt R., Poustka A., Rosenthal A.,
RA Lehrach H., Meindl A., Minx P.J., Hillier L.W., Willard H.F.,
RA Wilson R.K., Waterston R.H., Rice C.M., Vaudin M., Coulson A.,
RA Nelson D.L., Weinstock G., Sulston J.E., Durbin R.M., Hubbard T.,
RA Gibbs R.A., Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence of the human X chromosome.";
RL Nature 434:325-337(2005).
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] (ISOFORMS 1 AND 3), AND
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 69-360 (ISOFORM 2).
RC TISSUE=Brain, and Lung;
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 INVOLVEMENT IN NBIA5, AND FUNCTION.
RX PubMed=23435086; DOI=10.1038/ng.2562;
RA Saitsu H., Nishimura T., Muramatsu K., Kodera H., Kumada S., Sugai K.,
RA Kasai-Yoshida E., Sawaura N., Nishida H., Hoshino A., Ryujin F.,
RA Yoshioka S., Nishiyama K., Kondo Y., Tsurusaki Y., Nakashima M.,
RA Miyake N., Arakawa H., Kato M., Mizushima N., Matsumoto N.;
RT "De novo mutations in the autophagy gene WDR45 cause static
RT encephalopathy of childhood with neurodegeneration in adulthood.";
RL Nat. Genet. 45:445-449(2013).
CC -!- FUNCTION: Plays an important role in the autophagy pathway, which
CC is the major intracellular degradation system by which cytoplasmic
CC materials are packaged into autophagosomes and delivered to
CC lysosomes for degradation.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=Q9Y484-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9Y484-2; Sequence=VSP_016976;
CC Note=No experimental confirmation available;
CC Name=3;
CC IsoId=Q9Y484-3; Sequence=VSP_016975;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Ubiquitously expressed, with high expression
CC in skeletal muscle and heart. Weakly expressed in liver and
CC placenta. Expression is down-regulated in pancreatic and in kidney
CC tumors.
CC -!- DISEASE: Neurodegeneration with brain iron accumulation 5 (NBIA5)
CC [MIM:300894]: A neurodegenerative disorder associated with iron
CC accumulation in the brain, primarily in the basal ganglia. NBIA5
CC is characterized by global developmental delay in early childhood
CC that is essentially static, with slow motor and cognitive gains
CC until adolescence or early adulthood. In young adulthood, affected
CC individuals develop progressive dystonia, parkinsonism,
CC extrapyramidal signs, and dementia resulting in severe disability.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- SIMILARITY: Belongs to the WD repeat SVP1 family.
CC -!- SIMILARITY: Contains 3 WD repeats.
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; AY691428; AAV80764.1; -; mRNA.
DR EMBL; AJ005897; CAA06754.1; -; mRNA.
DR EMBL; CR456725; CAG33006.1; -; mRNA.
DR EMBL; AF196779; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471224; EAW50697.1; -; Genomic_DNA.
DR EMBL; CH471224; EAW50702.1; -; Genomic_DNA.
DR EMBL; BC000464; AAH00464.1; -; mRNA.
DR EMBL; BC003037; AAH03037.1; -; mRNA.
DR EMBL; BC009027; AAH09027.1; -; mRNA.
DR EMBL; BC069206; AAH69206.1; -; mRNA.
DR RefSeq; NP_001025067.1; NM_001029896.1.
DR RefSeq; NP_009006.2; NM_007075.3.
DR RefSeq; XP_005272641.1; XM_005272584.1.
DR RefSeq; XP_005278083.1; XM_005278026.1.
DR UniGene; Hs.632807; -.
DR ProteinModelPortal; Q9Y484; -.
DR SMR; Q9Y484; 9-302.
DR IntAct; Q9Y484; 5.
DR STRING; 9606.ENSP00000348848; -.
DR PhosphoSite; Q9Y484; -.
DR DMDM; 74762056; -.
DR PaxDb; Q9Y484; -.
DR PRIDE; Q9Y484; -.
DR DNASU; 11152; -.
DR Ensembl; ENST00000322995; ENSP00000365543; ENSG00000196998.
DR Ensembl; ENST00000356463; ENSP00000348848; ENSG00000196998.
DR Ensembl; ENST00000376368; ENSP00000365546; ENSG00000196998.
DR Ensembl; ENST00000376372; ENSP00000365551; ENSG00000196998.
DR GeneID; 11152; -.
DR KEGG; hsa:11152; -.
DR UCSC; uc004dmk.1; human.
DR CTD; 11152; -.
DR GeneCards; GC0XM048929; -.
DR HGNC; HGNC:28912; WDR45.
DR HPA; HPA027562; -.
DR MIM; 300526; gene.
DR MIM; 300894; phenotype.
DR neXtProt; NX_Q9Y484; -.
DR Orphanet; 329284; Beta-propeller protein-associated neurodegeneration.
DR PharmGKB; PA134927673; -.
DR eggNOG; NOG240108; -.
DR HOGENOM; HOG000217543; -.
DR HOVERGEN; HBG053275; -.
DR OMA; CICAFGK; -.
DR SignaLink; Q9Y484; -.
DR GeneWiki; WDR45; -.
DR GenomeRNAi; 11152; -.
DR NextBio; 42400; -.
DR PRO; PR:Q9Y484; -.
DR ArrayExpress; Q9Y484; -.
DR Bgee; Q9Y484; -.
DR CleanEx; HS_WDR45; -.
DR Genevestigator; Q9Y484; -.
DR GO; GO:0005737; C:cytoplasm; IBA:RefGenome.
DR GO; GO:0080025; F:phosphatidylinositol-3,5-bisphosphate binding; IBA:RefGenome.
DR GO; GO:0032266; F:phosphatidylinositol-3-phosphate binding; IBA:RefGenome.
DR GO; GO:0000045; P:autophagic vacuole assembly; IBA:RefGenome.
DR GO; GO:0008219; P:cell death; IEA:UniProtKB-KW.
DR Gene3D; 2.130.10.10; -; 1.
DR InterPro; IPR015943; WD40/YVTN_repeat-like_dom.
DR InterPro; IPR001680; WD40_repeat.
DR InterPro; IPR017986; WD40_repeat_dom.
DR Pfam; PF00400; WD40; 2.
DR SMART; SM00320; WD40; 4.
DR SUPFAM; SSF50978; SSF50978; 1.
DR PROSITE; PS00678; WD_REPEATS_1; FALSE_NEG.
DR PROSITE; PS50082; WD_REPEATS_2; FALSE_NEG.
DR PROSITE; PS50294; WD_REPEATS_REGION; FALSE_NEG.
PE 2: Evidence at transcript level;
KW Alternative splicing; Autophagy; Complete proteome; Neurodegeneration;
KW Reference proteome; Repeat; WD repeat.
FT CHAIN 1 360 WD repeat domain phosphoinositide-
FT interacting protein 4.
FT /FTId=PRO_0000051452.
FT REPEAT 4 42 WD 1.
FT REPEAT 190 230 WD 2.
FT REPEAT 235 274 WD 3.
FT VAR_SEQ 78 78 S -> SA (in isoform 3).
FT /FTId=VSP_016975.
FT VAR_SEQ 145 145 K -> KAAHPTPHLHTL (in isoform 2).
FT /FTId=VSP_016976.
FT CONFLICT 217 217 I -> T (in Ref. 3; CAG33006).
FT CONFLICT 300 302 FTV -> YTA (in Ref. 1; AAV80764).
SQ SEQUENCE 360 AA; 39868 MW; E1A6746277182AF9 CRC64;
MTQQPLRGVT SLRFNQDQSC FCCAMETGVR IYNVEPLMEK GHLDHEQVGS MGLVEMLHRS
NLLALVGGGS SPKFSEISVL IWDDAREGKD SKEKLVLEFT FTKPVLSVRM RHDKIVIVLK
NRIYVYSFPD NPRKLFEFDT RDNPKGLCDL CPSLEKQLLV FPGHKCGSLQ LVDLASTKPG
TSSAPFTINA HQSDIACVSL NQPGTVVASA SQKGTLIRLF DTQSKEKLVE LRRGTDPATL
YCINFSHDSS FLCASSDKGT VHIFALKDTR LNRRSALARV GKVGPMIGQY VDSQWSLASF
TVPAESACIC AFGRNTSKNV NSVIAICVDG TFHKYVFTPD GNCNREAFDV YLDICDDDDF
//
ID WIPI4_HUMAN Reviewed; 360 AA.
AC Q9Y484; A6NGH5; B7WPI2; Q5MNZ5; Q6IBS7; Q6NT94; Q96H03;
DT 10-JAN-2006, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-NOV-1999, sequence version 1.
DT 22-JAN-2014, entry version 106.
DE RecName: Full=WD repeat domain phosphoinositide-interacting protein 4;
DE Short=WIPI-4;
DE AltName: Full=WD repeat-containing protein 45;
GN Name=WDR45; Synonyms=WDRX1, WDRXI4, WIPI4; ORFNames=JM5;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND TISSUE SPECIFICITY.
RC TISSUE=Testis;
RX PubMed=15602573; DOI=10.1038/sj.onc.1208331;
RA Proikas-Cezanne T., Waddell S., Gaugel A., Frickey T., Lupas A.,
RA Nordheim A.;
RT "WIPI-1alpha (WIPI49), a member of the novel 7-bladed WIPI protein
RT family, is aberrantly expressed in human cancer and is linked to
RT starvation-induced autophagy.";
RL Oncogene 23:9314-9325(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA Strom T.M., Nyakatura G., Hellebrand H., Drescher B., Rosenthal A.,
RA Meindl A.;
RT "Transcription map in Xp11.23.";
RL Submitted (APR-1998) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15772651; DOI=10.1038/nature03440;
RA Ross M.T., Grafham D.V., Coffey A.J., Scherer S., McLay K., Muzny D.,
RA Platzer M., Howell G.R., Burrows C., Bird C.P., Frankish A.,
RA Lovell F.L., Howe K.L., Ashurst J.L., Fulton R.S., Sudbrak R., Wen G.,
RA Jones M.C., Hurles M.E., Andrews T.D., Scott C.E., Searle S.,
RA Ramser J., Whittaker A., Deadman R., Carter N.P., Hunt S.E., Chen R.,
RA Cree A., Gunaratne P., Havlak P., Hodgson A., Metzker M.L.,
RA Richards S., Scott G., Steffen D., Sodergren E., Wheeler D.A.,
RA Worley K.C., Ainscough R., Ambrose K.D., Ansari-Lari M.A., Aradhya S.,
RA Ashwell R.I., Babbage A.K., Bagguley C.L., Ballabio A., Banerjee R.,
RA Barker G.E., Barlow K.F., Barrett I.P., Bates K.N., Beare D.M.,
RA Beasley H., Beasley O., Beck A., Bethel G., Blechschmidt K., Brady N.,
RA Bray-Allen S., Bridgeman A.M., Brown A.J., Brown M.J., Bonnin D.,
RA Bruford E.A., Buhay C., Burch P., Burford D., Burgess J., Burrill W.,
RA Burton J., Bye J.M., Carder C., Carrel L., Chako J., Chapman J.C.,
RA Chavez D., Chen E., Chen G., Chen Y., Chen Z., Chinault C.,
RA Ciccodicola A., Clark S.Y., Clarke G., Clee C.M., Clegg S.,
RA Clerc-Blankenburg K., Clifford K., Cobley V., Cole C.G., Conquer J.S.,
RA Corby N., Connor R.E., David R., Davies J., Davis C., Davis J.,
RA Delgado O., Deshazo D., Dhami P., Ding Y., Dinh H., Dodsworth S.,
RA Draper H., Dugan-Rocha S., Dunham A., Dunn M., Durbin K.J., Dutta I.,
RA Eades T., Ellwood M., Emery-Cohen A., Errington H., Evans K.L.,
RA Faulkner L., Francis F., Frankland J., Fraser A.E., Galgoczy P.,
RA Gilbert J., Gill R., Gloeckner G., Gregory S.G., Gribble S.,
RA Griffiths C., Grocock R., Gu Y., Gwilliam R., Hamilton C., Hart E.A.,
RA Hawes A., Heath P.D., Heitmann K., Hennig S., Hernandez J.,
RA Hinzmann B., Ho S., Hoffs M., Howden P.J., Huckle E.J., Hume J.,
RA Hunt P.J., Hunt A.R., Isherwood J., Jacob L., Johnson D., Jones S.,
RA de Jong P.J., Joseph S.S., Keenan S., Kelly S., Kershaw J.K., Khan Z.,
RA Kioschis P., Klages S., Knights A.J., Kosiura A., Kovar-Smith C.,
RA Laird G.K., Langford C., Lawlor S., Leversha M., Lewis L., Liu W.,
RA Lloyd C., Lloyd D.M., Loulseged H., Loveland J.E., Lovell J.D.,
RA Lozado R., Lu J., Lyne R., Ma J., Maheshwari M., Matthews L.H.,
RA McDowall J., McLaren S., McMurray A., Meidl P., Meitinger T.,
RA Milne S., Miner G., Mistry S.L., Morgan M., Morris S., Mueller I.,
RA Mullikin J.C., Nguyen N., Nordsiek G., Nyakatura G., O'dell C.N.,
RA Okwuonu G., Palmer S., Pandian R., Parker D., Parrish J.,
RA Pasternak S., Patel D., Pearce A.V., Pearson D.M., Pelan S.E.,
RA Perez L., Porter K.M., Ramsey Y., Reichwald K., Rhodes S.,
RA Ridler K.A., Schlessinger D., Schueler M.G., Sehra H.K.,
RA Shaw-Smith C., Shen H., Sheridan E.M., Shownkeen R., Skuce C.D.,
RA Smith M.L., Sotheran E.C., Steingruber H.E., Steward C.A., Storey R.,
RA Swann R.M., Swarbreck D., Tabor P.E., Taudien S., Taylor T.,
RA Teague B., Thomas K., Thorpe A., Timms K., Tracey A., Trevanion S.,
RA Tromans A.C., d'Urso M., Verduzco D., Villasana D., Waldron L.,
RA Wall M., Wang Q., Warren J., Warry G.L., Wei X., West A.,
RA Whitehead S.L., Whiteley M.N., Wilkinson J.E., Willey D.L.,
RA Williams G., Williams L., Williamson A., Williamson H., Wilming L.,
RA Woodmansey R.L., Wray P.W., Yen J., Zhang J., Zhou J., Zoghbi H.,
RA Zorilla S., Buck D., Reinhardt R., Poustka A., Rosenthal A.,
RA Lehrach H., Meindl A., Minx P.J., Hillier L.W., Willard H.F.,
RA Wilson R.K., Waterston R.H., Rice C.M., Vaudin M., Coulson A.,
RA Nelson D.L., Weinstock G., Sulston J.E., Durbin R.M., Hubbard T.,
RA Gibbs R.A., Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence of the human X chromosome.";
RL Nature 434:325-337(2005).
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] (ISOFORMS 1 AND 3), AND
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 69-360 (ISOFORM 2).
RC TISSUE=Brain, and Lung;
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 INVOLVEMENT IN NBIA5, AND FUNCTION.
RX PubMed=23435086; DOI=10.1038/ng.2562;
RA Saitsu H., Nishimura T., Muramatsu K., Kodera H., Kumada S., Sugai K.,
RA Kasai-Yoshida E., Sawaura N., Nishida H., Hoshino A., Ryujin F.,
RA Yoshioka S., Nishiyama K., Kondo Y., Tsurusaki Y., Nakashima M.,
RA Miyake N., Arakawa H., Kato M., Mizushima N., Matsumoto N.;
RT "De novo mutations in the autophagy gene WDR45 cause static
RT encephalopathy of childhood with neurodegeneration in adulthood.";
RL Nat. Genet. 45:445-449(2013).
CC -!- FUNCTION: Plays an important role in the autophagy pathway, which
CC is the major intracellular degradation system by which cytoplasmic
CC materials are packaged into autophagosomes and delivered to
CC lysosomes for degradation.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=Q9Y484-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9Y484-2; Sequence=VSP_016976;
CC Note=No experimental confirmation available;
CC Name=3;
CC IsoId=Q9Y484-3; Sequence=VSP_016975;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Ubiquitously expressed, with high expression
CC in skeletal muscle and heart. Weakly expressed in liver and
CC placenta. Expression is down-regulated in pancreatic and in kidney
CC tumors.
CC -!- DISEASE: Neurodegeneration with brain iron accumulation 5 (NBIA5)
CC [MIM:300894]: A neurodegenerative disorder associated with iron
CC accumulation in the brain, primarily in the basal ganglia. NBIA5
CC is characterized by global developmental delay in early childhood
CC that is essentially static, with slow motor and cognitive gains
CC until adolescence or early adulthood. In young adulthood, affected
CC individuals develop progressive dystonia, parkinsonism,
CC extrapyramidal signs, and dementia resulting in severe disability.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- SIMILARITY: Belongs to the WD repeat SVP1 family.
CC -!- SIMILARITY: Contains 3 WD repeats.
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; AY691428; AAV80764.1; -; mRNA.
DR EMBL; AJ005897; CAA06754.1; -; mRNA.
DR EMBL; CR456725; CAG33006.1; -; mRNA.
DR EMBL; AF196779; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471224; EAW50697.1; -; Genomic_DNA.
DR EMBL; CH471224; EAW50702.1; -; Genomic_DNA.
DR EMBL; BC000464; AAH00464.1; -; mRNA.
DR EMBL; BC003037; AAH03037.1; -; mRNA.
DR EMBL; BC009027; AAH09027.1; -; mRNA.
DR EMBL; BC069206; AAH69206.1; -; mRNA.
DR RefSeq; NP_001025067.1; NM_001029896.1.
DR RefSeq; NP_009006.2; NM_007075.3.
DR RefSeq; XP_005272641.1; XM_005272584.1.
DR RefSeq; XP_005278083.1; XM_005278026.1.
DR UniGene; Hs.632807; -.
DR ProteinModelPortal; Q9Y484; -.
DR SMR; Q9Y484; 9-302.
DR IntAct; Q9Y484; 5.
DR STRING; 9606.ENSP00000348848; -.
DR PhosphoSite; Q9Y484; -.
DR DMDM; 74762056; -.
DR PaxDb; Q9Y484; -.
DR PRIDE; Q9Y484; -.
DR DNASU; 11152; -.
DR Ensembl; ENST00000322995; ENSP00000365543; ENSG00000196998.
DR Ensembl; ENST00000356463; ENSP00000348848; ENSG00000196998.
DR Ensembl; ENST00000376368; ENSP00000365546; ENSG00000196998.
DR Ensembl; ENST00000376372; ENSP00000365551; ENSG00000196998.
DR GeneID; 11152; -.
DR KEGG; hsa:11152; -.
DR UCSC; uc004dmk.1; human.
DR CTD; 11152; -.
DR GeneCards; GC0XM048929; -.
DR HGNC; HGNC:28912; WDR45.
DR HPA; HPA027562; -.
DR MIM; 300526; gene.
DR MIM; 300894; phenotype.
DR neXtProt; NX_Q9Y484; -.
DR Orphanet; 329284; Beta-propeller protein-associated neurodegeneration.
DR PharmGKB; PA134927673; -.
DR eggNOG; NOG240108; -.
DR HOGENOM; HOG000217543; -.
DR HOVERGEN; HBG053275; -.
DR OMA; CICAFGK; -.
DR SignaLink; Q9Y484; -.
DR GeneWiki; WDR45; -.
DR GenomeRNAi; 11152; -.
DR NextBio; 42400; -.
DR PRO; PR:Q9Y484; -.
DR ArrayExpress; Q9Y484; -.
DR Bgee; Q9Y484; -.
DR CleanEx; HS_WDR45; -.
DR Genevestigator; Q9Y484; -.
DR GO; GO:0005737; C:cytoplasm; IBA:RefGenome.
DR GO; GO:0080025; F:phosphatidylinositol-3,5-bisphosphate binding; IBA:RefGenome.
DR GO; GO:0032266; F:phosphatidylinositol-3-phosphate binding; IBA:RefGenome.
DR GO; GO:0000045; P:autophagic vacuole assembly; IBA:RefGenome.
DR GO; GO:0008219; P:cell death; IEA:UniProtKB-KW.
DR Gene3D; 2.130.10.10; -; 1.
DR InterPro; IPR015943; WD40/YVTN_repeat-like_dom.
DR InterPro; IPR001680; WD40_repeat.
DR InterPro; IPR017986; WD40_repeat_dom.
DR Pfam; PF00400; WD40; 2.
DR SMART; SM00320; WD40; 4.
DR SUPFAM; SSF50978; SSF50978; 1.
DR PROSITE; PS00678; WD_REPEATS_1; FALSE_NEG.
DR PROSITE; PS50082; WD_REPEATS_2; FALSE_NEG.
DR PROSITE; PS50294; WD_REPEATS_REGION; FALSE_NEG.
PE 2: Evidence at transcript level;
KW Alternative splicing; Autophagy; Complete proteome; Neurodegeneration;
KW Reference proteome; Repeat; WD repeat.
FT CHAIN 1 360 WD repeat domain phosphoinositide-
FT interacting protein 4.
FT /FTId=PRO_0000051452.
FT REPEAT 4 42 WD 1.
FT REPEAT 190 230 WD 2.
FT REPEAT 235 274 WD 3.
FT VAR_SEQ 78 78 S -> SA (in isoform 3).
FT /FTId=VSP_016975.
FT VAR_SEQ 145 145 K -> KAAHPTPHLHTL (in isoform 2).
FT /FTId=VSP_016976.
FT CONFLICT 217 217 I -> T (in Ref. 3; CAG33006).
FT CONFLICT 300 302 FTV -> YTA (in Ref. 1; AAV80764).
SQ SEQUENCE 360 AA; 39868 MW; E1A6746277182AF9 CRC64;
MTQQPLRGVT SLRFNQDQSC FCCAMETGVR IYNVEPLMEK GHLDHEQVGS MGLVEMLHRS
NLLALVGGGS SPKFSEISVL IWDDAREGKD SKEKLVLEFT FTKPVLSVRM RHDKIVIVLK
NRIYVYSFPD NPRKLFEFDT RDNPKGLCDL CPSLEKQLLV FPGHKCGSLQ LVDLASTKPG
TSSAPFTINA HQSDIACVSL NQPGTVVASA SQKGTLIRLF DTQSKEKLVE LRRGTDPATL
YCINFSHDSS FLCASSDKGT VHIFALKDTR LNRRSALARV GKVGPMIGQY VDSQWSLASF
TVPAESACIC AFGRNTSKNV NSVIAICVDG TFHKYVFTPD GNCNREAFDV YLDICDDDDF
//
MIM
300526
*RECORD*
*FIELD* NO
300526
*FIELD* TI
*300526 WD REPEAT-CONTAINING PROTEIN 45; WDR45
;;WD40 REPEAT PROTEIN INTERACTING WITH PHOSPHOINOSITIDES 4; WIPI4
read more*FIELD* TX
DESCRIPTION
WD40 repeat proteins are key components of many essential biologic
functions. They regulate the assembly of multiprotein complexes by
presenting a beta-propeller platform for simultaneous and reversible
protein-protein interactions. Members of the WIPI subfamily of WD40
repeat proteins, such as WIPI4, have a 7-bladed propeller structure and
contain a conserved motif for interaction with phospholipids
(Proikas-Cezanne et al., 2004).
CLONING
By searching a genomic database for sequences similar to WIPI1 (609224),
followed by RT-PCR of normal testis mRNA, Proikas-Cezanne et al. (2004)
cloned WIPI4. The deduced protein contains 7 WD-like repeats. Northern
blot analysis detected ubiquitous expression of an approximately 1.8-kb
transcript. Highest expression was in heart and skeletal muscle.
Proikas-Cezanne et al. (2004) also found that WIPI4 expression was
downregulated in a significant portion of renal and pancreatic cancers.
MAPPING
By genomic sequence analysis, Proikas-Cezanne et al. (2004) mapped the
WIPI4 gene to chromosome Xp11.23. They identified a putative WIPI4
pseudogene at chromosome 4q31.3.
GENE FUNCTION
The WDR45 gene has an important role in the autophagy pathway, which is
the major intracellular degradation system by which cytoplasmic
materials are packaged into autophagosomes and delivered to lysosomes
for degradation (summary by Saitsu et al., 2013).
MOLECULAR GENETICS
In 20 unrelated patients with neurodegeneration with brain iron
accumulation-5 (NBIA5; 300894), Haack et al. (2012) identified 19
different de novo heterozygous or hemizygous mutations in the WDR45 gene
(see, e.g., 300526.0001-300526.0002). Most of the mutations were
truncating, but 2 were missense mutations affecting highly conserved
residues. The mutations were located throughout the coding sequence.
Initial mutations were identified by exome sequencing and all were
confirmed by Sanger sequencing. Seventeen females and 3 males were
affected, and the phenotype was similar in all. Since WDR45 is on the X
chromosome, Haack et al. (2012) concluded that the males must be somatic
mosaic for the mutation, which was demonstrated in 1 affected male.
Presumably, males with germline WDR45 mutations are nonviable. Females
may either harbor germline or somatic mutations, and several affected
females had evidence of skewed X inactivation. These factors may
contribute to disease manifestations.
Saitsu et al. (2013) identified 5 different de novo heterozygous
truncating mutations in the WDR45 gene (see, e.g.,
300526.0003-300526.0005) in 5 unrelated women with NBIA5. The initial
mutations were identified by exome sequencing of 2 patients. Patients
had delayed psychomotor development in infancy or early childhood that
remained stable until young adulthood when all patients developed
further severe motor and cognitive decline, with parkinsonism, dystonia,
extrapyramidal signs, and dementia. Most became bedridden with an
inability to care for themselves. Brain MRI showed iron accumulation in
the globus pallidus and substantia nigra. Lymphoblastoid cells from 4 of
the patients showed exclusive expression of the mutant transcript,
suggesting X inactivation of the wildtype allele. All patient cells
showed decreased levels of the mutant proteins, suggesting protein
instability. Patient cells showed impaired autophagic flux.
Immunofluorescence studies showed the accumulation of autophagic
structures in patient cells, consistent with improper autophagosome
formation. The findings suggested that impairment of autophagy
contributes to the pathogenesis of this neurodegenerative disorder.
*FIELD* AV
.0001
NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 5
WDR45, 1-BP DEL, NT1007
In 2 unrelated females with neurodegeneration with brain iron
accumulation-5 (NBIA5; 300894), Haack et al. (2012) identified a de novo
heterozygous 1-bp deletion at nucleotide 1007 of the WDR45 gene,
resulting in a frameshift and premature termination (Tyr336CysfsTer5).
.0002
NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 5
WDR45, ARG234TER
In a female with NBIA5 (300894), Haack et al. (2012) identified a de
novo heterozygous 700C-T transition in the WDR45 gene, resulting in an
arg234-to-ter (R234X) substitution.
.0003
NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 5
WDR45, 516G-C
In a 28-year-old woman with NBIA5 (300894), Saitsu et al. (2013)
identified a heterozygous de novo 516G-C transversion in the last base
of exon 8 of the WDR45 gene, resulting in a 22-bp frameshift insertion
and premature termination (Asp174ValfsTer29). The mutation was
identified by exome sequencing and was not found in several large
control exome databases. Patient lymphoblastoid cells showed exclusive
expression of the mutant transcript, suggesting X inactivation of the
wildtype allele. There were decreased levels of mutant protein,
suggesting that it is unstable and degraded. Patient cells showed
impaired autophagic flux. Immunofluorescence studies showed the
accumulation of autophagic structures in patient cells, consistent with
improper autophagosome formation.
.0004
NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 5
WDR45, 1-BP DUP, 437A
In a 40-year-old Japanese woman with NBIA5 (300894) originally reported
by Kimura et al. (2013), Saitsu et al. (2013) identified a heterozygous
de novo 1-bp duplication (437dupA) in the WDR45 gene, resulting in a
frameshift and premature termination (Leu148AlafsTer3). The mutation was
not found in several large control exome databases. There were decreased
levels of mutant protein, suggesting that it is unstable and degraded.
Patient cells showed impaired autophagic flux. Immunofluorescence
studies showed the accumulation of autophagic structures in patient
cells, consistent with improper autophagosome formation.
.0005
NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 5
WDR45, GLN213TER
In a 51-year-old woman with NBIA5 (300894), Saitsu et al. (2013)
identified a de novo heterozygous 637C-T transition in the WDR45 gene,
resulting in a gln213-to-ter (Q213X) substitution. The mutation was not
found in several large control exome databases. Patient lymphoblastoid
cells showed exclusive expression of the mutant transcript, suggesting X
inactivation of the wildtype allele. There were decreased levels of
mutant protein, suggesting that it is unstable and degraded. Patient
cells showed impaired autophagic flux. Immunofluorescence studies showed
the accumulation of autophagic structures in patient cells, consistent
with improper autophagosome formation.
*FIELD* RF
1. Haack, T. B.; Hogarth, P.; Kruer, M. C.; Gregory, A.; Wieland,
T.; Schwarzmayr, T.; Graf, E.; Sanford, L.; Meyer, E.; Kara, E.; Cuno,
S. M.; Harik, S. I.; and 21 others: Exome sequencing reveals de
novo WDR45 mutations causing a phenotypically distinct, X-linked dominant
form of NBIA. Am. J. Hum. Genet. 91: 1144-1149, 2012.
2. Kimura, Y.; Sato, N.; Sugai, K.; Maruyama, S.; Ota, M.; Kamiya,
K.; Ito, K.; Nakata, Y.; Sasaki, M.; Sugimoto, H.: MRI, MR spectroscopy,
and diffusion tensor imaging findings in patient with static encephalopathy
of childhood with neurodegeneration in adulthood (SENDA). Brain Dev. 35:
458-461, 2013.
3. Proikas-Cezanne, T.; Waddell, S.; Gaugel, A.; Frickey, T.; Lupas,
A.; Nordheim, A.: WIPI-1-alpha (WIPI49), a member of the novel 7-bladed
WIPI protein family, is aberrantly expressed in human cancer and is
linked to starvation-induced autophagy. Oncogene 23: 9314-9325,
2004.
4. Saitsu, H.; Nishimura, T.; Muramatsu, K.; Kodera, H.; Kumada, S.;
Sugai, K.; Kasai-Yoshida, E.; Sawaura, N.; Nishida, H.; Hoshino, A.;
Ryujin, F.; Yoshioka, S.; and 9 others: De novo mutations in the
autophagy gene WDR45 cause static encephalopathy of childhood with
neurodegeneration in adulthood. Nature Genet. 45: 445-449, 2013.
*FIELD* CN
Cassandra L. Kniffin - updated: 4/15/2013
*FIELD* CD
Patricia A. Hartz: 2/28/2005
*FIELD* ED
carol: 09/05/2013
carol: 4/16/2013
ckniffin: 4/15/2013
mgross: 2/28/2005
*RECORD*
*FIELD* NO
300526
*FIELD* TI
*300526 WD REPEAT-CONTAINING PROTEIN 45; WDR45
;;WD40 REPEAT PROTEIN INTERACTING WITH PHOSPHOINOSITIDES 4; WIPI4
read more*FIELD* TX
DESCRIPTION
WD40 repeat proteins are key components of many essential biologic
functions. They regulate the assembly of multiprotein complexes by
presenting a beta-propeller platform for simultaneous and reversible
protein-protein interactions. Members of the WIPI subfamily of WD40
repeat proteins, such as WIPI4, have a 7-bladed propeller structure and
contain a conserved motif for interaction with phospholipids
(Proikas-Cezanne et al., 2004).
CLONING
By searching a genomic database for sequences similar to WIPI1 (609224),
followed by RT-PCR of normal testis mRNA, Proikas-Cezanne et al. (2004)
cloned WIPI4. The deduced protein contains 7 WD-like repeats. Northern
blot analysis detected ubiquitous expression of an approximately 1.8-kb
transcript. Highest expression was in heart and skeletal muscle.
Proikas-Cezanne et al. (2004) also found that WIPI4 expression was
downregulated in a significant portion of renal and pancreatic cancers.
MAPPING
By genomic sequence analysis, Proikas-Cezanne et al. (2004) mapped the
WIPI4 gene to chromosome Xp11.23. They identified a putative WIPI4
pseudogene at chromosome 4q31.3.
GENE FUNCTION
The WDR45 gene has an important role in the autophagy pathway, which is
the major intracellular degradation system by which cytoplasmic
materials are packaged into autophagosomes and delivered to lysosomes
for degradation (summary by Saitsu et al., 2013).
MOLECULAR GENETICS
In 20 unrelated patients with neurodegeneration with brain iron
accumulation-5 (NBIA5; 300894), Haack et al. (2012) identified 19
different de novo heterozygous or hemizygous mutations in the WDR45 gene
(see, e.g., 300526.0001-300526.0002). Most of the mutations were
truncating, but 2 were missense mutations affecting highly conserved
residues. The mutations were located throughout the coding sequence.
Initial mutations were identified by exome sequencing and all were
confirmed by Sanger sequencing. Seventeen females and 3 males were
affected, and the phenotype was similar in all. Since WDR45 is on the X
chromosome, Haack et al. (2012) concluded that the males must be somatic
mosaic for the mutation, which was demonstrated in 1 affected male.
Presumably, males with germline WDR45 mutations are nonviable. Females
may either harbor germline or somatic mutations, and several affected
females had evidence of skewed X inactivation. These factors may
contribute to disease manifestations.
Saitsu et al. (2013) identified 5 different de novo heterozygous
truncating mutations in the WDR45 gene (see, e.g.,
300526.0003-300526.0005) in 5 unrelated women with NBIA5. The initial
mutations were identified by exome sequencing of 2 patients. Patients
had delayed psychomotor development in infancy or early childhood that
remained stable until young adulthood when all patients developed
further severe motor and cognitive decline, with parkinsonism, dystonia,
extrapyramidal signs, and dementia. Most became bedridden with an
inability to care for themselves. Brain MRI showed iron accumulation in
the globus pallidus and substantia nigra. Lymphoblastoid cells from 4 of
the patients showed exclusive expression of the mutant transcript,
suggesting X inactivation of the wildtype allele. All patient cells
showed decreased levels of the mutant proteins, suggesting protein
instability. Patient cells showed impaired autophagic flux.
Immunofluorescence studies showed the accumulation of autophagic
structures in patient cells, consistent with improper autophagosome
formation. The findings suggested that impairment of autophagy
contributes to the pathogenesis of this neurodegenerative disorder.
*FIELD* AV
.0001
NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 5
WDR45, 1-BP DEL, NT1007
In 2 unrelated females with neurodegeneration with brain iron
accumulation-5 (NBIA5; 300894), Haack et al. (2012) identified a de novo
heterozygous 1-bp deletion at nucleotide 1007 of the WDR45 gene,
resulting in a frameshift and premature termination (Tyr336CysfsTer5).
.0002
NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 5
WDR45, ARG234TER
In a female with NBIA5 (300894), Haack et al. (2012) identified a de
novo heterozygous 700C-T transition in the WDR45 gene, resulting in an
arg234-to-ter (R234X) substitution.
.0003
NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 5
WDR45, 516G-C
In a 28-year-old woman with NBIA5 (300894), Saitsu et al. (2013)
identified a heterozygous de novo 516G-C transversion in the last base
of exon 8 of the WDR45 gene, resulting in a 22-bp frameshift insertion
and premature termination (Asp174ValfsTer29). The mutation was
identified by exome sequencing and was not found in several large
control exome databases. Patient lymphoblastoid cells showed exclusive
expression of the mutant transcript, suggesting X inactivation of the
wildtype allele. There were decreased levels of mutant protein,
suggesting that it is unstable and degraded. Patient cells showed
impaired autophagic flux. Immunofluorescence studies showed the
accumulation of autophagic structures in patient cells, consistent with
improper autophagosome formation.
.0004
NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 5
WDR45, 1-BP DUP, 437A
In a 40-year-old Japanese woman with NBIA5 (300894) originally reported
by Kimura et al. (2013), Saitsu et al. (2013) identified a heterozygous
de novo 1-bp duplication (437dupA) in the WDR45 gene, resulting in a
frameshift and premature termination (Leu148AlafsTer3). The mutation was
not found in several large control exome databases. There were decreased
levels of mutant protein, suggesting that it is unstable and degraded.
Patient cells showed impaired autophagic flux. Immunofluorescence
studies showed the accumulation of autophagic structures in patient
cells, consistent with improper autophagosome formation.
.0005
NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 5
WDR45, GLN213TER
In a 51-year-old woman with NBIA5 (300894), Saitsu et al. (2013)
identified a de novo heterozygous 637C-T transition in the WDR45 gene,
resulting in a gln213-to-ter (Q213X) substitution. The mutation was not
found in several large control exome databases. Patient lymphoblastoid
cells showed exclusive expression of the mutant transcript, suggesting X
inactivation of the wildtype allele. There were decreased levels of
mutant protein, suggesting that it is unstable and degraded. Patient
cells showed impaired autophagic flux. Immunofluorescence studies showed
the accumulation of autophagic structures in patient cells, consistent
with improper autophagosome formation.
*FIELD* RF
1. Haack, T. B.; Hogarth, P.; Kruer, M. C.; Gregory, A.; Wieland,
T.; Schwarzmayr, T.; Graf, E.; Sanford, L.; Meyer, E.; Kara, E.; Cuno,
S. M.; Harik, S. I.; and 21 others: Exome sequencing reveals de
novo WDR45 mutations causing a phenotypically distinct, X-linked dominant
form of NBIA. Am. J. Hum. Genet. 91: 1144-1149, 2012.
2. Kimura, Y.; Sato, N.; Sugai, K.; Maruyama, S.; Ota, M.; Kamiya,
K.; Ito, K.; Nakata, Y.; Sasaki, M.; Sugimoto, H.: MRI, MR spectroscopy,
and diffusion tensor imaging findings in patient with static encephalopathy
of childhood with neurodegeneration in adulthood (SENDA). Brain Dev. 35:
458-461, 2013.
3. Proikas-Cezanne, T.; Waddell, S.; Gaugel, A.; Frickey, T.; Lupas,
A.; Nordheim, A.: WIPI-1-alpha (WIPI49), a member of the novel 7-bladed
WIPI protein family, is aberrantly expressed in human cancer and is
linked to starvation-induced autophagy. Oncogene 23: 9314-9325,
2004.
4. Saitsu, H.; Nishimura, T.; Muramatsu, K.; Kodera, H.; Kumada, S.;
Sugai, K.; Kasai-Yoshida, E.; Sawaura, N.; Nishida, H.; Hoshino, A.;
Ryujin, F.; Yoshioka, S.; and 9 others: De novo mutations in the
autophagy gene WDR45 cause static encephalopathy of childhood with
neurodegeneration in adulthood. Nature Genet. 45: 445-449, 2013.
*FIELD* CN
Cassandra L. Kniffin - updated: 4/15/2013
*FIELD* CD
Patricia A. Hartz: 2/28/2005
*FIELD* ED
carol: 09/05/2013
carol: 4/16/2013
ckniffin: 4/15/2013
mgross: 2/28/2005
MIM
300894
*RECORD*
*FIELD* NO
300894
*FIELD* TI
#300894 NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 5; NBIA5
;;BETA-PROPELLER PROTEIN-ASSOCIATED NEURODEGENERATION; BPAN;;
read moreSTATIC ENCEPHALOPATHY OF CHILDHOOD WITH NEURODEGENERATION IN ADULTHOOD;
SENDA
*FIELD* TX
A number sign (#) is used with this entry because neurodegeneration with
brain iron accumulation-5 (NBIA5) is caused by de novo heterozygous or
hemizygous mutation in the WDR45 (300526) gene on chromosome Xp11.
DESCRIPTION
NBIA5, sometimes referred to as 'static encephalopathy of childhood with
neurodegeneration in adulthood (SENDA),' is an X-linked
neurodegenerative disorder characterized by global developmental delay
in early childhood that is essentially static, with slow motor and
cognitive gains until adolescence or early adulthood. In young
adulthood, affected individuals develop progressive dystonia,
parkinsonism, extrapyramidal signs, and dementia resulting in severe
disability. Brain MRI shows iron accumulation in the globus pallidus and
substantia nigra. A characteristic finding is T1-weighted hyperintensity
surrounding a central band of hypointensity in the substantia nigra.
Cerebral and cerebellar atrophy are also observed (summary by Haack et
al., 2012 and Saitsu et al., 2013).
For a general phenotypic description and a discussion of genetic
heterogeneity of NBIA, see NBIA1 (234200).
CLINICAL FEATURES
In a review of the clinical and genetic features of various forms of
NBIA, Gregory et al. (2009) identified a group of 7 patients with a
distinctive form of idiopathic NBIA in whom no mutations had been found.
These individuals had global developmental delay or frank mental
retardation in infancy or early childhood, which remained static for at
least 2 decades. Then, during their late twenties to thirties, they
developed parkinsonism followed by rapid progression with dystonia,
dysarthria, spastic paraparesis, and loss of ambulation. Many responded
well to levodopa therapy. Neuroimaging showed abnormal iron accumulation
in the substantia nigra in addition to the globus pallidus.
In reviews of NBIA, Schneider and Bhatia (2012) and Schneider and Bhatia
(2013) stated that SENDA is characterized by early-onset mental
retardation and spastic paraplegia that remains static until the
twenties or thirties when it progresses to parkinsonism and dystonia.
Variable features include eye movement abnormalities, sleep disorders,
frontal release signs, and dysautonomia. Brain MRI shows brain iron
accumulation in the globus pallidus and substantia nigra.
Kimura et al. (2013) reported a 39-year-old Japanese woman with SENDA.
She had psychomotor retardation since childhood that remained
nonprogressive until age 30 when she developed severe dystonia and gait
disturbance, resulting in her being bedridden within 3 years. Brain MRI
at age 33 years showed marked hypointensity in the globus pallidus and
substantia nigra on T2-weighted imaging, consistent with iron
deposition. T1-weighted imaging showed hyperintensity of the substantia
nigra with a central band of hypointensity. Mild cerebral and cerebellar
atrophy was also present. Treatment with levodopa resulted in mild
clinical improvement. Reexamination at age 39 years showed clinical
progression and progression of the lesions on brain imaging. Magnetic
resonance spectroscopy showed increased N-acetylaspartate in the globus
pallidus and substantia nigra, suggesting neuronal loss in these
regions. Increased myoinositol suggested gliosis.
Saitsu et al. (2013) reported 5 unrelated women with NBIA5, including
the patient reported by Kimura et al. (2013). The patients ranged in age
from 28 to 51 years, and all showed a similar disease course with
delayed psychomotor development in infancy or early childhood, very poor
or no speech development, and nonprogressive cognitive dysfunction in
childhood. More variable features early in life included seizures,
broad-based gait, hand flapping, and spasticity. The phenotype was
stable in each until the early twenties or thirties when the patients
developed parkinsonism, rigidity, tremor, further cognitive decline,
dystonia, and dysphagia. All became bedridden or wheelchair-dependent
and fully dependent for all activities of daily living, and some showed
aggressive behavior. Brain MRI as young adults showed iron deposition in
the globus pallidus and substantia nigra, with a characteristic
hyperintensity of the substantia nigra with a central band of
hypointensity on T1-weighted images. Cerebral and cerebellar atrophy
were also apparent. Two patients had atrophy of the retinal nerve.
- Neuroradiologic Findings
In a review of the neuroradiologic findings of various forms of NBIA,
Kruer et al. (2012) noted that SENDA is characterized by iron deposition
in the globus pallidus and substantia nigra, as well as T1
hyperintensity of the substantia nigra with a central band of T1
hypointensity. Significant cerebral and milder cerebellar atrophy also
occur.
INHERITANCE
NBIA5 does not follow a pattern of inheritance typical of an X-linked
disorder, although molecular analysis has shown it to be X-linked
dominant. Haack et al. (2012) reported 17 affected females and 3
affected males who exhibited a homogeneous phenotype. Since WDR45 is on
the X chromosome, Haack et al. (2012) concluded that the males must be
somatic mosaic for the mutation, which was demonstrated in 1 affected
male. Presumably, males with germline WDR45 mutations are nonviable.
Females may either harbor germline or somatic mutations, and several
affected females had evidence of skewed X-inactivation. All of these
factors may contribute to disease manifestations.
MOLECULAR GENETICS
In 20 unrelated patients with neurodegeneration with brain iron
accumulation-5, Haack et al. (2012) identified 19 different hemizygous
or heterozygous de novo mutations in the WDR45 gene (see, e.g.,
300526.0001-300526.0002). Most of the mutations were truncating, but 2
were missense mutations affecting highly conserved residues. The
mutations were located throughout the coding sequence. Initial mutations
were identified by exome sequencing and all were confirmed by Sanger
sequencing. There were 17 females and 3 males.
Saitsu et al. (2013) identified 5 different de novo heterozygous
truncating mutations in the WDR45 gene (see, e.g.,
300526.0003-300526.0005) in 5 unrelated women with NBIA5. The initial
mutations were identified by exome sequencing of 2 patients.
Lymphoblastoid cells from 4 of the patients showed exclusive expression
of the mutant transcript, suggesting X inactivation of the wildtype
allele. All patient cells showed decreased levels of the mutant
proteins, suggesting protein instability. Patient cells showed impaired
autophagic flux. Immunofluorescence studies showed the accumulation of
autophagic structures in patient cells, consistent with improper
autophagosome formation. The findings suggested that impairment of
autophagy contributes to the pathogenesis of this neurodegenerative
disorder.
NOMENCLATURE
Haack et al. (2012) recommended that the term 'SENDA' not be used for
this disorder, and proposed the term 'beta-propeller protein-associated
neurodegeneration (BPAN).' The disorder caused by WDR45 mutation is here
designated 'neurodegeneration with brain iron accumulation-5 (NBIA5).'
*FIELD* RF
1. Gregory, A.; Polster, B. J.; Hayflick, S. J.: Clinical and genetic
delineation of neurodegeneration with brain iron accumulation. J.
Med. Genet. 46: 73-80, 2009.
2. Haack, T. B.; Hogarth, P.; Kruer, M. C.; Gregory, A.; Wieland,
T.; Schwarzmayr, T.; Graf, E.; Sanford, L.; Meyer, E.; Kara, E.; Cuno,
S. M.; Harik, S. I.; and 21 others: Exome sequencing reveals de
novo WDR45 mutations causing a phenotypically distinct, X-linked dominant
form of NBIA. Am. J. Hum. Genet. 91: 1144-1149, 2012.
3. Kimura, Y.; Sato, N.; Sugai, K.; Maruyama, S.; Ota, M.; Kamiya,
K.; Ito, K.; Nakata, Y.; Sasaki, M.; Sugimoto, H.: MRI, MR spectroscopy,
and diffusion tensor imaging findings in patient with static encephalopathy
of childhood with neurodegeneration in adulthood (SENDA). Brain Dev. 35:
458-461, 2013.
4. Kruer, M. C.; Boddaert, N.; Schneider, S. A.; Houlden, H.; Bhatia,
K. P.; Gregory, A.; Anderson, J. C.; Rooney, W. D.; Hogarth, P.; Hayflick,
S. J.: Neuroimaging features of neurodegeneration with brain iron
accumulation. Am. J. Neuroradiol. 33: 407-414, 2012.
5. Saitsu, H.; Nishimura, T.; Muramatsu, K.; Kodera, H.; Kumada, S.;
Sugai, K.; Kasai-Yoshida, E.; Sawaura, N.; Nishida, H.; Hoshino, A.;
Ryujin, F.; Yoshioka, S.; and 9 others: De novo mutations in the
autophagy gene WDR45 cause static encephalopathy of childhood with
neurodegeneration in adulthood. Nature Genet. 45: 445-449, 2013.
6. Schneider, S. A.; Bhatia, K. P.: Excess iron harms the brain:
the syndromes of neurodegeneration with brain iron accumulation (NBIA). J.
Neural Transm. 120: 695-703, 2013.
7. Schneider, S. A.; Bhatia, K. P.: Syndromes of neurodegeneration
with brain iron accumulation. Semin. Pediat. Neurol. 19: 57-66,
2012.
*FIELD* CS
INHERITANCE:
X-linked dominant
HEAD AND NECK:
[Eyes];
Eye movement abnormalities;
Retinal nerve atrophy (in some patients)
NEUROLOGIC:
[Central nervous system];
Delayed psychomotor development;
Mental retardation;
Poor speech;
Lack of speech;
Parkinsonism;
Rigidity;
Bradykinesia;
Dystonia;
Tremor;
Extrapyramidal signs;
Spastic paraparesis;
Dementia;
Sleep disorders;
Seizures (in some patients);
Frontal release signs;
Dysautonomia;
Iron deposition in the globus pallidus and substantia nigra seen on
MRI;
T1-weighted hyperintensity surrounding a central band of hypointensity
in the substantia nigra;
Cerebral atrophy;
Cerebellar atrophy;
[Behavioral/psychiatric manifestations];
Aggressive behavior (in some patients)
MISCELLANEOUS:
De novo mutation;
Onset in infancy or early childhood;
Disorder is static for first 2 decades and then shows progression
of movement disorders and further cognitive decline;
Affected males are somatic mosaic for mutations;
Motor symptoms show mild clinical improvement with levodopa treatment;
Patients are severely disabled as adults
MOLECULAR BASIS:
Caused by mutation in the WD repeat-containing protein 45 gene (WDR45,
300526.0001)
*FIELD* CD
Cassandra L. Kniffin: 4/15/2013
*FIELD* ED
joanna: 04/17/2013
ckniffin: 4/15/2013
*FIELD* CD
Cassandra L. Kniffin: 4/15/2013
*FIELD* ED
carol: 04/16/2013
ckniffin: 4/15/2013
*RECORD*
*FIELD* NO
300894
*FIELD* TI
#300894 NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 5; NBIA5
;;BETA-PROPELLER PROTEIN-ASSOCIATED NEURODEGENERATION; BPAN;;
read moreSTATIC ENCEPHALOPATHY OF CHILDHOOD WITH NEURODEGENERATION IN ADULTHOOD;
SENDA
*FIELD* TX
A number sign (#) is used with this entry because neurodegeneration with
brain iron accumulation-5 (NBIA5) is caused by de novo heterozygous or
hemizygous mutation in the WDR45 (300526) gene on chromosome Xp11.
DESCRIPTION
NBIA5, sometimes referred to as 'static encephalopathy of childhood with
neurodegeneration in adulthood (SENDA),' is an X-linked
neurodegenerative disorder characterized by global developmental delay
in early childhood that is essentially static, with slow motor and
cognitive gains until adolescence or early adulthood. In young
adulthood, affected individuals develop progressive dystonia,
parkinsonism, extrapyramidal signs, and dementia resulting in severe
disability. Brain MRI shows iron accumulation in the globus pallidus and
substantia nigra. A characteristic finding is T1-weighted hyperintensity
surrounding a central band of hypointensity in the substantia nigra.
Cerebral and cerebellar atrophy are also observed (summary by Haack et
al., 2012 and Saitsu et al., 2013).
For a general phenotypic description and a discussion of genetic
heterogeneity of NBIA, see NBIA1 (234200).
CLINICAL FEATURES
In a review of the clinical and genetic features of various forms of
NBIA, Gregory et al. (2009) identified a group of 7 patients with a
distinctive form of idiopathic NBIA in whom no mutations had been found.
These individuals had global developmental delay or frank mental
retardation in infancy or early childhood, which remained static for at
least 2 decades. Then, during their late twenties to thirties, they
developed parkinsonism followed by rapid progression with dystonia,
dysarthria, spastic paraparesis, and loss of ambulation. Many responded
well to levodopa therapy. Neuroimaging showed abnormal iron accumulation
in the substantia nigra in addition to the globus pallidus.
In reviews of NBIA, Schneider and Bhatia (2012) and Schneider and Bhatia
(2013) stated that SENDA is characterized by early-onset mental
retardation and spastic paraplegia that remains static until the
twenties or thirties when it progresses to parkinsonism and dystonia.
Variable features include eye movement abnormalities, sleep disorders,
frontal release signs, and dysautonomia. Brain MRI shows brain iron
accumulation in the globus pallidus and substantia nigra.
Kimura et al. (2013) reported a 39-year-old Japanese woman with SENDA.
She had psychomotor retardation since childhood that remained
nonprogressive until age 30 when she developed severe dystonia and gait
disturbance, resulting in her being bedridden within 3 years. Brain MRI
at age 33 years showed marked hypointensity in the globus pallidus and
substantia nigra on T2-weighted imaging, consistent with iron
deposition. T1-weighted imaging showed hyperintensity of the substantia
nigra with a central band of hypointensity. Mild cerebral and cerebellar
atrophy was also present. Treatment with levodopa resulted in mild
clinical improvement. Reexamination at age 39 years showed clinical
progression and progression of the lesions on brain imaging. Magnetic
resonance spectroscopy showed increased N-acetylaspartate in the globus
pallidus and substantia nigra, suggesting neuronal loss in these
regions. Increased myoinositol suggested gliosis.
Saitsu et al. (2013) reported 5 unrelated women with NBIA5, including
the patient reported by Kimura et al. (2013). The patients ranged in age
from 28 to 51 years, and all showed a similar disease course with
delayed psychomotor development in infancy or early childhood, very poor
or no speech development, and nonprogressive cognitive dysfunction in
childhood. More variable features early in life included seizures,
broad-based gait, hand flapping, and spasticity. The phenotype was
stable in each until the early twenties or thirties when the patients
developed parkinsonism, rigidity, tremor, further cognitive decline,
dystonia, and dysphagia. All became bedridden or wheelchair-dependent
and fully dependent for all activities of daily living, and some showed
aggressive behavior. Brain MRI as young adults showed iron deposition in
the globus pallidus and substantia nigra, with a characteristic
hyperintensity of the substantia nigra with a central band of
hypointensity on T1-weighted images. Cerebral and cerebellar atrophy
were also apparent. Two patients had atrophy of the retinal nerve.
- Neuroradiologic Findings
In a review of the neuroradiologic findings of various forms of NBIA,
Kruer et al. (2012) noted that SENDA is characterized by iron deposition
in the globus pallidus and substantia nigra, as well as T1
hyperintensity of the substantia nigra with a central band of T1
hypointensity. Significant cerebral and milder cerebellar atrophy also
occur.
INHERITANCE
NBIA5 does not follow a pattern of inheritance typical of an X-linked
disorder, although molecular analysis has shown it to be X-linked
dominant. Haack et al. (2012) reported 17 affected females and 3
affected males who exhibited a homogeneous phenotype. Since WDR45 is on
the X chromosome, Haack et al. (2012) concluded that the males must be
somatic mosaic for the mutation, which was demonstrated in 1 affected
male. Presumably, males with germline WDR45 mutations are nonviable.
Females may either harbor germline or somatic mutations, and several
affected females had evidence of skewed X-inactivation. All of these
factors may contribute to disease manifestations.
MOLECULAR GENETICS
In 20 unrelated patients with neurodegeneration with brain iron
accumulation-5, Haack et al. (2012) identified 19 different hemizygous
or heterozygous de novo mutations in the WDR45 gene (see, e.g.,
300526.0001-300526.0002). Most of the mutations were truncating, but 2
were missense mutations affecting highly conserved residues. The
mutations were located throughout the coding sequence. Initial mutations
were identified by exome sequencing and all were confirmed by Sanger
sequencing. There were 17 females and 3 males.
Saitsu et al. (2013) identified 5 different de novo heterozygous
truncating mutations in the WDR45 gene (see, e.g.,
300526.0003-300526.0005) in 5 unrelated women with NBIA5. The initial
mutations were identified by exome sequencing of 2 patients.
Lymphoblastoid cells from 4 of the patients showed exclusive expression
of the mutant transcript, suggesting X inactivation of the wildtype
allele. All patient cells showed decreased levels of the mutant
proteins, suggesting protein instability. Patient cells showed impaired
autophagic flux. Immunofluorescence studies showed the accumulation of
autophagic structures in patient cells, consistent with improper
autophagosome formation. The findings suggested that impairment of
autophagy contributes to the pathogenesis of this neurodegenerative
disorder.
NOMENCLATURE
Haack et al. (2012) recommended that the term 'SENDA' not be used for
this disorder, and proposed the term 'beta-propeller protein-associated
neurodegeneration (BPAN).' The disorder caused by WDR45 mutation is here
designated 'neurodegeneration with brain iron accumulation-5 (NBIA5).'
*FIELD* RF
1. Gregory, A.; Polster, B. J.; Hayflick, S. J.: Clinical and genetic
delineation of neurodegeneration with brain iron accumulation. J.
Med. Genet. 46: 73-80, 2009.
2. Haack, T. B.; Hogarth, P.; Kruer, M. C.; Gregory, A.; Wieland,
T.; Schwarzmayr, T.; Graf, E.; Sanford, L.; Meyer, E.; Kara, E.; Cuno,
S. M.; Harik, S. I.; and 21 others: Exome sequencing reveals de
novo WDR45 mutations causing a phenotypically distinct, X-linked dominant
form of NBIA. Am. J. Hum. Genet. 91: 1144-1149, 2012.
3. Kimura, Y.; Sato, N.; Sugai, K.; Maruyama, S.; Ota, M.; Kamiya,
K.; Ito, K.; Nakata, Y.; Sasaki, M.; Sugimoto, H.: MRI, MR spectroscopy,
and diffusion tensor imaging findings in patient with static encephalopathy
of childhood with neurodegeneration in adulthood (SENDA). Brain Dev. 35:
458-461, 2013.
4. Kruer, M. C.; Boddaert, N.; Schneider, S. A.; Houlden, H.; Bhatia,
K. P.; Gregory, A.; Anderson, J. C.; Rooney, W. D.; Hogarth, P.; Hayflick,
S. J.: Neuroimaging features of neurodegeneration with brain iron
accumulation. Am. J. Neuroradiol. 33: 407-414, 2012.
5. Saitsu, H.; Nishimura, T.; Muramatsu, K.; Kodera, H.; Kumada, S.;
Sugai, K.; Kasai-Yoshida, E.; Sawaura, N.; Nishida, H.; Hoshino, A.;
Ryujin, F.; Yoshioka, S.; and 9 others: De novo mutations in the
autophagy gene WDR45 cause static encephalopathy of childhood with
neurodegeneration in adulthood. Nature Genet. 45: 445-449, 2013.
6. Schneider, S. A.; Bhatia, K. P.: Excess iron harms the brain:
the syndromes of neurodegeneration with brain iron accumulation (NBIA). J.
Neural Transm. 120: 695-703, 2013.
7. Schneider, S. A.; Bhatia, K. P.: Syndromes of neurodegeneration
with brain iron accumulation. Semin. Pediat. Neurol. 19: 57-66,
2012.
*FIELD* CS
INHERITANCE:
X-linked dominant
HEAD AND NECK:
[Eyes];
Eye movement abnormalities;
Retinal nerve atrophy (in some patients)
NEUROLOGIC:
[Central nervous system];
Delayed psychomotor development;
Mental retardation;
Poor speech;
Lack of speech;
Parkinsonism;
Rigidity;
Bradykinesia;
Dystonia;
Tremor;
Extrapyramidal signs;
Spastic paraparesis;
Dementia;
Sleep disorders;
Seizures (in some patients);
Frontal release signs;
Dysautonomia;
Iron deposition in the globus pallidus and substantia nigra seen on
MRI;
T1-weighted hyperintensity surrounding a central band of hypointensity
in the substantia nigra;
Cerebral atrophy;
Cerebellar atrophy;
[Behavioral/psychiatric manifestations];
Aggressive behavior (in some patients)
MISCELLANEOUS:
De novo mutation;
Onset in infancy or early childhood;
Disorder is static for first 2 decades and then shows progression
of movement disorders and further cognitive decline;
Affected males are somatic mosaic for mutations;
Motor symptoms show mild clinical improvement with levodopa treatment;
Patients are severely disabled as adults
MOLECULAR BASIS:
Caused by mutation in the WD repeat-containing protein 45 gene (WDR45,
300526.0001)
*FIELD* CD
Cassandra L. Kniffin: 4/15/2013
*FIELD* ED
joanna: 04/17/2013
ckniffin: 4/15/2013
*FIELD* CD
Cassandra L. Kniffin: 4/15/2013
*FIELD* ED
carol: 04/16/2013
ckniffin: 4/15/2013