O95409 (ZIC2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Zinc finger protein ZIC 2

Alternative name(s):
Zinc finger protein of the cerebellum 2

Gene names

Name:

ZIC2

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	532 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Acts as a transcriptional activator or repressor. Plays important roles in the early stage of organogenesis of the CNS. Activates the transcription of the serotonin transporter SERT in uncrossed ipsilateral retinal ganglion cells (iRGCs) to refine eye-specific projections in primary visual targets. Its transcriptional activity is repressed by MDFIC. Involved in the formation of the ipsilateral retinal projection at the optic chiasm midline. Drives the expression of EPHB1 on ipsilaterally projecting growth cones. Binds to the minimal GLI-consensus sequence 5'-TGGGTGGTC-3'. Associates to the basal SERT promoter region from ventrotemporal retinal segments of retinal embryos.
Subunit structure	Interacts with RNF180. Interacts (via the C2H2-type domains 3, 4 and 5) with MDFIC (via the C2H2-type domains 3, 4 and 5); the interaction reduces its transcriptional activity. Interacts with DHX9 By similarity.
Subcellular location	Nucleus. Cytoplasm By similarity. Note: Localizes in the cytoplasm in presence of MDFIC overexpression. Both phosphorylated and unphosphorylated forms are localized in the nucleus By similarity.
Domain	The C2H2-type 3, 4 and 5 zinc finger domains are necessary for transcription activation By similarity.
Post-translational modification	Phosphorylated. Ubiquitinated by RNF180, leading to its degradation.
Polymorphism	The poly-His region between amino acids 231-239 of ZIC2 is polymorphic and the number of His can vary from 8 to 12.
Involvement in disease	Defects in ZIC2 are a cause of holoprosencephaly type 5 (HPE5) [MIM:609637]. A structural anomaly of the brain, in which the developing forebrain fails to correctly separate into right and left hemispheres. Holoprosencephaly is genetically heterogeneous and associated with several distinct facies and phenotypic variability. Although severe facial anomalies are common in HPE, patients with ZINC2 mutations have relatively normal faces. Ref.1 Ref.4 Ref.5 Ref.6 Ref.7
Sequence similarities	Belongs to the GLI C2H2-type zinc-finger protein family. Contains 5 C2H2-type zinc fingers.

Ontologies

Keywords
Biological process	Differentiation Neurogenesis Transcription Transcription regulation
Cellular component	Cytoplasm Nucleus
Coding sequence diversity	Polymorphism
Disease	Disease mutation Holoprosencephaly
Domain	Repeat Zinc-finger
Ligand	DNA-binding Metal-binding Zinc
Molecular function	Activator Developmental protein Repressor
PTM	Phosphoprotein Ubl conjugation
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological process	brain development Traceable author statement. Source: ProtInc negative regulation of transcription, DNA-dependent Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of sequence-specific DNA binding transcription factor activity Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of transcription, DNA-dependent Inferred from sequence or structural similarity. Source: UniProtKB transcription, DNA-dependent Inferred from electronic annotation. Source: UniProtKB-KW visual perception Inferred from sequence or structural similarity. Source: UniProtKB
Cellular component	cytoplasm Inferred from sequence or structural similarity. Source: UniProtKB nucleus Inferred from sequence or structural similarity. Source: UniProtKB
Molecular function	chromatin DNA binding Inferred from sequence or structural similarity. Source: UniProtKB sequence-specific DNA binding transcription factor activity Inferred from sequence or structural similarity. Source: UniProtKB zinc ion binding Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 532	532	Zinc finger protein ZIC 2		PRO_0000047247
Regions
	Zinc finger	256 – 291	36	C2H2-type 1; atypical
	Zinc finger	300 – 327	28	C2H2-type 2; atypical
	Zinc finger	333 – 357	25	C2H2-type 3
	Zinc finger	363 – 387	25	C2H2-type 4
	Zinc finger	393 – 415	23	C2H2-type 5
	Region	100 – 255	156	Necessary for interaction with MDFIC and transcriptional activation or repression By similarity
	Compositional bias	20 – 23	4	Poly-His
	Compositional bias	25 – 33	9	Poly-Ala
	Compositional bias	89 – 97	9	Poly-Ala
	Compositional bias	226 – 230	5	Poly-Ala
	Compositional bias	231 – 239	9	Poly-His
	Compositional bias	456 – 470	15	Poly-Ala
	Compositional bias	490 – 508	19	Poly-Gly
Amino acid modifications
	Modified residue	191	1	Phosphoserine By similarity
	Modified residue	199	1	Phosphoserine By similarity
Natural variations
	Natural variant	36	1	Q → P in HPE5; 2-fold increase in luciferase activity. Ref.5 Ref.6		VAR_023793
	Natural variant	37	1	D → N in HPE5. Ref.7		VAR_058592
	Natural variant	128	1	D → N in HPE5. Ref.7		VAR_058593
	Natural variant	152	1	D → F in HPE5; requires 2 nucleotide substitutions; 50% reduction of luciferase activity. Ref.4 Ref.5 Ref.6		VAR_023794
	Natural variant	239	1	H → HH. Ref.5		VAR_023795
	Natural variant	239	1	Missing. Ref.5		VAR_023796
	Natural variant	272	1	S → N in HPE5. Ref.7		VAR_058594
	Natural variant	286	1	H → L in HPE5. Ref.7		VAR_058595
	Natural variant	286	1	H → Q in HPE5. Ref.7		VAR_058596
	Natural variant	286	1	H → Y in HPE5. Ref.7		VAR_058597
	Natural variant	291	1	H → Y in HPE5. Ref.7		VAR_058598
	Natural variant	304	1	W → R in HPE5. Ref.7		VAR_058599
	Natural variant	314	1	F → C in HPE5. Ref.7		VAR_058600
	Natural variant	325	1	R → L in HPE5. Ref.7		VAR_058601
	Natural variant	325	1	R → S in HPE5. Ref.7		VAR_058602
	Natural variant	327	1	H → Y in HPE5. Ref.7		VAR_058603
	Natural variant	335	1	C → F in HPE5. Ref.7		VAR_058604
	Natural variant	373	1	R → P in HPE5. Ref.7		VAR_058605
	Natural variant	402	1	Y → N in HPE5. Ref.7		VAR_058606
	Natural variant	403	1	T → K in HPE5. Ref.7		VAR_058607
	Natural variant	404	1	H → R in HPE5. Ref.7		VAR_058608
	Natural variant	409	1	R → W in HPE5. Ref.7		VAR_058609
	Natural variant	415	1	H → Q in HPE5. Ref.7		VAR_058610
	Natural variant	470	1	A → AAAAAAAAAAA in HPE5; near-complete loss of luciferase activity.		VAR_008856
Experimental info
	Sequence conflict	124 – 128	5	RGFGD → ARLPGT in AAC96325. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	O95409 [UniParc]. Last modified April 16, 2002. Version 2. Checksum: BA3E6455DAF97EAC	FASTA	532	55,006
	10 20 30 40 50 60 MLLDAGPQFP AIGVGSFARH HHHSAAAAAA AAAEMQDREL SLAAAQNGFV DSAAAHMGAF 70 80 90 100 110 120 KLNPGAHELS PGQSSAFTSQ GPGAYPGSAA AAAAAAALGP HAAHVGSYSG PPFNSTRDFL 130 140 150 160 170 180 FRSRGFGDSA PGGGQHGLFG PGAGGLHHAH SDAQGHLLFP GLPEQHGPHG SQNVLNGQMR 190 200 210 220 230 240 LGLPGEVFGR SEQYRQVASP RTDPYSAAQL HNQYGPMNMN MGMNMAAAAA HHHHHHHHHP 250 260 270 280 290 300 GAFFRYMRQQ CIKQELICKW IDPEQLSNPK KSCNKTFSTM HELVTHVSVE HVGGPEQSNH 310 320 330 340 350 360 VCFWEECPRE GKPFKAKYKL VNHIRVHTGE KPFPCPFPGC GKVFARSENL KIHKRTHTGE 370 380 390 400 410 420 KPFQCEFEGC DRRFANSSDR KKHMHVHTSD KPYLCKMCDK SYTHPSSLRK HMKVHESSPQ 430 440 450 460 470 480 GSESSPAASS GYESSTPPGL VSPSAEPQSS SNLSPAAAAA AAAAAAAAAA VSAVHRGGGS 490 500 510 520 530 GSGGAGGGSG GGSGSGGGGG GAGGGGGGSS GGGSGTAGGH SGLSSNFNEW YV

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Holoprosencephaly due to mutations in ZIC2, a homologue of Drosophila odd-paired." Brown S.A., Warburton D., Brown L.Y., Yu C.Y., Roeder E.R., Stengel-Rutkowski S., Hennekam R.C.M., Muenke M. Nat. Genet. 20:180-183(1998) [PubMed: 9771712] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], CHARACTERIZATION OF VARIANT HPE5 POLY-ALA INS.
[2]	"ZIC2 and Sp3 repress Sp1-induced activation of the human D1A dopamine receptor gene." Yang Y., Hwang C.K., Junn E., Lee G., Mouradian M.M. J. Biol. Chem. 275:38863-38869(2000) [PubMed: 10984499] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Brain.
[3]	"The DNA sequence and analysis of human chromosome 13." Dunham A., Matthews L.H., Burton J., Ashurst J.L., Howe K.L., Ashcroft K.J., Beare D.M., Burford D.C., Hunt S.E., Griffiths-Jones S., Jones M.C., Keenan S.J., Oliver K., Scott C.E., Ainscough R., Almeida J.P., Ambrose K.D., Andrews D.T. , Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., Bannerjee R., Barlow K.F., Bates K., Beasley H., Bird C.P., Bray-Allen S., Brown A.J., Brown J.Y., Burrill W., Carder C., Carter N.P., Chapman J.C., Clamp M.E., Clark S.Y., Clarke G., Clee C.M., Clegg S.C., Cobley V., Collins J.E., Corby N., Coville G.J., Deloukas P., Dhami P., Dunham I., Dunn M., Earthrowl M.E., Ellington A.G., Faulkner L., Frankish A.G., Frankland J., French L., Garner P., Garnett J., Gilbert J.G.R., Gilson C.J., Ghori J., Grafham D.V., Gribble S.M., Griffiths C., Hall R.E., Hammond S., Harley J.L., Hart E.A., Heath P.D., Howden P.J., Huckle E.J., Hunt P.J., Hunt A.R., Johnson C., Johnson D., Kay M., Kimberley A.M., King A., Laird G.K., Langford C.J., Lawlor S., Leongamornlert D.A., Lloyd D.M., Lloyd C., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M., McLaren S.J., McMurray A., Milne S., Moore M.J.F., Nickerson T., Palmer S.A., Pearce A.V., Peck A.I., Pelan S., Phillimore B., Porter K.M., Rice C.M., Searle S., Sehra H.K., Shownkeen R., Skuce C.D., Smith M., Steward C.A., Sycamore N., Tester J., Thomas D.W., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., West A.P., Whitehead S.L., Willey D.L., Wilming L., Wray P.W., Wright M.W., Young L., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Beck S., Bentley D.R., Rogers J., Ross M.T. Nature 428:522-528(2004) [PubMed: 15057823] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]	"Holoprosencephaly due to mutations in ZIC2: alanine tract expansion mutations may be caused by parental somatic recombination." Brown L.Y., Odent S., David V., Blayau M., Dubourg C., Apacik C., Delgado M.A., Hall B.D., Reynolds J.F., Sommer A., Wieczorek D., Brown S.A., Muenke M. Hum. Mol. Genet. 10:791-796(2001) [PubMed: 11285244] [Abstract] Cited for: VARIANTS HPE5 POLY-ALA INS AND PHE-152, POLYMORPHISM OF POLY-HIS REGION.
[5]	"Molecular screening of SHH, ZIC2, SIX3, and TGIF genes in patients with features of holoprosencephaly spectrum: mutation review and genotype-phenotype correlations." Dubourg C., Lazaro L., Pasquier L., Bendavid C., Blayau M., Le Duff F., Durou M.-R., Odent S., David V. Hum. Mutat. 24:43-51(2004) [PubMed: 15221788] [Abstract] Cited for: VARIANTS HPE5 PRO-36 AND PHE-152, VARIANTS HIS-239 INS AND HIS-239 DEL.
[6]	"In vitro analysis of partial loss-of-function ZIC2 mutations in holoprosencephaly: alanine tract expansion modulates DNA binding and transactivation." Brown L., Paraso M., Arkell R., Brown S. Hum. Mol. Genet. 14:411-420(2005) [PubMed: 15590697] [Abstract] Cited for: CHARACTERIZATION OF VARIANTS HPE5 PRO-36; PHE-152 AND POLY-ALA INS.
[7]	"The full spectrum of holoprosencephaly-associated mutations within the ZIC2 gene in humans predicts loss-of-function as the predominant disease mechanism." Roessler E., Lacbawan F., Dubourg C., Paulussen A., Herbergs J., Hehr U., Bendavid C., Zhou N., Ouspenskaia M., Bale S., Odent S., David V., Muenke M. Hum. Mutat. 30:E541-E554(2009) [PubMed: 19177455] [Abstract] Cited for: VARIANTS HPE5 ASN-37; ASN-128; ASN-272; LEU-286; GLN-286; TYR-286; TYR-291; ARG-304; CYS-314; SER-325; LEU-325; TYR-327; PHE-335; PRO-373; ASN-402; LYS-403; ARG-404; TRP-409 AND GLN-415.
+	Additional computationally mapped references.

Web resources

GeneReviews

Cross-references

Sequence databases
EMBL GenBank DDBJ	AF104902 mRNA. Translation: AAC96325.1. AF193855 mRNA. Translation: AAG28409.1. AL355338 Genomic DNA. Translation: CAH70367.1.
IPI	IPI00030652.
RefSeq	NP_009060.2. NM_007129.3.
UniGene	Hs.653700.
3D structure databases
ProteinModelPortal	O95409.
SMR	O95409. Positions 250-418.
ModBase	Search...
Protein-protein interaction databases
MINT	MINT-2798893.
STRING	O95409.
PTM databases
PhosphoSite	O95409.
Proteomic databases
PeptideAtlas	O95409.
PRIDE	O95409.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000376335; ENSP00000365514; ENSG00000043355.
GeneID	7546.
KEGG	hsa:7546.
UCSC	uc001von.1. human.
Organism-specific databases
CTD	7546.
GeneCards	GC13P100634.
HGNC	HGNC:12873. ZIC2.
MIM	603073. gene. 609637. phenotype.
neXtProt	NX_O95409.
Orphanet	93925. Alobar holoprosencephaly. 93924. Lobar holoprosencephaly. 93926. Midline interhemispheric variant of holoprosencephaly.
PharmGKB	PA37462.
GenAtlas	Search...
Phylogenomic databases
eggNOG	prNOG19700.
GeneTree	ENSGT00600000084058.
HOGENOM	HBG506538.
HOVERGEN	HBG007135.
InParanoid	O95409.
OMA	QGHILFP.
PhylomeDB	O95409.
Gene expression databases
ArrayExpress	O95409.
Bgee	O95409.
CleanEx	HS_ZIC2.
Genevestigator	O95409.
GermOnline	ENSG00000043355. Homo sapiens.
Family and domain databases
InterPro	IPR007087. Znf_C2H2. IPR015880. Znf_C2H2-like. IPR013087. Znf_C2H2/integrase_DNA-bd. [Graphical view]
Gene3D	G3DSA:3.30.160.60. Znf_C2H2/integrase_DNA-bd. 4 hits.
KO	K06235.
Pfam	PF00096. zf-C2H2. 5 hits. [Graphical view]
SMART	SM00355. ZnF_C2H2. 5 hits. [Graphical view]
PROSITE	PS00028. ZINC_FINGER_C2H2_1. 3 hits. PS50157. ZINC_FINGER_C2H2_2. 4 hits. [Graphical view]
ProtoNet	Search...
Other
NextBio	29525.
SOURCE	Search...

Entry information

Entry name

ZIC2_HUMAN

Accession

Primary (citable) accession number: O95409
Secondary accession number(s): Q5VYA9, Q9H309

Entry history

Integrated into UniProtKB/Swiss-Prot:	May 30, 2000
Last sequence update:	April 16, 2002
Last modified:	January 25, 2012
This is version 112 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.