Full text data of WNT3
WNT3
(INT4)
[Confidence: low (only semi-automatic identification from reviews)]
Proto-oncogene Wnt-3 (Proto-oncogene Int-4 homolog; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Proto-oncogene Wnt-3 (Proto-oncogene Int-4 homolog; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
P56703
ID WNT3_HUMAN Reviewed; 355 AA.
AC P56703; Q2M237; Q9H1J9;
DT 15-JUL-1999, integrated into UniProtKB/Swiss-Prot.
read moreDT 20-JUN-2001, sequence version 2.
DT 22-JAN-2014, entry version 118.
DE RecName: Full=Proto-oncogene Wnt-3;
DE AltName: Full=Proto-oncogene Int-4 homolog;
DE Flags: Precursor;
GN Name=WNT3; Synonyms=INT4;
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].
RA Testa T.T., Mossakowska D.E., Carter P.S., Hu E., Zhu Y.,
RA Kelsell D.P., Murdock P.R., Herrity N.C., Lewis C.J., Cross D.A.,
RA Culbert A.A., Reith A.D., Barnes M.R.;
RT "Molecular cloning and characterization of six novel human WNT
RT genes.";
RL Submitted (AUG-2000) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=11604997;
RA Katoh M.;
RT "Molecular cloning and characterization of human WNT3.";
RL Int. J. Oncol. 19:977-982(2001).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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 [MRNA] OF 1-333.
RX PubMed=8244403; DOI=10.1006/geno.1993.1412;
RA Roelink H., Wang J., Black D.M., Solomon E., Nusse R.;
RT "Molecular cloning and chromosomal localization to 17q21 of the human
RT WNT3 gene.";
RL Genomics 17:790-792(1993).
RN [5]
RP INVOLVEMENT IN ARTTRA.
RX PubMed=14872406; DOI=10.1086/382196;
RA Niemann S., Zhao C., Pascu F., Stahl U., Aulepp U., Niswander L.,
RA Weber J.L., Mueller U.;
RT "Homozygous WNT3 mutation causes tetra-amelia in a large
RT consanguineous family.";
RL Am. J. Hum. Genet. 74:558-563(2004).
CC -!- FUNCTION: Ligand for members of the frizzled family of seven
CC transmembrane receptors. Wnt-3 and Wnt-3a play distinct roles in
CC cell-cell signaling during morphogenesis of the developing neural
CC tube (By similarity).
CC -!- SUBUNIT: Interacts with PORCN (By similarity). Interacts with WLS
CC (By similarity).
CC -!- SUBCELLULAR LOCATION: Secreted, extracellular space, extracellular
CC matrix.
CC -!- PTM: Palmitoylation at Ser-212 is required for efficient binding
CC to frizzled receptors. It is also required for subsequent
CC palmitoylation at Cys-80. Palmitoylation is necessary for proper
CC trafficking to cell surface (By similarity).
CC -!- DISEASE: Tetraamelia, autosomal recessive (ARTTRA) [MIM:273395]: A
CC rare human genetic disorder characterized by complete absence of
CC all four limbs and other anomalies such as craniofacial, nervous
CC system, pulmonary, skeletal and urogenital defects. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- SIMILARITY: Belongs to the Wnt family.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/WNT3";
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; AY009397; AAG38657.1; -; mRNA.
DR EMBL; AB067628; BAB70502.1; -; mRNA.
DR EMBL; BC112116; AAI12117.1; -; mRNA.
DR EMBL; BC112118; AAI12119.1; -; mRNA.
DR EMBL; BC114219; AAI14220.1; -; mRNA.
DR PIR; A47536; A47536.
DR RefSeq; NP_110380.1; NM_030753.4.
DR UniGene; Hs.445884; -.
DR UniGene; Hs.745220; -.
DR ProteinModelPortal; P56703; -.
DR SMR; P56703; 60-354.
DR IntAct; P56703; 1.
DR STRING; 9606.ENSP00000225512; -.
DR BindingDB; P56703; -.
DR ChEMBL; CHEMBL6079; -.
DR PhosphoSite; P56703; -.
DR DMDM; 14424477; -.
DR PaxDb; P56703; -.
DR PRIDE; P56703; -.
DR DNASU; 7473; -.
DR Ensembl; ENST00000225512; ENSP00000225512; ENSG00000108379.
DR GeneID; 7473; -.
DR KEGG; hsa:7473; -.
DR UCSC; uc002ikv.3; human.
DR CTD; 7473; -.
DR GeneCards; GC17M044839; -.
DR HGNC; HGNC:12782; WNT3.
DR MIM; 165330; gene.
DR MIM; 273395; phenotype.
DR neXtProt; NX_P56703; -.
DR Orphanet; 3301; Tetraamelia - multiple malformations.
DR PharmGKB; PA37383; -.
DR eggNOG; NOG284879; -.
DR HOGENOM; HOG000039529; -.
DR HOVERGEN; HBG001595; -.
DR InParanoid; P56703; -.
DR KO; K00312; -.
DR OMA; MCGCDSH; -.
DR OrthoDB; EOG7C8GJ8; -.
DR PhylomeDB; P56703; -.
DR Reactome; REACT_111102; Signal Transduction.
DR GeneWiki; WNT3; -.
DR GenomeRNAi; 7473; -.
DR NextBio; 29272; -.
DR PRO; PR:P56703; -.
DR Bgee; P56703; -.
DR CleanEx; HS_WNT3; -.
DR Genevestigator; P56703; -.
DR GO; GO:0005788; C:endoplasmic reticulum lumen; TAS:Reactome.
DR GO; GO:0005615; C:extracellular space; TAS:BHF-UCL.
DR GO; GO:0005796; C:Golgi lumen; TAS:Reactome.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0005578; C:proteinaceous extracellular matrix; IEA:UniProtKB-SubCell.
DR GO; GO:0048018; F:receptor agonist activity; IC:BHF-UCL.
DR GO; GO:0009948; P:anterior/posterior axis specification; IEA:Ensembl.
DR GO; GO:0007411; P:axon guidance; IEA:Ensembl.
DR GO; GO:0044338; P:canonical Wnt receptor signaling pathway involved in mesenchymal stem cell differentiation; IMP:BHF-UCL.
DR GO; GO:0044339; P:canonical Wnt receptor signaling pathway involved in osteoblast differentiation; IMP:BHF-UCL.
DR GO; GO:0045165; P:cell fate commitment; IBA:RefGenome.
DR GO; GO:0000902; P:cell morphogenesis; IMP:BHF-UCL.
DR GO; GO:0071300; P:cellular response to retinoic acid; ISS:UniProtKB.
DR GO; GO:0009950; P:dorsal/ventral axis specification; IEA:Ensembl.
DR GO; GO:0035115; P:embryonic forelimb morphogenesis; IEA:Ensembl.
DR GO; GO:0035116; P:embryonic hindlimb morphogenesis; IEA:Ensembl.
DR GO; GO:0060323; P:head morphogenesis; IEA:Ensembl.
DR GO; GO:0060174; P:limb bud formation; IMP:BHF-UCL.
DR GO; GO:0061180; P:mammary gland epithelium development; IEP:UniProtKB.
DR GO; GO:0001707; P:mesoderm formation; IEA:Ensembl.
DR GO; GO:0048843; P:negative regulation of axon extension involved in axon guidance; IEA:Ensembl.
DR GO; GO:0030182; P:neuron differentiation; ISS:UniProtKB.
DR GO; GO:0048697; P:positive regulation of collateral sprouting in absence of injury; IEA:Ensembl.
DR GO; GO:0010628; P:positive regulation of gene expression; IEA:Ensembl.
DR GO; GO:0060064; P:Spemann organizer formation at the anterior end of the primitive streak; IEA:Ensembl.
DR InterPro; IPR005817; Wnt.
DR InterPro; IPR009141; Wnt3.
DR InterPro; IPR018161; Wnt_CS.
DR PANTHER; PTHR12027; PTHR12027; 1.
DR PANTHER; PTHR12027:SF18; PTHR12027:SF18; 1.
DR Pfam; PF00110; wnt; 1.
DR PRINTS; PR01843; WNT3PROTEIN.
DR PRINTS; PR01349; WNTPROTEIN.
DR SMART; SM00097; WNT1; 1.
DR PROSITE; PS00246; WNT1; 1.
PE 2: Evidence at transcript level;
KW Complete proteome; Developmental protein; Extracellular matrix;
KW Glycoprotein; Lipoprotein; Palmitate; Proto-oncogene;
KW Reference proteome; Secreted; Signal; Wnt signaling pathway.
FT SIGNAL 1 21 Potential.
FT CHAIN 22 355 Proto-oncogene Wnt-3.
FT /FTId=PRO_0000041416.
FT LIPID 80 80 S-palmitoyl cysteine (By similarity).
FT LIPID 212 212 O-palmitoyl serine; by PORCN (By
FT similarity).
FT CARBOHYD 90 90 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 301 301 N-linked (GlcNAc...) (Potential).
SQ SEQUENCE 355 AA; 39645 MW; 85D15F2C7884A64F CRC64;
MEPHLLGLLL GLLLGGTRVL AGYPIWWSLA LGQQYTSLGS QPLLCGSIPG LVPKQLRFCR
NYIEIMPSVA EGVKLGIQEC QHQFRGRRWN CTTIDDSLAI FGPVLDKATR ESAFVHAIAS
AGVAFAVTRS CAEGTSTICG CDSHHKGPPG EGWKWGGCSE DADFGVLVSR EFADARENRP
DARSAMNKHN NEAGRTTILD HMHLKCKCHG LSGSCEVKTC WWAQPDFRAI GDFLKDKYDS
ASEMVVEKHR ESRGWVETLR AKYSLFKPPT ERDLVYYENS PNFCEPNPET GSFGTRDRTC
NVTSHGIDGC DLLCCGRGHN TRTEKRKEKC HCIFHWCCYV SCQECIRIYD VHTCK
//
ID WNT3_HUMAN Reviewed; 355 AA.
AC P56703; Q2M237; Q9H1J9;
DT 15-JUL-1999, integrated into UniProtKB/Swiss-Prot.
read moreDT 20-JUN-2001, sequence version 2.
DT 22-JAN-2014, entry version 118.
DE RecName: Full=Proto-oncogene Wnt-3;
DE AltName: Full=Proto-oncogene Int-4 homolog;
DE Flags: Precursor;
GN Name=WNT3; Synonyms=INT4;
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].
RA Testa T.T., Mossakowska D.E., Carter P.S., Hu E., Zhu Y.,
RA Kelsell D.P., Murdock P.R., Herrity N.C., Lewis C.J., Cross D.A.,
RA Culbert A.A., Reith A.D., Barnes M.R.;
RT "Molecular cloning and characterization of six novel human WNT
RT genes.";
RL Submitted (AUG-2000) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=11604997;
RA Katoh M.;
RT "Molecular cloning and characterization of human WNT3.";
RL Int. J. Oncol. 19:977-982(2001).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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 [MRNA] OF 1-333.
RX PubMed=8244403; DOI=10.1006/geno.1993.1412;
RA Roelink H., Wang J., Black D.M., Solomon E., Nusse R.;
RT "Molecular cloning and chromosomal localization to 17q21 of the human
RT WNT3 gene.";
RL Genomics 17:790-792(1993).
RN [5]
RP INVOLVEMENT IN ARTTRA.
RX PubMed=14872406; DOI=10.1086/382196;
RA Niemann S., Zhao C., Pascu F., Stahl U., Aulepp U., Niswander L.,
RA Weber J.L., Mueller U.;
RT "Homozygous WNT3 mutation causes tetra-amelia in a large
RT consanguineous family.";
RL Am. J. Hum. Genet. 74:558-563(2004).
CC -!- FUNCTION: Ligand for members of the frizzled family of seven
CC transmembrane receptors. Wnt-3 and Wnt-3a play distinct roles in
CC cell-cell signaling during morphogenesis of the developing neural
CC tube (By similarity).
CC -!- SUBUNIT: Interacts with PORCN (By similarity). Interacts with WLS
CC (By similarity).
CC -!- SUBCELLULAR LOCATION: Secreted, extracellular space, extracellular
CC matrix.
CC -!- PTM: Palmitoylation at Ser-212 is required for efficient binding
CC to frizzled receptors. It is also required for subsequent
CC palmitoylation at Cys-80. Palmitoylation is necessary for proper
CC trafficking to cell surface (By similarity).
CC -!- DISEASE: Tetraamelia, autosomal recessive (ARTTRA) [MIM:273395]: A
CC rare human genetic disorder characterized by complete absence of
CC all four limbs and other anomalies such as craniofacial, nervous
CC system, pulmonary, skeletal and urogenital defects. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- SIMILARITY: Belongs to the Wnt family.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/WNT3";
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; AY009397; AAG38657.1; -; mRNA.
DR EMBL; AB067628; BAB70502.1; -; mRNA.
DR EMBL; BC112116; AAI12117.1; -; mRNA.
DR EMBL; BC112118; AAI12119.1; -; mRNA.
DR EMBL; BC114219; AAI14220.1; -; mRNA.
DR PIR; A47536; A47536.
DR RefSeq; NP_110380.1; NM_030753.4.
DR UniGene; Hs.445884; -.
DR UniGene; Hs.745220; -.
DR ProteinModelPortal; P56703; -.
DR SMR; P56703; 60-354.
DR IntAct; P56703; 1.
DR STRING; 9606.ENSP00000225512; -.
DR BindingDB; P56703; -.
DR ChEMBL; CHEMBL6079; -.
DR PhosphoSite; P56703; -.
DR DMDM; 14424477; -.
DR PaxDb; P56703; -.
DR PRIDE; P56703; -.
DR DNASU; 7473; -.
DR Ensembl; ENST00000225512; ENSP00000225512; ENSG00000108379.
DR GeneID; 7473; -.
DR KEGG; hsa:7473; -.
DR UCSC; uc002ikv.3; human.
DR CTD; 7473; -.
DR GeneCards; GC17M044839; -.
DR HGNC; HGNC:12782; WNT3.
DR MIM; 165330; gene.
DR MIM; 273395; phenotype.
DR neXtProt; NX_P56703; -.
DR Orphanet; 3301; Tetraamelia - multiple malformations.
DR PharmGKB; PA37383; -.
DR eggNOG; NOG284879; -.
DR HOGENOM; HOG000039529; -.
DR HOVERGEN; HBG001595; -.
DR InParanoid; P56703; -.
DR KO; K00312; -.
DR OMA; MCGCDSH; -.
DR OrthoDB; EOG7C8GJ8; -.
DR PhylomeDB; P56703; -.
DR Reactome; REACT_111102; Signal Transduction.
DR GeneWiki; WNT3; -.
DR GenomeRNAi; 7473; -.
DR NextBio; 29272; -.
DR PRO; PR:P56703; -.
DR Bgee; P56703; -.
DR CleanEx; HS_WNT3; -.
DR Genevestigator; P56703; -.
DR GO; GO:0005788; C:endoplasmic reticulum lumen; TAS:Reactome.
DR GO; GO:0005615; C:extracellular space; TAS:BHF-UCL.
DR GO; GO:0005796; C:Golgi lumen; TAS:Reactome.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0005578; C:proteinaceous extracellular matrix; IEA:UniProtKB-SubCell.
DR GO; GO:0048018; F:receptor agonist activity; IC:BHF-UCL.
DR GO; GO:0009948; P:anterior/posterior axis specification; IEA:Ensembl.
DR GO; GO:0007411; P:axon guidance; IEA:Ensembl.
DR GO; GO:0044338; P:canonical Wnt receptor signaling pathway involved in mesenchymal stem cell differentiation; IMP:BHF-UCL.
DR GO; GO:0044339; P:canonical Wnt receptor signaling pathway involved in osteoblast differentiation; IMP:BHF-UCL.
DR GO; GO:0045165; P:cell fate commitment; IBA:RefGenome.
DR GO; GO:0000902; P:cell morphogenesis; IMP:BHF-UCL.
DR GO; GO:0071300; P:cellular response to retinoic acid; ISS:UniProtKB.
DR GO; GO:0009950; P:dorsal/ventral axis specification; IEA:Ensembl.
DR GO; GO:0035115; P:embryonic forelimb morphogenesis; IEA:Ensembl.
DR GO; GO:0035116; P:embryonic hindlimb morphogenesis; IEA:Ensembl.
DR GO; GO:0060323; P:head morphogenesis; IEA:Ensembl.
DR GO; GO:0060174; P:limb bud formation; IMP:BHF-UCL.
DR GO; GO:0061180; P:mammary gland epithelium development; IEP:UniProtKB.
DR GO; GO:0001707; P:mesoderm formation; IEA:Ensembl.
DR GO; GO:0048843; P:negative regulation of axon extension involved in axon guidance; IEA:Ensembl.
DR GO; GO:0030182; P:neuron differentiation; ISS:UniProtKB.
DR GO; GO:0048697; P:positive regulation of collateral sprouting in absence of injury; IEA:Ensembl.
DR GO; GO:0010628; P:positive regulation of gene expression; IEA:Ensembl.
DR GO; GO:0060064; P:Spemann organizer formation at the anterior end of the primitive streak; IEA:Ensembl.
DR InterPro; IPR005817; Wnt.
DR InterPro; IPR009141; Wnt3.
DR InterPro; IPR018161; Wnt_CS.
DR PANTHER; PTHR12027; PTHR12027; 1.
DR PANTHER; PTHR12027:SF18; PTHR12027:SF18; 1.
DR Pfam; PF00110; wnt; 1.
DR PRINTS; PR01843; WNT3PROTEIN.
DR PRINTS; PR01349; WNTPROTEIN.
DR SMART; SM00097; WNT1; 1.
DR PROSITE; PS00246; WNT1; 1.
PE 2: Evidence at transcript level;
KW Complete proteome; Developmental protein; Extracellular matrix;
KW Glycoprotein; Lipoprotein; Palmitate; Proto-oncogene;
KW Reference proteome; Secreted; Signal; Wnt signaling pathway.
FT SIGNAL 1 21 Potential.
FT CHAIN 22 355 Proto-oncogene Wnt-3.
FT /FTId=PRO_0000041416.
FT LIPID 80 80 S-palmitoyl cysteine (By similarity).
FT LIPID 212 212 O-palmitoyl serine; by PORCN (By
FT similarity).
FT CARBOHYD 90 90 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 301 301 N-linked (GlcNAc...) (Potential).
SQ SEQUENCE 355 AA; 39645 MW; 85D15F2C7884A64F CRC64;
MEPHLLGLLL GLLLGGTRVL AGYPIWWSLA LGQQYTSLGS QPLLCGSIPG LVPKQLRFCR
NYIEIMPSVA EGVKLGIQEC QHQFRGRRWN CTTIDDSLAI FGPVLDKATR ESAFVHAIAS
AGVAFAVTRS CAEGTSTICG CDSHHKGPPG EGWKWGGCSE DADFGVLVSR EFADARENRP
DARSAMNKHN NEAGRTTILD HMHLKCKCHG LSGSCEVKTC WWAQPDFRAI GDFLKDKYDS
ASEMVVEKHR ESRGWVETLR AKYSLFKPPT ERDLVYYENS PNFCEPNPET GSFGTRDRTC
NVTSHGIDGC DLLCCGRGHN TRTEKRKEKC HCIFHWCCYV SCQECIRIYD VHTCK
//
MIM
165330
*RECORD*
*FIELD* NO
165330
*FIELD* TI
*165330 WINGLESS-TYPE MMTV INTEGRATION SITE FAMILY, MEMBER 3; WNT3
;;ONCOGENE INT4; INT4
read moreMOUSE MAMMARY TUMOR VIRUS INTEGRATION SITE 4, INCLUDED
*FIELD* TX
CLONING
Roelink et al. (1993) used mouse Wnt3 sequences as a probe to isolate a
genomic clone of the human homolog, WNT3. Comparison of the deduced
mouse and human WNT3 protein sequences showed 4 changes in 333 amino
acids.
Using ribonuclease protection analysis, Huguet et al. (1994)
investigated expression of WNT genes, including WNT3, in human cell
lines, as well as in normal, benign, and malignant breast tissue. They
detected WNT3 in breast cell lines and in breast tissue.
MAPPING
Rider et al. (1989) assigned the INT4 gene to 17q21-q22 using a DNA
probe in the study of a panel of chromosome-mediated gene transfectants
and conventional hybrids, in particular those with well-defined breaks
on human chromosome 17. In situ hybridization was performed for more
precise localization. The mouse MMTV integration site int4 was mapped to
mouse chromosome 11 in a region homologous to the region of human
chromosome 17 carrying the INT4 locus.
Roelink et al. (1993) localized the WNT3 gene to 17q21 by isotopic in
situ hybridization.
GENE FUNCTION
Several studies had implicated Wnt signaling in primary axis formation
during vertebrate embryogenesis, yet no Wnt protein had been shown to be
essential for this process. In the mouse, primitive streak formation is
the first overt morphologic sign of the anterior-posterior axis in
mesoderm. Liu et al. (1999) generated Wnt3 -/- mice by targeted
disruption of the mouse Wnt3 gene. Wnt3 -/- mice developed a normal egg
cylinder but did not form a primitive streak, mesoderm, or node. The
epiblast continued to proliferate in an undifferentiated state that
lacked anterior-posterior neural patterning, but anterior visceral
endoderm markers were expressed and correctly positioned. Liu et al.
(1999) concluded that regional patterning of the visceral endoderm is
independent of primitive streak formation, but the subsequent
establishment of anterior-posterior neural pattern in the ectoderm is
dependent on derivatives of the primitive streak. Their studies provided
genetic proof for the requirement of Wnt3 in primary axis formation in
the mouse.
Krylova et al. (2002) investigated the role of Wnt proteins in the
formation of the sensorimotor connections in the mouse spinal cord.
Using in situ hybridization, they detected Wnt3 gene expression in
motoneurons of the lateral motor column at a time when sensory axons
make contact with them. In neuronal cultures, Wnt3 increased branching
and growth cone size while inhibiting axonal extension in axons
responsive to neurotrophin-3 (Ntf3; 162660), but not in axons responsive
to nerve growth factor (NGF). In explant cultures, the ventral spinal
cord secreted factors with Wnt3-like axonal remodeling activity that was
blocked by Sfrp1 (604156), a Wnt antagonist. Krylova et al. (2002)
concluded that WNT3 acts as a retrograde branching and stop signal for
muscle afferents during the formation of sensorimotor circuits in the
spinal cord.
Lie et al. (2005) demonstrated that adult hippocampal stem/progenitor
cells (AHPs) express receptors and signaling components for Wnt
proteins, which are key regulators of neural stem behavior in embryonic
development. Lie et al. (2005) also showed that the Wnt/beta-catenin
(116806) pathway is active and that Wnt3 is expressed in the hippocampal
neurogenic niche. Overexpression of Wnt3 was sufficient to increase
neurogenesis from AHPs in vitro and in vivo. By contrast, blockade of
Wnt signaling reduced neurogenesis from AHPs in vitro and abolished
neurogenesis almost completely in vivo. Lie et al. (2005) concluded that
their data showed that Wnt signaling is a principal regulator of adult
hippocampal neurogenesis and provided evidence that Wnt proteins have a
role in adult hippocampal function.
Schmitt et al. (2006) found that Wnt3 is expressed in a medial-lateral
decreasing gradient in chick optic tectum and mouse superior colliculus.
Retinal ganglion cell axons from different dorsal-ventral positions
showed graded and biphasic response to Wnt3 in a concentration-dependent
manner. Wnt3 repulsion is mediated by Ryk (600524), expressed in a
ventral-to-dorsal decreasing gradient, whereas attraction of dorsal
axons at lower Wnt3 concentrations is mediated by Frizzled(s) (see
603408). Overexpression of Wnt3 in the lateral tectum repelled the
termination zones of dorsal retinal ganglion cell axons in vivo.
Expression of a dominant-negative Ryk in dorsal retinal ganglion cell
axons caused a medial shift of the termination zones, promoting medially
directed interstitial branches and eliminating laterally directed
branches. Therefore, Schmitt et al. (2006) concluded that a classic
morphogen, Wnt3, acting as an axon guidance molecule, plays a role in
retinotectal mapping along the medial-lateral axis, counterbalancing the
medial-directed EphrinB1-EphB (see 300035) activity.
MOLECULAR GENETICS
In 4 affected fetuses of a consanguineous Turkish family with autosomal
recessive tetraamelia (273395), Niemann et al. (2004) identified a
homozygous nonsense mutation in the WNT3 gene (165330.0001). Based on
the phenotypic findings in the affected patients, Niemann et al. (2004)
concluded that WNT3 is required at the early stages of limb formation,
as well as for craniofacial and urogenital development.
NOMENCLATURE
For the group of related genes of which the first to be discovered was
INT1 (164820), Nusse et al. (1991) suggested the designation Wnt
(pronounced 'wint'), a mnemonic for the 'wingless' homolog. The product
INT1 (renamed WNT1) encodes a novel secretory glycoprotein similar to
the product of the Drosophila melanogaster 'wingless' gene. The INT4
locus was renamed WNT3.
*FIELD* AV
.0001
TETRAAMELIA, AUTOSOMAL RECESSIVE
WNT3, GLN83TER
In 4 affected fetuses of a consanguineous Turkish family with autosomal
recessive tetraamelia (273395), Niemann et al. (2004) identified a
homozygous 366C-T transition in the WNT3 gene, resulting in a
gln83-to-ter (Q83X) mutation. The mutation was predicted to result in a
truncated protein of only 82 amino acids. Hence, loss of function of
both copies of WNT3 is the most likely pathogenic mechanism in these
patients.
*FIELD* RF
1. Huguet, E. L.; McMahon, J. A.; McMahon, A. P.; Bicknell, R.; Harris,
A. L.: Differential expression of human Wnt genes 2, 3, 4, and 7B
in human breast cell lines and normal and disease states of human
breast tissue. Cancer Res. 54: 2615-2621, 1994.
2. Krylova, O.; Herreros, J.; Cleverley, K. E.; Ehler, E.; Henriquez,
J. P.; Hughes, S. M.; Salinas, P. C.: WNT-3, expressed by motoneurons,
regulates terminal arborization of neurotrophin-3-responsive spinal
sensory neurons. Neuron 35: 1043-1056, 2002.
3. Lie, D.-C.; Colamarino, S. A.; Song, H.-J.; Desire, L.; Mira, H.;
Consiglio, A.; Lein, E. S.; Jessberger, S.; Lansford, H.; Dearie,
A. R.; Gage, F. H.: Wnt signalling regulates adult hippocampal neurogenesis. Nature 437:
1370-1375, 2005.
4. Liu, P.; Wakamiya, M.; Shea, M. J.; Albrecht, U.; Behringer, R.
R.; Bradley, A.: Requirement for Wnt3 in vertebrate axis formation. Nature
Genet. 22: 361-365, 1999.
5. Niemann, S.; Zhao, C.; Pascu, F.; Stahl, U.; Aulepp, U.; Niswander,
L.; Weber, J. L.; Muller, U.: Homozygous WNT3 mutation causes tetra-amelia
in a large consanguineous family. Am. J. Hum. Genet. 74: 558-563,
2004.
6. Nusse, R.; Brown, A.; Papkoff, J.; Scambler, P.; Shackleford, G.;
McMahon, A.; Moon, R.; Varmus, H.: A new nomenclature for int-1 and
related genes: the Wnt gene family. Cell 64: 231-232, 1991.
7. Rider, S. H.; Gorman, P. A.; Shipley, J.; Roeling, H.; Nusse, R.;
Xu, W.; Sheer, D.; Solomon, E.: Localisation of the human int-4 (INT4)
gene. (Abstract) Cytogenet. Cell Genet. 51: 1066 only, 1989.
8. Roelink, H.; Wang, J.; Black, D. M.; Solomon, E.; Nusse, R.: Molecular
cloning and chromosomal localization to 17q21 of the human WNT3 gene. Genomics 17:
790-792, 1993.
9. Schmitt, A. M.; Shi, J.; Wolf, A. M.; Lu, C.-C.; King, L. A.; Zou,
Y.: Wnt-Ryk signalling mediates medial-lateral retinotectal topographic
mapping. Nature 439: 31-37, 2006.
*FIELD* CN
Ada Hamosh - updated: 5/1/2006
Ada Hamosh - updated: 11/8/2005
Cassandra L. Kniffin - updated: 3/23/2004
Dawn Watkins-Chow - updated: 7/18/2003
Dawn Watkins-Chow - updated: 2/1/2002
Ada Hamosh - updated: 8/2/1999
*FIELD* CD
Victor A. McKusick: 6/1/1989
*FIELD* ED
carol: 06/20/2012
carol: 8/5/2009
alopez: 5/3/2006
terry: 5/1/2006
alopez: 11/8/2005
terry: 11/8/2005
tkritzer: 3/24/2004
ckniffin: 3/23/2004
tkritzer: 8/21/2003
tkritzer: 8/20/2003
terry: 7/18/2003
terry: 2/1/2002
alopez: 8/2/1999
terry: 8/2/1999
psherman: 11/23/1998
psherman: 11/21/1998
carol: 7/28/1998
dkim: 7/17/1998
mark: 5/24/1997
carol: 9/15/1993
supermim: 3/16/1992
carol: 7/10/1991
supermim: 3/20/1990
carol: 12/12/1989
ddp: 10/27/1989
*RECORD*
*FIELD* NO
165330
*FIELD* TI
*165330 WINGLESS-TYPE MMTV INTEGRATION SITE FAMILY, MEMBER 3; WNT3
;;ONCOGENE INT4; INT4
read moreMOUSE MAMMARY TUMOR VIRUS INTEGRATION SITE 4, INCLUDED
*FIELD* TX
CLONING
Roelink et al. (1993) used mouse Wnt3 sequences as a probe to isolate a
genomic clone of the human homolog, WNT3. Comparison of the deduced
mouse and human WNT3 protein sequences showed 4 changes in 333 amino
acids.
Using ribonuclease protection analysis, Huguet et al. (1994)
investigated expression of WNT genes, including WNT3, in human cell
lines, as well as in normal, benign, and malignant breast tissue. They
detected WNT3 in breast cell lines and in breast tissue.
MAPPING
Rider et al. (1989) assigned the INT4 gene to 17q21-q22 using a DNA
probe in the study of a panel of chromosome-mediated gene transfectants
and conventional hybrids, in particular those with well-defined breaks
on human chromosome 17. In situ hybridization was performed for more
precise localization. The mouse MMTV integration site int4 was mapped to
mouse chromosome 11 in a region homologous to the region of human
chromosome 17 carrying the INT4 locus.
Roelink et al. (1993) localized the WNT3 gene to 17q21 by isotopic in
situ hybridization.
GENE FUNCTION
Several studies had implicated Wnt signaling in primary axis formation
during vertebrate embryogenesis, yet no Wnt protein had been shown to be
essential for this process. In the mouse, primitive streak formation is
the first overt morphologic sign of the anterior-posterior axis in
mesoderm. Liu et al. (1999) generated Wnt3 -/- mice by targeted
disruption of the mouse Wnt3 gene. Wnt3 -/- mice developed a normal egg
cylinder but did not form a primitive streak, mesoderm, or node. The
epiblast continued to proliferate in an undifferentiated state that
lacked anterior-posterior neural patterning, but anterior visceral
endoderm markers were expressed and correctly positioned. Liu et al.
(1999) concluded that regional patterning of the visceral endoderm is
independent of primitive streak formation, but the subsequent
establishment of anterior-posterior neural pattern in the ectoderm is
dependent on derivatives of the primitive streak. Their studies provided
genetic proof for the requirement of Wnt3 in primary axis formation in
the mouse.
Krylova et al. (2002) investigated the role of Wnt proteins in the
formation of the sensorimotor connections in the mouse spinal cord.
Using in situ hybridization, they detected Wnt3 gene expression in
motoneurons of the lateral motor column at a time when sensory axons
make contact with them. In neuronal cultures, Wnt3 increased branching
and growth cone size while inhibiting axonal extension in axons
responsive to neurotrophin-3 (Ntf3; 162660), but not in axons responsive
to nerve growth factor (NGF). In explant cultures, the ventral spinal
cord secreted factors with Wnt3-like axonal remodeling activity that was
blocked by Sfrp1 (604156), a Wnt antagonist. Krylova et al. (2002)
concluded that WNT3 acts as a retrograde branching and stop signal for
muscle afferents during the formation of sensorimotor circuits in the
spinal cord.
Lie et al. (2005) demonstrated that adult hippocampal stem/progenitor
cells (AHPs) express receptors and signaling components for Wnt
proteins, which are key regulators of neural stem behavior in embryonic
development. Lie et al. (2005) also showed that the Wnt/beta-catenin
(116806) pathway is active and that Wnt3 is expressed in the hippocampal
neurogenic niche. Overexpression of Wnt3 was sufficient to increase
neurogenesis from AHPs in vitro and in vivo. By contrast, blockade of
Wnt signaling reduced neurogenesis from AHPs in vitro and abolished
neurogenesis almost completely in vivo. Lie et al. (2005) concluded that
their data showed that Wnt signaling is a principal regulator of adult
hippocampal neurogenesis and provided evidence that Wnt proteins have a
role in adult hippocampal function.
Schmitt et al. (2006) found that Wnt3 is expressed in a medial-lateral
decreasing gradient in chick optic tectum and mouse superior colliculus.
Retinal ganglion cell axons from different dorsal-ventral positions
showed graded and biphasic response to Wnt3 in a concentration-dependent
manner. Wnt3 repulsion is mediated by Ryk (600524), expressed in a
ventral-to-dorsal decreasing gradient, whereas attraction of dorsal
axons at lower Wnt3 concentrations is mediated by Frizzled(s) (see
603408). Overexpression of Wnt3 in the lateral tectum repelled the
termination zones of dorsal retinal ganglion cell axons in vivo.
Expression of a dominant-negative Ryk in dorsal retinal ganglion cell
axons caused a medial shift of the termination zones, promoting medially
directed interstitial branches and eliminating laterally directed
branches. Therefore, Schmitt et al. (2006) concluded that a classic
morphogen, Wnt3, acting as an axon guidance molecule, plays a role in
retinotectal mapping along the medial-lateral axis, counterbalancing the
medial-directed EphrinB1-EphB (see 300035) activity.
MOLECULAR GENETICS
In 4 affected fetuses of a consanguineous Turkish family with autosomal
recessive tetraamelia (273395), Niemann et al. (2004) identified a
homozygous nonsense mutation in the WNT3 gene (165330.0001). Based on
the phenotypic findings in the affected patients, Niemann et al. (2004)
concluded that WNT3 is required at the early stages of limb formation,
as well as for craniofacial and urogenital development.
NOMENCLATURE
For the group of related genes of which the first to be discovered was
INT1 (164820), Nusse et al. (1991) suggested the designation Wnt
(pronounced 'wint'), a mnemonic for the 'wingless' homolog. The product
INT1 (renamed WNT1) encodes a novel secretory glycoprotein similar to
the product of the Drosophila melanogaster 'wingless' gene. The INT4
locus was renamed WNT3.
*FIELD* AV
.0001
TETRAAMELIA, AUTOSOMAL RECESSIVE
WNT3, GLN83TER
In 4 affected fetuses of a consanguineous Turkish family with autosomal
recessive tetraamelia (273395), Niemann et al. (2004) identified a
homozygous 366C-T transition in the WNT3 gene, resulting in a
gln83-to-ter (Q83X) mutation. The mutation was predicted to result in a
truncated protein of only 82 amino acids. Hence, loss of function of
both copies of WNT3 is the most likely pathogenic mechanism in these
patients.
*FIELD* RF
1. Huguet, E. L.; McMahon, J. A.; McMahon, A. P.; Bicknell, R.; Harris,
A. L.: Differential expression of human Wnt genes 2, 3, 4, and 7B
in human breast cell lines and normal and disease states of human
breast tissue. Cancer Res. 54: 2615-2621, 1994.
2. Krylova, O.; Herreros, J.; Cleverley, K. E.; Ehler, E.; Henriquez,
J. P.; Hughes, S. M.; Salinas, P. C.: WNT-3, expressed by motoneurons,
regulates terminal arborization of neurotrophin-3-responsive spinal
sensory neurons. Neuron 35: 1043-1056, 2002.
3. Lie, D.-C.; Colamarino, S. A.; Song, H.-J.; Desire, L.; Mira, H.;
Consiglio, A.; Lein, E. S.; Jessberger, S.; Lansford, H.; Dearie,
A. R.; Gage, F. H.: Wnt signalling regulates adult hippocampal neurogenesis. Nature 437:
1370-1375, 2005.
4. Liu, P.; Wakamiya, M.; Shea, M. J.; Albrecht, U.; Behringer, R.
R.; Bradley, A.: Requirement for Wnt3 in vertebrate axis formation. Nature
Genet. 22: 361-365, 1999.
5. Niemann, S.; Zhao, C.; Pascu, F.; Stahl, U.; Aulepp, U.; Niswander,
L.; Weber, J. L.; Muller, U.: Homozygous WNT3 mutation causes tetra-amelia
in a large consanguineous family. Am. J. Hum. Genet. 74: 558-563,
2004.
6. Nusse, R.; Brown, A.; Papkoff, J.; Scambler, P.; Shackleford, G.;
McMahon, A.; Moon, R.; Varmus, H.: A new nomenclature for int-1 and
related genes: the Wnt gene family. Cell 64: 231-232, 1991.
7. Rider, S. H.; Gorman, P. A.; Shipley, J.; Roeling, H.; Nusse, R.;
Xu, W.; Sheer, D.; Solomon, E.: Localisation of the human int-4 (INT4)
gene. (Abstract) Cytogenet. Cell Genet. 51: 1066 only, 1989.
8. Roelink, H.; Wang, J.; Black, D. M.; Solomon, E.; Nusse, R.: Molecular
cloning and chromosomal localization to 17q21 of the human WNT3 gene. Genomics 17:
790-792, 1993.
9. Schmitt, A. M.; Shi, J.; Wolf, A. M.; Lu, C.-C.; King, L. A.; Zou,
Y.: Wnt-Ryk signalling mediates medial-lateral retinotectal topographic
mapping. Nature 439: 31-37, 2006.
*FIELD* CN
Ada Hamosh - updated: 5/1/2006
Ada Hamosh - updated: 11/8/2005
Cassandra L. Kniffin - updated: 3/23/2004
Dawn Watkins-Chow - updated: 7/18/2003
Dawn Watkins-Chow - updated: 2/1/2002
Ada Hamosh - updated: 8/2/1999
*FIELD* CD
Victor A. McKusick: 6/1/1989
*FIELD* ED
carol: 06/20/2012
carol: 8/5/2009
alopez: 5/3/2006
terry: 5/1/2006
alopez: 11/8/2005
terry: 11/8/2005
tkritzer: 3/24/2004
ckniffin: 3/23/2004
tkritzer: 8/21/2003
tkritzer: 8/20/2003
terry: 7/18/2003
terry: 2/1/2002
alopez: 8/2/1999
terry: 8/2/1999
psherman: 11/23/1998
psherman: 11/21/1998
carol: 7/28/1998
dkim: 7/17/1998
mark: 5/24/1997
carol: 9/15/1993
supermim: 3/16/1992
carol: 7/10/1991
supermim: 3/20/1990
carol: 12/12/1989
ddp: 10/27/1989
MIM
273395
*RECORD*
*FIELD* NO
273395
*FIELD* TI
#273395 TETRAAMELIA, AUTOSOMAL RECESSIVE
*FIELD* TX
A number sign (#) is used with this entry because a mutation in the WNT3
read moregene (165330) has been identified in 1 family with autosomal recessive
tetraamelia.
CLINICAL FEATURES
Zimmer et al. (1985) reported a highly consanguineous Arab Moslem family
in which 6 male infants had tetraamelia and hydrocephalus. All were
severely affected with a malformed head and absence of upper and lower
limbs. Postmortem examination of 1 affected fetus showed 12 left ribs,
11 right ribs, and complete absence of pelvic bones. All limbs were
replaced with small, irregular soft tissue appendages. There was cleft
lip, malformed mouth, no nose, no ears, and agenesis of the corpus
callosum. Other features included bilateral left lung, patent ductus
arteriosus, anal atresia, and empty scrotal sac with enlarged penis.
Cytogenetic studies showed no abnormalities, including lack of the
premature sister chromatid separation that had been observed in patients
with Roberts syndrome. Zimmer et al. (1985) concluded that the entity
was distinct from Roberts syndrome, and postulated X-linked recessive
inheritance, although autosomal recessive inheritance could not be
excluded. In a follow-up of the family reported by Zimmer et al. (1985),
Gershoni-Baruch et al. (1990) reported another affected male and noted
that the phenotype was suggestive of Roberts syndrome (268300), but the
absence of the affected females suggested an X-linked disorder, best
termed 'X-linked amelia.' However, Kosaki et al. (1996) suggested that
the inheritance pattern in the family reported by Zimmer et al. (1985)
and Gershoni-Baruch et al. (1990) may be autosomal recessive. and
proposed the term 'Zimmer phocomelia.'
Kosaki et al. (1996) reported a 46,XX fetus with tetraphocomelia. She
also had absence of frontal bones and external ears, rudimentary nose,
cleft palate, severe pulmonary hypoplasia with adenomatoid malformation,
monolobated lungs, absence of thyroid, dysplastic kidneys, gallbladder,
spleen, uterus, and ovaries, imperforate anus and vagina, and the
presence of a phallus-like structure on an otherwise undefined perineum.
The parents of this fetus were of Hispanic origin and nonconsanguineous.
Kosaki et al. (1996) distinguished the condition from Roberts syndrome
by the findings of severe craniofacial involvement, severe genital
malformations, and pulmonary hypoplasia, which are not commonly observed
in Roberts syndrome. Manifestations in this fetus were very similar to
the cases reported by Zimmer et al. (1985). Multiple consanguinity in
that family and the possibility that sex could be misinterpreted due to
abnormal genitalia suggested that the actual inheritance of the defect
in the original family (Zimmer et al., 1985) was autosomal recessive.
Principal coordinate analysis was used to demonstrate that this
condition was distinct from other phocomelia syndromes.
Rosenak et al. (1991) described amelia, severe lung hypoplasia, and
aplasia of the peripheral pulmonary vessels in 2 fetuses of a
nonconsanguineous Arab Moslem couple. The couple previously had an
affected term female infant who died shortly after birth. The 2 fetuses
were diagnosed by ultrasound and the pregnancies were terminated. One
fetus had low-set ears and micrognathia. The other had apparent
hydrocephaly and a left cleft lip in addition to the lung hypoplasia and
abnormal pulmonary artery. The authors suggested that this represents a
previously undescribed autosomal recessive malformation syndrome.
Absence of premature centromere separation in chromosome studies
excluded classic Roberts phocomelia syndrome.
Zlotogora et al. (1993) reported 2 additional families. In both
instances, the parents of the affected children were Muslim Palestinian
Arabs. No relationship was known between the 2 families and they
originated from different areas; however, they had the same family name.
The 2 families were not related to either of the parents of the patients
reported by Rosenak et al. (1991), who originated from the same region
as one of the families of Zlotogora et al. (1993). All the patients died
soon after birth and were thought to have pulmonary hypoplasia. Cleft
lip or hydrocephalus was found in some of the patients.
Basaran et al. (1994) reported a family in which 2 sons had tetraamelia,
cleft lip/palate, bilateral agenesis of the lungs, and heart defects.
The mode of inheritance was unclear.
Niemann et al. (2004) reported a consanguineous Turkish family of
Aramaic descent in which 4 of 8 sibs, 3 female and 1 male, were affected
with tetraamelia and multiple other various anomalies. All 4 cases were
diagnosed prenatally and were terminated by 20 weeks' gestation. In
addition to absence of all 4 limbs, postmortem analysis of 3 fetuses
showed multiple defects in each one, including cleft lip/palate,
hypoplasia of the pelvis, malformed uterus, atresia of the urethra,
vagina, and anus, and agenesis of the kidney, spleen, and adrenal
glands. One fetus had a diaphragmatic defect with malposition of a
bilobed right lung. Genetic analysis identified a mutation in the WNT3
gene (165330.0001).
Krahn et al. (2005) reported 2 sibs, born of consanguineous Moroccan
parents, with tetraamelia and severe lung hypoplasia. Both had complete
absence of the limb bones with normal clavicles and scapulae in the
second fetus. Karyotype was normal. The findings were similar to those
reported by Rosenak et al. (1991).
Sousa et al. (2008) reported a fetus with tetraamelia, bilateral cleft
lip/palate, and possible pulmonary hypoplasia identified by ultrasound
at 20 weeks' gestation. The pregnancy was terminated. Physical
examination confirmed the prenatal findings and also showed micrognathia
and low-set ears. There was bilateral lung agenesis with bilateral
pulmonary artery agenesis and a small right heart. Fetal X-ray confirmed
the complete absence of limb bones and revealed normal clavicles,
scapulae and pelvis. No mutations were identified in the coding region
of the WNT3 gene.
Bermejo-Sanchez et al. (2011) described the epidemiology of congenital
amelia using data gathered from 20 surveillance programs on congenital
anomalies, all International Clearinghouse for Birth Defects
Surveillance and Research members, from all continents but Africa, from
1968 to 2006, depending on the program. Reported clinical information on
cases was thoroughly reviewed to identify those strictly meeting the
definition of amelia. Those with amniotic bands or limb-body wall
complex were excluded. The primary epidemiologic analyses focused on
isolated cases (about one-third) and those with multiple congenital
anomalies (MCA) (two-thirds). A total of 326 amelia cases were
ascertained among 23,110,591 live births, stillbirths, and, for some
programs, elective terminations of pregnancy for fetal anomalies. The
overall total prevalence was 1.41 per 100,000 (95% confidence interval
1.26-1.57). Only China, Beijing, and Mexico RYVEMCE had total
prevalences, which were significantly higher than this overall total
prevalence. Some underregistration could have influenced the total
prevalence in some programs. Liveborn cases represented 54.6% of the
total. Among monomelic cases (representing 65.2% of nonsyndromic amelia
cases), both sides were equally involved, and the upper limbs (53.9%)
were slightly more frequently affected. One of the most interesting
findings was a higher prevalence of amelia among offspring of mothers
younger than 20 years. Sixty-nine percent of the cases had MCA or
syndromes. The most frequent defects associated with amelia were other
types of musculoskeletal defects, intestinal defects, some renal and
genital defects, oral clefts, defects of cardiac septa, and anencephaly.
MAPPING
By homozygosity mapping of a consanguineous Turkish family with
tetraamelia, Niemann et al. (2004) assigned a disease locus to an 8.9-Mb
region between D17S1299 and D17S797 on chromosome 17q21 (maximum lod
score of 2.9).
MOLECULAR GENETICS
In affected fetuses of a Turkish family with tetraamelia, Niemann et al.
(2004) identified a homozygous nonsense mutation in the WNT3 gene
(165330.0001).
HETEROGENEITY
Possible genetic heterogeneity of tetraamelia was suggested by Krahn et
al. (2005) and Sousa et al. (2008), neither of whom found mutations in
the coding exons of the WNT3 gene in the parents of affected fetus or
cultured amniocytes from an affected fetus, respectively. Both authors
also suggested that the presence of severe pulmonary hypoplasia may be a
distinguishing phenotypic factor.
*FIELD* RF
1. Basaran, S.; Yuksel, A.; Ermis, H.; Kuseyri, F.; Agan, M.; Yuksel-Apak,
M.: Tetra-amelia, lung hypo-/aplasia, cleft lip-palate, and heart
defect: a new syndrome? Am. J. Med. Genet. 51: 77-80, 1994.
2. Bermejo-Sanchez, E.; Cuevas, L.; Amar, E.; Bakker, M. K.; Bianca,
S.; Bianchi, F.; Canfield, M. A.; Castilla, E. E.; Clementi, M.; Cocchi,
G.; Feldkamp, M. L.; Landau, D.; and 11 others: Amelia: a multi-center
descriptive epidemiologic study in a large dataset from the International
Clearinghouse for Birth Defects Surveillance and Research, and overview
of the literature. Am. J. Med. Genet. C Semin. Med. Genet. 157C:
288-304, 2011.
3. Gershoni-Baruch, R.; Drugan, A.; Bronshtein, M.; Zimmer, E. Z.
: Roberts syndrome or 'X-linked amelia'? Am. J. Med. Genet. 37:
569-572, 1990.
4. Kosaki, K.; Jones, M. C.; Stayboldt, C.: Zimmer phocomelia: delineation
by principal coordinate analysis. Am. J. Med. Genet. 66: 55-59,
1996.
5. Krahn, M.; Julia, S.; Sigaudy, S.; Liprandi, A.; Bernard, R.; Gonnet,
K.; Heuertz, S.; Bonaventure, J.; Chau, C.; Fredouille, C.; Levy,
N.; Philip, N.: Tetra-amelia and lung aplasia syndrome: report of
a new family and exclusion of candidate genes. (Letter) Clin. Genet. 68:
558-560, 2005.
6. Niemann, S.; Zhao, C.; Pascu, F.; Stahl, U.; Aulepp, U.; Niswander,
L.; Weber, J. L.; Muller, U.: Homozygous WNT3 mutation causes tetra-amelia
in a large consanguineous family. Am. J. Hum. Genet. 74: 558-563,
2004.
7. Rosenak, D.; Ariel, I.; Arnon, J.; Diamant, Y. Z.; Ben Chetrit,
A.; Nadjari, M.; Zilberman, R.; Yaffe, H.; Cohen, T.; Ornoy, A.:
Recurrent tetraamelia and pulmonary hypoplasia with multiple malformations
in sibs. Am. J. Med. Genet. 38: 25-28, 1991.
8. Sousa, S. B.; Pina, R.; Ramos, L.; Pereira, N.; Krahn, M.; Borozdin,
W.; Kohlhase, J.; Amorim, M.; Gonnet, K.; Levy, N.; Carreira, I. M.;
Couceiro, A. B.; Saraiva, J. M.: Tetra-amelia and lung hypo/aplasia
syndrome: new case report and review. Am. J. Med. Genet. 146A: 2799-2803,
2008.
9. Zimmer, E. Z.; Taub, E.; Sova, Y.; Divon, M. Y.; Pery, M.; Peretz,
B. A.: Tetra-amelia with multiple malformations in six male fetuses
in one kindred. Europ. J. Pediat. 144: 412-414, 1985.
10. Zlotogora, J.; Sagi, M.; Shabany, Y. O.; Jarallah, R. Y.: Syndrome
of tetraamelia with pulmonary hypoplasia. (Letter) Am. J. Med. Genet. 47:
570-571, 1993.
*FIELD* CS
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Face];
Micrognathia;
[Ears];
Low-set ears;
[Eyes];
Cataract;
Microphthalmia;
[Nose];
Single nares;
[Mouth];
Cleft lip;
Cleft palate
CARDIOVASCULAR:
[Vascular];
Peripheral pulmonary vessel aplasia
RESPIRATORY:
[Nasopharynx];
Choanal atresia;
[Lung];
Pulmonary hypoplasia;
Bilobar right lung
CHEST:
[Ribs, sternum, clavicle, and scapulae];
Normal scapulae;
Normal clavicles;
[Diaphragm];
Diaphragmatic defect
ABDOMEN:
[External features];
Gastroschisis;
[Spleen];
Splenic agenesis;
[Gastrointestinal];
Anal atresia
GENITOURINARY:
[External genitalia, male];
Absent external genitalia;
[Internal genitalia, female];
Malformed uterus;
Rudimentary ovaries;
Rudimentary salpinges;
Vaginal atresia;
[Kidneys];
Renal agenesis;
[Bladder];
Urethral atresia
SKELETAL:
[Pelvis];
Pelvic hypoplasia;
[Limbs];
Limb amelia;
Tetra-amelia
NEUROLOGIC:
[Central nervous system];
Hydrocephalus
ENDOCRINE FEATURES:
Adrenal gland agenesis
PRENATAL MANIFESTATIONS:
[Placenta & Umbilical Cord];
Single umbilical artery
MISCELLANEOUS:
Affected infants die in neonatal period;
Genetic heterogeneity;
A WNT3 mutation has been identified in 1 affected family
MOLECULAR BASIS:
Caused by mutation in the wingless-type MMTV integration site family,
member 3 gene (WNT3, 165330.0001)
*FIELD* CN
Kelly A. Przylepa - revised: 6/23/2004
Cassandra L. Kniffin - revised: 3/23/2004
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
ckniffin: 08/04/2009
joanna: 8/4/2009
joanna: 6/25/2004
joanna: 6/23/2004
ckniffin: 3/23/2004
*FIELD* CN
Ada Hamosh - updated: 12/20/2011
Cassandra L. Kniffin - updated: 8/4/2009
Cassandra L. Kniffin - updated: 3/23/2004
*FIELD* CD
Victor A. McKusick: 3/15/1991
*FIELD* ED
alopez: 01/10/2012
terry: 12/20/2011
carol: 8/5/2009
ckniffin: 8/4/2009
tkritzer: 3/24/2004
ckniffin: 3/23/2004
mgross: 3/18/2004
mimadm: 7/7/1994
carol: 11/3/1993
supermim: 3/17/1992
carol: 3/15/1991
*RECORD*
*FIELD* NO
273395
*FIELD* TI
#273395 TETRAAMELIA, AUTOSOMAL RECESSIVE
*FIELD* TX
A number sign (#) is used with this entry because a mutation in the WNT3
read moregene (165330) has been identified in 1 family with autosomal recessive
tetraamelia.
CLINICAL FEATURES
Zimmer et al. (1985) reported a highly consanguineous Arab Moslem family
in which 6 male infants had tetraamelia and hydrocephalus. All were
severely affected with a malformed head and absence of upper and lower
limbs. Postmortem examination of 1 affected fetus showed 12 left ribs,
11 right ribs, and complete absence of pelvic bones. All limbs were
replaced with small, irregular soft tissue appendages. There was cleft
lip, malformed mouth, no nose, no ears, and agenesis of the corpus
callosum. Other features included bilateral left lung, patent ductus
arteriosus, anal atresia, and empty scrotal sac with enlarged penis.
Cytogenetic studies showed no abnormalities, including lack of the
premature sister chromatid separation that had been observed in patients
with Roberts syndrome. Zimmer et al. (1985) concluded that the entity
was distinct from Roberts syndrome, and postulated X-linked recessive
inheritance, although autosomal recessive inheritance could not be
excluded. In a follow-up of the family reported by Zimmer et al. (1985),
Gershoni-Baruch et al. (1990) reported another affected male and noted
that the phenotype was suggestive of Roberts syndrome (268300), but the
absence of the affected females suggested an X-linked disorder, best
termed 'X-linked amelia.' However, Kosaki et al. (1996) suggested that
the inheritance pattern in the family reported by Zimmer et al. (1985)
and Gershoni-Baruch et al. (1990) may be autosomal recessive. and
proposed the term 'Zimmer phocomelia.'
Kosaki et al. (1996) reported a 46,XX fetus with tetraphocomelia. She
also had absence of frontal bones and external ears, rudimentary nose,
cleft palate, severe pulmonary hypoplasia with adenomatoid malformation,
monolobated lungs, absence of thyroid, dysplastic kidneys, gallbladder,
spleen, uterus, and ovaries, imperforate anus and vagina, and the
presence of a phallus-like structure on an otherwise undefined perineum.
The parents of this fetus were of Hispanic origin and nonconsanguineous.
Kosaki et al. (1996) distinguished the condition from Roberts syndrome
by the findings of severe craniofacial involvement, severe genital
malformations, and pulmonary hypoplasia, which are not commonly observed
in Roberts syndrome. Manifestations in this fetus were very similar to
the cases reported by Zimmer et al. (1985). Multiple consanguinity in
that family and the possibility that sex could be misinterpreted due to
abnormal genitalia suggested that the actual inheritance of the defect
in the original family (Zimmer et al., 1985) was autosomal recessive.
Principal coordinate analysis was used to demonstrate that this
condition was distinct from other phocomelia syndromes.
Rosenak et al. (1991) described amelia, severe lung hypoplasia, and
aplasia of the peripheral pulmonary vessels in 2 fetuses of a
nonconsanguineous Arab Moslem couple. The couple previously had an
affected term female infant who died shortly after birth. The 2 fetuses
were diagnosed by ultrasound and the pregnancies were terminated. One
fetus had low-set ears and micrognathia. The other had apparent
hydrocephaly and a left cleft lip in addition to the lung hypoplasia and
abnormal pulmonary artery. The authors suggested that this represents a
previously undescribed autosomal recessive malformation syndrome.
Absence of premature centromere separation in chromosome studies
excluded classic Roberts phocomelia syndrome.
Zlotogora et al. (1993) reported 2 additional families. In both
instances, the parents of the affected children were Muslim Palestinian
Arabs. No relationship was known between the 2 families and they
originated from different areas; however, they had the same family name.
The 2 families were not related to either of the parents of the patients
reported by Rosenak et al. (1991), who originated from the same region
as one of the families of Zlotogora et al. (1993). All the patients died
soon after birth and were thought to have pulmonary hypoplasia. Cleft
lip or hydrocephalus was found in some of the patients.
Basaran et al. (1994) reported a family in which 2 sons had tetraamelia,
cleft lip/palate, bilateral agenesis of the lungs, and heart defects.
The mode of inheritance was unclear.
Niemann et al. (2004) reported a consanguineous Turkish family of
Aramaic descent in which 4 of 8 sibs, 3 female and 1 male, were affected
with tetraamelia and multiple other various anomalies. All 4 cases were
diagnosed prenatally and were terminated by 20 weeks' gestation. In
addition to absence of all 4 limbs, postmortem analysis of 3 fetuses
showed multiple defects in each one, including cleft lip/palate,
hypoplasia of the pelvis, malformed uterus, atresia of the urethra,
vagina, and anus, and agenesis of the kidney, spleen, and adrenal
glands. One fetus had a diaphragmatic defect with malposition of a
bilobed right lung. Genetic analysis identified a mutation in the WNT3
gene (165330.0001).
Krahn et al. (2005) reported 2 sibs, born of consanguineous Moroccan
parents, with tetraamelia and severe lung hypoplasia. Both had complete
absence of the limb bones with normal clavicles and scapulae in the
second fetus. Karyotype was normal. The findings were similar to those
reported by Rosenak et al. (1991).
Sousa et al. (2008) reported a fetus with tetraamelia, bilateral cleft
lip/palate, and possible pulmonary hypoplasia identified by ultrasound
at 20 weeks' gestation. The pregnancy was terminated. Physical
examination confirmed the prenatal findings and also showed micrognathia
and low-set ears. There was bilateral lung agenesis with bilateral
pulmonary artery agenesis and a small right heart. Fetal X-ray confirmed
the complete absence of limb bones and revealed normal clavicles,
scapulae and pelvis. No mutations were identified in the coding region
of the WNT3 gene.
Bermejo-Sanchez et al. (2011) described the epidemiology of congenital
amelia using data gathered from 20 surveillance programs on congenital
anomalies, all International Clearinghouse for Birth Defects
Surveillance and Research members, from all continents but Africa, from
1968 to 2006, depending on the program. Reported clinical information on
cases was thoroughly reviewed to identify those strictly meeting the
definition of amelia. Those with amniotic bands or limb-body wall
complex were excluded. The primary epidemiologic analyses focused on
isolated cases (about one-third) and those with multiple congenital
anomalies (MCA) (two-thirds). A total of 326 amelia cases were
ascertained among 23,110,591 live births, stillbirths, and, for some
programs, elective terminations of pregnancy for fetal anomalies. The
overall total prevalence was 1.41 per 100,000 (95% confidence interval
1.26-1.57). Only China, Beijing, and Mexico RYVEMCE had total
prevalences, which were significantly higher than this overall total
prevalence. Some underregistration could have influenced the total
prevalence in some programs. Liveborn cases represented 54.6% of the
total. Among monomelic cases (representing 65.2% of nonsyndromic amelia
cases), both sides were equally involved, and the upper limbs (53.9%)
were slightly more frequently affected. One of the most interesting
findings was a higher prevalence of amelia among offspring of mothers
younger than 20 years. Sixty-nine percent of the cases had MCA or
syndromes. The most frequent defects associated with amelia were other
types of musculoskeletal defects, intestinal defects, some renal and
genital defects, oral clefts, defects of cardiac septa, and anencephaly.
MAPPING
By homozygosity mapping of a consanguineous Turkish family with
tetraamelia, Niemann et al. (2004) assigned a disease locus to an 8.9-Mb
region between D17S1299 and D17S797 on chromosome 17q21 (maximum lod
score of 2.9).
MOLECULAR GENETICS
In affected fetuses of a Turkish family with tetraamelia, Niemann et al.
(2004) identified a homozygous nonsense mutation in the WNT3 gene
(165330.0001).
HETEROGENEITY
Possible genetic heterogeneity of tetraamelia was suggested by Krahn et
al. (2005) and Sousa et al. (2008), neither of whom found mutations in
the coding exons of the WNT3 gene in the parents of affected fetus or
cultured amniocytes from an affected fetus, respectively. Both authors
also suggested that the presence of severe pulmonary hypoplasia may be a
distinguishing phenotypic factor.
*FIELD* RF
1. Basaran, S.; Yuksel, A.; Ermis, H.; Kuseyri, F.; Agan, M.; Yuksel-Apak,
M.: Tetra-amelia, lung hypo-/aplasia, cleft lip-palate, and heart
defect: a new syndrome? Am. J. Med. Genet. 51: 77-80, 1994.
2. Bermejo-Sanchez, E.; Cuevas, L.; Amar, E.; Bakker, M. K.; Bianca,
S.; Bianchi, F.; Canfield, M. A.; Castilla, E. E.; Clementi, M.; Cocchi,
G.; Feldkamp, M. L.; Landau, D.; and 11 others: Amelia: a multi-center
descriptive epidemiologic study in a large dataset from the International
Clearinghouse for Birth Defects Surveillance and Research, and overview
of the literature. Am. J. Med. Genet. C Semin. Med. Genet. 157C:
288-304, 2011.
3. Gershoni-Baruch, R.; Drugan, A.; Bronshtein, M.; Zimmer, E. Z.
: Roberts syndrome or 'X-linked amelia'? Am. J. Med. Genet. 37:
569-572, 1990.
4. Kosaki, K.; Jones, M. C.; Stayboldt, C.: Zimmer phocomelia: delineation
by principal coordinate analysis. Am. J. Med. Genet. 66: 55-59,
1996.
5. Krahn, M.; Julia, S.; Sigaudy, S.; Liprandi, A.; Bernard, R.; Gonnet,
K.; Heuertz, S.; Bonaventure, J.; Chau, C.; Fredouille, C.; Levy,
N.; Philip, N.: Tetra-amelia and lung aplasia syndrome: report of
a new family and exclusion of candidate genes. (Letter) Clin. Genet. 68:
558-560, 2005.
6. Niemann, S.; Zhao, C.; Pascu, F.; Stahl, U.; Aulepp, U.; Niswander,
L.; Weber, J. L.; Muller, U.: Homozygous WNT3 mutation causes tetra-amelia
in a large consanguineous family. Am. J. Hum. Genet. 74: 558-563,
2004.
7. Rosenak, D.; Ariel, I.; Arnon, J.; Diamant, Y. Z.; Ben Chetrit,
A.; Nadjari, M.; Zilberman, R.; Yaffe, H.; Cohen, T.; Ornoy, A.:
Recurrent tetraamelia and pulmonary hypoplasia with multiple malformations
in sibs. Am. J. Med. Genet. 38: 25-28, 1991.
8. Sousa, S. B.; Pina, R.; Ramos, L.; Pereira, N.; Krahn, M.; Borozdin,
W.; Kohlhase, J.; Amorim, M.; Gonnet, K.; Levy, N.; Carreira, I. M.;
Couceiro, A. B.; Saraiva, J. M.: Tetra-amelia and lung hypo/aplasia
syndrome: new case report and review. Am. J. Med. Genet. 146A: 2799-2803,
2008.
9. Zimmer, E. Z.; Taub, E.; Sova, Y.; Divon, M. Y.; Pery, M.; Peretz,
B. A.: Tetra-amelia with multiple malformations in six male fetuses
in one kindred. Europ. J. Pediat. 144: 412-414, 1985.
10. Zlotogora, J.; Sagi, M.; Shabany, Y. O.; Jarallah, R. Y.: Syndrome
of tetraamelia with pulmonary hypoplasia. (Letter) Am. J. Med. Genet. 47:
570-571, 1993.
*FIELD* CS
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Face];
Micrognathia;
[Ears];
Low-set ears;
[Eyes];
Cataract;
Microphthalmia;
[Nose];
Single nares;
[Mouth];
Cleft lip;
Cleft palate
CARDIOVASCULAR:
[Vascular];
Peripheral pulmonary vessel aplasia
RESPIRATORY:
[Nasopharynx];
Choanal atresia;
[Lung];
Pulmonary hypoplasia;
Bilobar right lung
CHEST:
[Ribs, sternum, clavicle, and scapulae];
Normal scapulae;
Normal clavicles;
[Diaphragm];
Diaphragmatic defect
ABDOMEN:
[External features];
Gastroschisis;
[Spleen];
Splenic agenesis;
[Gastrointestinal];
Anal atresia
GENITOURINARY:
[External genitalia, male];
Absent external genitalia;
[Internal genitalia, female];
Malformed uterus;
Rudimentary ovaries;
Rudimentary salpinges;
Vaginal atresia;
[Kidneys];
Renal agenesis;
[Bladder];
Urethral atresia
SKELETAL:
[Pelvis];
Pelvic hypoplasia;
[Limbs];
Limb amelia;
Tetra-amelia
NEUROLOGIC:
[Central nervous system];
Hydrocephalus
ENDOCRINE FEATURES:
Adrenal gland agenesis
PRENATAL MANIFESTATIONS:
[Placenta & Umbilical Cord];
Single umbilical artery
MISCELLANEOUS:
Affected infants die in neonatal period;
Genetic heterogeneity;
A WNT3 mutation has been identified in 1 affected family
MOLECULAR BASIS:
Caused by mutation in the wingless-type MMTV integration site family,
member 3 gene (WNT3, 165330.0001)
*FIELD* CN
Kelly A. Przylepa - revised: 6/23/2004
Cassandra L. Kniffin - revised: 3/23/2004
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
ckniffin: 08/04/2009
joanna: 8/4/2009
joanna: 6/25/2004
joanna: 6/23/2004
ckniffin: 3/23/2004
*FIELD* CN
Ada Hamosh - updated: 12/20/2011
Cassandra L. Kniffin - updated: 8/4/2009
Cassandra L. Kniffin - updated: 3/23/2004
*FIELD* CD
Victor A. McKusick: 3/15/1991
*FIELD* ED
alopez: 01/10/2012
terry: 12/20/2011
carol: 8/5/2009
ckniffin: 8/4/2009
tkritzer: 3/24/2004
ckniffin: 3/23/2004
mgross: 3/18/2004
mimadm: 7/7/1994
carol: 11/3/1993
supermim: 3/17/1992
carol: 3/15/1991