* 601968

WINGLESS-TYPE MMTV INTEGRATION SITE FAMILY, MEMBER 2B; WNT2B


Alternative titles; symbols

XWNT2, XENOPUS, HOMOLOG OF
WINGLESS-TYPE MMTV INTEGRATION SITE FAMILY, MEMBER 13, FORMERLY; WNT13, FORMERLY


HGNC Approved Gene Symbol: WNT2B

Cytogenetic location: 1p13.2     Genomic coordinates (GRCh38): 1:112,466,541-112,530,165 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
1p13.2 Diarrhea 9 618168 AR 3

TEXT

Cloning and Expression

Katoh et al. (1996) cloned a novel WNT gene from a human gastric cancer cDNA library. Sequence analysis revealed that WNT13 was the human homolog of Xwnt2, a WNT gene cloned from Xenopus by Wolda and Moon (1992). Katoh et al. (1996) reported that the WNT13 gene encodes a 372-amino acid polypeptide including a putative secretory signal peptide. Northern blot analysis revealed that WNT13 was expressed as a 2.5-kb mRNA in fetal brain, lung, and kidney. Unlike most other WNTs, which tend to have restricted expression in adult tissues, its transcript was found in a wide variety of adult tissues.


Mapping

Katoh et al. (1996) used fluorescence in situ hybridization to map the WNT13 gene to chromosome 1p13.


Molecular Genetics

In a Kuwaiti brother and sister and a Vietnamese boy with neonatal-onset chronic diarrhea (DIAR9; 618168), O'Connell et al. (2018) identified homozygosity for nonsense mutations in the WNT2B gene, R69X (601968.0001) and R105X (601968.0002), respectively. Analysis of patient intestinal enteroid cultures indicated alterations in canonical WNT and microbial pattern-recognition signaling.


Animal Model

Ober et al. (2006) used a screen for mutations affecting endodermal organ morphogenesis to identify a unique phenotype, which they called 'prometheus' (prt). Prometheus mutants exhibit profound, though transient, defects in liver specification. Positional cloning revealed that prt encodes a previously unidentified Wnt2b homolog. Prt/Wnt2bb is expressed in restricted bilateral domains in the lateral plate mesoderm directly adjacent to the liver-forming endoderm. Mosaic analyses showed the requirement for Prt/Wnt2bb in the lateral plate mesoderm, in agreement with the inductive properties of Wnt signaling. Taken together, Ober et al. (2006) concluded that their data revealed an unexpected positive role for Wnt signaling in liver specification, and indicate a possible common theme for the localized formation of endodermal organs along the gut tube.


ALLELIC VARIANTS ( 2 Selected Examples):

.0001 DIARRHEA 9

WNT2B, ARG69TER
  
RCV000656393...

In a Kuwaiti brother and sister with neonatal-onset chronic diarrhea (DIAR9; 618168), O'Connell et al. (2018) identified homozygosity for a c.205C-T transition (c.205C-T, NM_024494) in the WNT2B gene, resulting in an arg69-to-ter (R69X) substitution. Their unaffected parents and 3 unaffected sibs were heterozygous for the mutation, which was detected in heterozygous state 3 times in the gnomAD database and 1 time in the ExAC database. Immunofluorescence showed diminished staining for OLFM4 (614061), a marker for intestinal stem cells, and enteroid cultures generated from patient intestinal epithelium could not be expanded and did not survive passage. Quantitative RT-PCR of patient enteroids showed a 10-fold increase in LEF1 (153245) mRNA and a 100-fold reduction in TLR4 (603030) expression compared to controls, indicating alterations in canonical WNT and microbial pattern-recognition signaling.


.0002 DIARRHEA 9

WNT2B, ARG105TER
  
RCV000238850...

In a 7-year-old Vietnamese boy with neonatal-onset chronic diarrhea (DIAR9; 618168), O'Connell et al. (2018) identified homozygosity for a c.313C-T transition (c.313C-T, NM_024494) in the WNT2B gene, resulting in an arg105-to-ter (R105X) substitution. His unaffected parents were heterozygous for the mutation, which was not found in the ExAC or gnomAD databases.


REFERENCES

  1. Katoh, M., Hirai, M., Sugimura, T., Terada, M. Cloning, expression and chromosomal localization of Wnt-13, a novel member of the Wnt gene family. Oncogene 13: 873-876, 1996. [PubMed: 8761309, related citations]

  2. O'Connell, A. E., Zhou, F., Shah, M. S., Murphy, Q., Rickner, H., Kelsen, J., Boyle, J., Doyle, J. J., Gangwani, B., Thiagarajah, J. R., Kamin, D. S., Goldsmith, J. D., Richmond, C., Breault, D. T., Agrawal, P. B. Neonatal-onset chronic diarrhea caused by homozygous nonsense WNT2B mutations. Am. J. Hum. Genet. 103: 131-137, 2018. [PubMed: 29909964, related citations] [Full Text]

  3. Ober, E. A., Verkade, H., Field, H. A., Stainier, D. Y. R. Mesodermal Wnt2b signalling positively regulates liver specification. Nature 442: 688-691, 2006. [PubMed: 16799568, related citations] [Full Text]

  4. Wolda, S. L., Moon, R. T. Cloning and developmental expression in Xenopus laevis of seven additional members of the Wnt family. Oncogene 7: 1941-1947, 1992. [PubMed: 1408135, related citations]


Marla J. F. O'Neill - updated : 10/31/2018
Ada Hamosh - updated : 9/8/2006
Creation Date:
Jennifer P. Macke : 9/2/1997
carol : 10/31/2018
alopez : 09/19/2006
terry : 9/8/2006
psherman : 11/23/1998
psherman : 11/21/1998
carol : 7/28/1998
alopez : 9/11/1997
alopez : 9/2/1997

* 601968

WINGLESS-TYPE MMTV INTEGRATION SITE FAMILY, MEMBER 2B; WNT2B


Alternative titles; symbols

XWNT2, XENOPUS, HOMOLOG OF
WINGLESS-TYPE MMTV INTEGRATION SITE FAMILY, MEMBER 13, FORMERLY; WNT13, FORMERLY


HGNC Approved Gene Symbol: WNT2B

Cytogenetic location: 1p13.2     Genomic coordinates (GRCh38): 1:112,466,541-112,530,165 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
1p13.2 Diarrhea 9 618168 Autosomal recessive 3

TEXT

Cloning and Expression

Katoh et al. (1996) cloned a novel WNT gene from a human gastric cancer cDNA library. Sequence analysis revealed that WNT13 was the human homolog of Xwnt2, a WNT gene cloned from Xenopus by Wolda and Moon (1992). Katoh et al. (1996) reported that the WNT13 gene encodes a 372-amino acid polypeptide including a putative secretory signal peptide. Northern blot analysis revealed that WNT13 was expressed as a 2.5-kb mRNA in fetal brain, lung, and kidney. Unlike most other WNTs, which tend to have restricted expression in adult tissues, its transcript was found in a wide variety of adult tissues.


Mapping

Katoh et al. (1996) used fluorescence in situ hybridization to map the WNT13 gene to chromosome 1p13.


Molecular Genetics

In a Kuwaiti brother and sister and a Vietnamese boy with neonatal-onset chronic diarrhea (DIAR9; 618168), O'Connell et al. (2018) identified homozygosity for nonsense mutations in the WNT2B gene, R69X (601968.0001) and R105X (601968.0002), respectively. Analysis of patient intestinal enteroid cultures indicated alterations in canonical WNT and microbial pattern-recognition signaling.


Animal Model

Ober et al. (2006) used a screen for mutations affecting endodermal organ morphogenesis to identify a unique phenotype, which they called 'prometheus' (prt). Prometheus mutants exhibit profound, though transient, defects in liver specification. Positional cloning revealed that prt encodes a previously unidentified Wnt2b homolog. Prt/Wnt2bb is expressed in restricted bilateral domains in the lateral plate mesoderm directly adjacent to the liver-forming endoderm. Mosaic analyses showed the requirement for Prt/Wnt2bb in the lateral plate mesoderm, in agreement with the inductive properties of Wnt signaling. Taken together, Ober et al. (2006) concluded that their data revealed an unexpected positive role for Wnt signaling in liver specification, and indicate a possible common theme for the localized formation of endodermal organs along the gut tube.


ALLELIC VARIANTS 2 Selected Examples):

.0001   DIARRHEA 9

WNT2B, ARG69TER
SNP: rs370244148, gnomAD: rs370244148, ClinVar: RCV000656393, RCV000714963

In a Kuwaiti brother and sister with neonatal-onset chronic diarrhea (DIAR9; 618168), O'Connell et al. (2018) identified homozygosity for a c.205C-T transition (c.205C-T, NM_024494) in the WNT2B gene, resulting in an arg69-to-ter (R69X) substitution. Their unaffected parents and 3 unaffected sibs were heterozygous for the mutation, which was detected in heterozygous state 3 times in the gnomAD database and 1 time in the ExAC database. Immunofluorescence showed diminished staining for OLFM4 (614061), a marker for intestinal stem cells, and enteroid cultures generated from patient intestinal epithelium could not be expanded and did not survive passage. Quantitative RT-PCR of patient enteroids showed a 10-fold increase in LEF1 (153245) mRNA and a 100-fold reduction in TLR4 (603030) expression compared to controls, indicating alterations in canonical WNT and microbial pattern-recognition signaling.


.0002   DIARRHEA 9

WNT2B, ARG105TER
SNP: rs879255420, ClinVar: RCV000238850, RCV000714964

In a 7-year-old Vietnamese boy with neonatal-onset chronic diarrhea (DIAR9; 618168), O'Connell et al. (2018) identified homozygosity for a c.313C-T transition (c.313C-T, NM_024494) in the WNT2B gene, resulting in an arg105-to-ter (R105X) substitution. His unaffected parents were heterozygous for the mutation, which was not found in the ExAC or gnomAD databases.


REFERENCES

  1. Katoh, M., Hirai, M., Sugimura, T., Terada, M. Cloning, expression and chromosomal localization of Wnt-13, a novel member of the Wnt gene family. Oncogene 13: 873-876, 1996. [PubMed: 8761309]

  2. O'Connell, A. E., Zhou, F., Shah, M. S., Murphy, Q., Rickner, H., Kelsen, J., Boyle, J., Doyle, J. J., Gangwani, B., Thiagarajah, J. R., Kamin, D. S., Goldsmith, J. D., Richmond, C., Breault, D. T., Agrawal, P. B. Neonatal-onset chronic diarrhea caused by homozygous nonsense WNT2B mutations. Am. J. Hum. Genet. 103: 131-137, 2018. [PubMed: 29909964] [Full Text: https://doi.org/10.1016/j.ajhg.2018.05.007]

  3. Ober, E. A., Verkade, H., Field, H. A., Stainier, D. Y. R. Mesodermal Wnt2b signalling positively regulates liver specification. Nature 442: 688-691, 2006. [PubMed: 16799568] [Full Text: https://doi.org/10.1038/nature04888]

  4. Wolda, S. L., Moon, R. T. Cloning and developmental expression in Xenopus laevis of seven additional members of the Wnt family. Oncogene 7: 1941-1947, 1992. [PubMed: 1408135]


Contributors:
Marla J. F. O'Neill - updated : 10/31/2018
Ada Hamosh - updated : 9/8/2006

Creation Date:
Jennifer P. Macke : 9/2/1997

Edit History:
carol : 10/31/2018
alopez : 09/19/2006
terry : 9/8/2006
psherman : 11/23/1998
psherman : 11/21/1998
carol : 7/28/1998
alopez : 9/11/1997
alopez : 9/2/1997