Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: WNT1
Cytogenetic location: 12q13.12 Genomic coordinates (GRCh38) : 12:48,978,322-48,982,620 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q13.12 | {Osteoporosis, early-onset, susceptibility to, autosomal dominant} | 615221 | Autosomal dominant | 3 |
| Osteogenesis imperfecta, type XV | 615220 | Autosomal recessive | 3 |
The Int oncogenes, including Int1, were first identified as targets for insertional activation by the mouse mammary tumor virus (MMTV) in mammary carcinomas. Int2 (see 164950) and Int3 (see 164951) are fundamentally unrelated genes; the similarity in nomenclature is based on the criterion of being a target for MMTV insertion mutation.
Nusse et al. (1991) proposed that the INT1 gene be termed WNT1 (pronounced 'wint 1'), because it was both an INT gene and a homolog of the Drosophila 'wingless' gene. The WNTs are a family of secreted glycoproteins that have been shown to be involved in a variety of developmental processes in many organisms. The prototype of the family is the Drosophila protein 'wingless' which acts as a segment polarity gene during embryogenesis and later participates in pattern formation of other body parts. Gavin et al. (1990) isolated 7 murine Wnt family members; Wolda and Moon (1992) isolated 7 Xenopus Wnt family members. McMahon (1992) discussed the Wnt family of developmental regulators, with particular reference to mouse mammary gland and the development of mouse mammary tumors. INT1 has a highly specific (both temporal and spatial) pattern of expression in fetal brain and spinal cord from 9- to 10-day-old mouse embryos but has been demonstrated to be expressed in only 1 adult tissue, postmyotic spermatids. The Drosophila homolog of INT1 is 'wingless,' a segment-polarity gene. Indirect evidence that INT1 is secreted and that the product of 'wingless' is a diffusible gene product suggests that these proteins are secreted growth factors.
By analyzing human genome draft sequence, Kirikoshi et al. (2001) determined that WNT1 is encoded by 4 exons and is clustered with WNT10B (601906) in a head-to-head manner within an interval of less than 7 kb. They discussed possibilities for the origin of WNT gene clusters through duplication of an ancestral WNT gene cluster.
Lee et al. (2004) demonstrated that WNT/beta-catenin (116806) signal activation in emigrating mouse neural crest stem cells had little effect on the population size and instead regulated fate decisions. Sustained beta-catenin activity in neural crest cells promoted the formation of sensory neural cells in vivo at the expense of virtually all other neural crest derivatives. Moreover, Lee et al. (2004) demonstrated that WNT is able to instruct early neural crest stem cells to adopt a sensory neuronal fate in a beta-catenin-dependent manner. Thus, Lee et al. (2004) concluded that the role of WNT/beta-catenin in stem cells is cell-type dependent.
Kleber et al. (2005) found that Bmp2 (112261) signaling antagonized the sensory fate-inducing activity of Wnt/beta-catenin. Wnt and Bmp2 acted synergistically to suppress differentiation and to maintain mouse neural crest stem cell marker expression and multipotency.
In studies in transgenic mice, Riccomagno et al. (2005) demonstrated that Wnt3a (606359) and Wnt1 signaling in dorsal regions of the otic vesicle regulates expression of genes (i.e., Dlx5/6, 600029, 600030; Gbx2, 601135) necessary for vestibular morphogenesis. In addition, they found that restriction of the Wnt target genes to the dorsal otocyst is also influenced by Shh (600725). Riccomagno et al. (2005) suggested that a balance between Wnt and Shh signaling activities is key in distinguishing between vestibular and auditory cell types.
Using microarray studies of the mouse presomitic mesoderm transcriptome, Dequeant et al. (2006) demonstrated that the oscillator associated with this process, the segmentation clock, drives the periodic expression of a large network of cyclic genes involved in cell signaling. Mutually exclusive activation of the Notch (see 190198)-fibroblast growth factor (FGF) and Wnt pathways during each cycle suggested that coordinated regulation of these 3 pathways underlies the clock oscillator. Dequeant et al. (2006) collected presomitic mesoderm samples from 40 mouse embryos ranging from 19 to 23 somites and used their Lfng (602576) expression patterns as a proxy to select 17 samples covering an entire oscillation cycle. Six of the 8 known mouse cyclic genes, Hes1 (139605), Hes5 (607348), Hey1 (602953), Lfng, Axin2 (604025), and Nkd1 (607851), were identified with periods of 94, 102, 112, 81, 102, and 112 minutes, respectively. Two clusters were identified. One cluster contains the known cyclic genes of the Notch pathway: Hes1, Hes5, and Hey1, as well as Id1 (600349). This cluster also contains Nrarp (619987), a direct target of Notch signaling. In the same cluster as the Notch pathway were members of the FGF-MAPK pathway, including Spry2 (602466) and Dusp6 (602748). The second cluster of periodic genes contained genes cycling in opposite phase to the Notch-FGF cluster; in this cluster were a majority of the cyclic genes associated with Wnt signaling, including Dkk1 (605189), cMyc (190080), Axin2, Sp5 (609391), and Tnfrsf19 (606122).
Using a combined experimental and computational modeling approach, Sick et al. (2006) identified Wnt and its inhibitor Dkk as primary determinants of murine hair follicle spacing. Transgenic Dkk overexpression reduced overall appendage density. Moderate suppression of endogenous Wnt signaling forced follicles to form clusters during an otherwise normal morphogenetic program. Sick et al. (2006) concluded that their results confirmed predictions of a WNT/DDK-specific mathematical model and provided in vivo corroboration of the reaction-diffusion mechanism for epidermal appendage formation.
Ito et al. (2007) demonstrated that after wounding, hair follicles formed de novo in genetically normal adult mice. The regenerated hair follicles established a stem cell population, expressed known molecular markers of follicle differentiation, produced a hair shaft, and progressed through all stages of the hair follicle cycle. Lineage analysis demonstrated that the nascent follicles arose from epithelial cells outside of the hair follicle stem cell niche, suggesting that epidermal cells in the wound assume a hair follicle stem cell phenotype. Inhibition of Wnt signaling after reepithelialization completely abrogated this wound-healing folliculogenesis, whereas overexpression of Wnt ligand in the epidermis increased the number of regenerated hair follicles. Ito et al. (2007) concluded that these remarkable regenerative capabilities of the adult support the notion that wounding induces an embryonic phenotype in the skin, and that this provides a window for manipulation of hair follicle neogenesis by Wnt proteins.
By microarray analysis, Hashimi et al. (2009) identified MIR21 (611020) and MIR34A (611172) among 20 miRNAs that were expressed in a stage-specific manner during differentiation of cultured human monocyte-derived dendritic cells (MDDCs). They also found that WNT1 was a functional target of MIR34A and that JAG1 (601920) was a functional target of both MIR21 and MIR34A. Inhibition of both MIR21 and MIR34A or overexpression of WNT1 and JAG1 stalled differentiation of MDDCs and reduced their endocytic capacity to levels characteristic of immature DCs. RT-PCR and Western blot analyses revealed that MIR21 and MIR34A functioned by translational suppression of WNT1 and JAG1.
The INT1 oncogene has been assigned to chromosome 12 by study of somatic cell hybrids (Nusse et al., 1984). The regional localization is 12pter-q14. The mouse homolog is coded by mouse chromosome 15. Turc-Carel et al. (1987) mapped INT1 to 12q12-q13 by in situ hybridization. Turc-Carel et al. (1987) found that the INT1 gene was not rearranged in a case of myxoid liposarcoma (151900) with t(12;16)(q13;p11). By in situ hybridization, Arheden et al. (1988) localized the INT1 gene to 12q13.
Osteogenesis Imperfecta, Type XV
By whole-exome sequencing and homozygosity mapping in affected members of a consanguineous Turkish family segregating OI (OI15; 615220), Keupp et al. (2013) identified a homozygous 1-bp duplication (c.859dupC; 164820.0001) in the WNT1 gene. Keupp et al. (2013) sequenced the entire WNT1 coding region in 11 additional families with autosomal recessive OI for which all known genes affected in OI had been excluded and identified 4 additional homozygous mutations in 4 families (see, e.g., 164820.0002-164820.0003). Keupp et al. (2013) demonstrated that the altered WNT1 proteins failed to activate canonical LRP5-mediated WNT-regulated beta-catenin signaling. In addition, osteoblasts cultured in vitro showed enhanced Wnt1 expression with advancing differentiation, indicating a role of WNT1 in osteoblast function and bone development.
In affected members of 4 consanguineous families segregating a moderately severe and progressive form of OI, Pyott et al. (2013) identified 5 different mutations in the WNT1 gene in homozygous or compound heterozygous state (see, e.g., 164820.0004). In 3 of the families, the affected individuals also had learning and developmental delays, and 2 affected individuals from different families had brain malformations. The mutations in 2 of the families were predicted to result in nonsense-mediated mRNA decay and the absence of WNT1.
In 4 affected children from 3 unrelated families segregating OI, Fahiminiya et al. (2013) identified 4 different mutations in the WNT1 gene in homozygous or compound heterozygous state (see, e.g., 164820.0005-164820.0006). All of those affected had short stature, low bone density, and severe vertebral compression fractures in addition to multiple long bone fractures in the first years of life.
In 2 Lao Hmong sisters with a severe form of osteogenesis imperfecta, Laine et al. (2013) identified a homozygous nonsense mutation in the WNT1 gene (S295X; 164820.0008). Both parents were heterozygous for the mutation. The 44-year-old mother had normal bone mineral density (BMD) on dual-energy x-ray absorptiometry (DXA) and normal spinal radiographs. The 43-year-old father had normal femoral BMD but had a z score of 1.8 for BMD of the lumbar spine (vertebral bodies L1 through L4). His height was normal (160 cm). His spinal radiographs showed a mild compression deformity involving the superior end plate of the L5 vertebral body. Laine et al. (2013) demonstrated that, in vitro, aberrant forms of the WNT1 protein showed impaired capacity to induce canonical WNT signaling, their target genes, and mineralization. Laine et al. (2013) also showed that mouse Wnt1 was clearly expressed in bone marrow, especially in B-cell lineage and hematopoietic progenitors; lineage tracing identified the expression of the gene in a subset of osteocytes, suggesting the presence of altered cross-talk in WNT signaling between the hematopoietic and osteoblastic lineage cells in OI type XV and in osteoporosis.
Osteoporosis, Early-Onset, Susceptibility to
By whole-exome sequencing of 2 affected individuals from a 4-generation family segregating early-onset osteoporosis and fractures (BMND16; 615221), Keupp et al. (2013) identified a heterozygous mutation in the WNT1 gene (R235W; 164820.0007). The mutation segregated with the phenotype in the family and was not found in over 13,000 alleles listed in the Exome Variant Server. Also see 164820.0001.
In 10 affected members of a Finnish family segregating severe early-onset osteoporosis and fractures mapping to chromosome 12, Laine et al. (2013) identified a heterozygous missense mutation in the WNT1 gene (C218G; 164820.0009).
Tsukamoto et al. (1988) generated transgenic mice ectopically expressing Wnt1 RNA at high levels in mammary and salivary glands of male and female mice and in male reproductive organs. The mammary glands of males and virgin females were grossly hyperplastic compared with those of nontransgenic littermates. Tsukamoto et al. (1988) observed mammary and (less frequently) salivary adenocarcinomas in these animals at rates indicating that transcriptional activation of Wnt1 and associated hyperplasia are initiating events in multistep carcinogenesis.
Thomas and Capecchi (1990) explored the function of int1 in the mouse by disrupting one of the 2 int1 alleles in mouse embryo-derived stem cells using positive-negative selection. This cell line was then used to generate a chimeric mouse that transmitted the mutant allele to its progeny. Mice heterozygous for the null mutation were normal and fertile, whereas mice homozygous for the mutation exhibited a range of phenotypes from death before birth to survival with severe ataxia. Examination of homozygous mice at several stages of embryogenesis showed severe abnormalities in the development of the mesencephalon and metencephalon, indicating a prominent role for the int1 protein in the induction of the mesencephalon and cerebellum.
The 'swaying' (sw) mouse, first described by Lane (1967), is characterized by rotational behavior and a severe cerebellar defect that is also present in some patients with OI. These mice are homozygous for a spontaneous 1-bp deletion (c.565delG) in the Wnt1 gene that results in a frameshift beginning at codon 189 and premature termination 10 codons downstream from the deletion (Thomas et al., 1991). Joeng et al. (2014) noted that the swaying mutation occurs in the same codon as an OI-linked nonsense mutation in human WNT1 (E189X; 164820.0003). Joeng et al. (2014) found that sw/sw mice developed major features of OI, including spontaneous fractures and severe osteopenia caused by decreased osteoblast activity. Biomechanical analysis showed that sw/sw bone had reduced strength compared with wildtype. Spectroscopic analysis suggested that the matrix of sw/sw bone had reduced mineral and collagen content compared with wildtype, a finding distinct from bone in collagen-related forms of OI (see 166200).
In 3 affected members of a consanguineous Turkish family segregating moderate to severe osteogenesis imperfecta (OI15; 615220), Keupp et al. (2013) identified a homozygous 1-bp duplication (c.859dupC) in the WNT1 gene by whole-exome sequencing and homozygosity mapping. The mutation is predicted to lead to a frameshift and early truncation of the C-terminal part of the protein (His287ProfsTer30). One of the patients had delayed intellectual development. The parents were heterozygous carriers. Keupp et al. (2013) performed bone-density measurements in the parents of 2 of these patients and found that 1 father had signs of osteoporosis at age 42 (BMND16; 615221); the other parents had low normal measurements.
In an affected member of a consanguineous family segregating osteogenesis imperfecta (OI15; 615220), Keupp et al. (2013) identified a donor splice site mutation in exon 3 of the WNT1 gene (c.624+4A-G). Keupp et al. (2013) observed that, compared to the control, the mutation caused a dramatic reduction in normal WNT1 transcripts, suggesting that the mutant transcripts are unstable and degraded by nonsense-mediated mRNA decay.
In an affected member of a consanguineous family segregating osteogenesis imperfecta (OI15; 615220), Keupp et al. (2013) identified a homozygous c.565G-T transversion in the WNT1 gene, resulting in a glu189-to-ter (E189X) substitution.
In 2 brothers, born to first-cousin parents of Hmong origin, with severe osteogenesis imperfecta (OI15; 615220), Pyott et al. (2013) identified a homozygous 884C-A transversion in the WNT1 gene, resulting in a ser295-to-ter (S295X) substitution. Both brothers had significant learning and developmental delays and one had brain malformations.
In a girl with a form of osteogenesis imperfecta (OI15) that was similar to OI4 (166220), Fahiminiya et al. (2013) identified compound heterozygous mutations in the WNT1 gene: a 4-bp insertion (c.946_949insAACA) resulting in a frameshift (ser317lysfs), and a 1063G-T transversion resulting in a val355-to-phe (V355F) substitution (164820.0006). The child was short and had a history of 30 long bone fractures before the age of 3 years and multiple vertebral compression fractures.
For discussion of the val355-to-phe (V355F) mutation in the WNT1 gene that was found in compound heterozygous state in a patient with osteogenesis imperfecta type XV (OI15; 615220) by Fahiminiya et al. (2013), see 164820.0005.
By whole-exome sequencing in 2 affected individuals from a 4-generation family segregating early-onset osteoporosis and fractures (BMND16; 615221), Keupp et al. (2013) identified a heterozygous c.703C-T transition in the WNT1 gene, resulting in an arg235-to-trp (R235W) substitution. The mutation segregated with the phenotype in the family and was not found in over 13,000 alleles listed in the Exome Variant Server.
In 2 Lao Hmong sisters with osteogenesis imperfecta type XV (OI15; 615220), Laine et al. (2013) identified a homozygous c.884C-A transversion in the WNT1 gene, resulting in a ser295-to-ter (S295X) substitution. Both parents were heterozygous for the mutation. The mutation resides in the last exon of WNT1 and thus escapes nonsense-mediated decay, which allows for the expression of a WNT1 protein in which the last 76 amino acids are missing.
In affected members of a Finnish family segregating severe early-onset osteoporosis and fractures mapping to chromosome 12 (BMND16; 615221), Laine et al. (2013) identified a heterozygous c.652T-G transversion in the WNT1 gene, resulting in a cys218-to-gly (C218G) substitution. The mutation affects the first cysteine of the so-called WNT motif, which is conserved across species.
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