HGNC Approved Gene Symbol: WNT7A
SNOMEDCT: 715522000, 721296004;
Cytogenetic location: 3p25.1 Genomic coordinates (GRCh38): 3:13,816,258-13,880,071 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3p25.1 | Fuhrmann syndrome | 228930 | Autosomal recessive | 3 |
| Ulna and fibula, absence of, with severe limb deficiency | 276820 | Autosomal recessive | 3 |
The Wnt gene family consists of structurally related genes encoding secreted signaling molecules that have been implicated in oncogenesis and in several developmental processes, including regulation of cell fate and patterning during embryogenesis. A Wnt gene was first defined as a protooncogene, int1 (WNT1; 164820), by Nusse and Varmus (1982). The designation 'Wnt' was derived from 'wingless' and 'int.' Wnt genes have been identified in many organisms.
Using degenerate PCR and cDNA library screening to search for new members of the mouse Wnt family, Gavin et al. (1990) identified Wnt7a. By Northern blot analysis, they detected expression of Wnt7a in brain and lung.
Ikegawa et al. (1996) isolated a full-length cDNA clone that appeared to represent a novel member of the Wnt gene family. Designated WNT7A, the gene encodes a deduced 349-amino acid polypeptide that has 98% and 64% sequence identity to mouse Wnt7a and human WNT5A (164975), respectively. Expression of the WNT7A gene is restricted to placenta, kidney, testis, uterus, fetal lung, and fetal and adult brain.
For a review of the role of the WNT7A gene in limb development, see Johnson and Tabin (1997).
The WNT7A gene not only guides the development of the anterior-posterior axis in the female reproductive tract, but also plays a critical role in uterine smooth muscle pattering and maintenance of adult uterine function. WNT7A is also responsive to changes in the levels of sex steroid hormone in the female reproductive tract. To explore the molecular mechanisms underlying the pathogenesis of uterine leiomyoma, Li et al. (2001) studied the expression of WNT7A mRNA in the leiomyoma. RT-PCR was performed on uterine leiomyomas and the adjacent myometria. Of 30 cases of leiomyoma studied, 67% showed a decreased mRNA level as compared to the paired myometria. On the other hand, ESRA mRNA is hyperexpressed in 67% of the leiomyomas as compared to their paired myometrium. The authors concluded that an inverse association at mRNA expression was found between WNT7A and ESRA.
Using genetic mouse models, Stenman et al. (2008) found that WNT7A and WNT7B (601967) directly target the vascular endothelium and that the central nervous system uses the canonical Wnt signaling pathway to promote formation and central nervous system-specific differentiation of the organ's vasculature.
Both Ikegawa et al. (1996) and Bui et al. (1997) isolated a genomic clone of WNT7A and mapped the gene to 3p25 by fluorescence in situ hybridization. This region shows syntenic homology with a region of mouse chromosome 6 where the murine Wnt7a gene maps (Adamson et al., 1994).
Fuhrmann syndrome (228930) and the Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome (AARRS; 276820) have been considered to be distinct limb malformation disorders characterized by various degrees of limb aplasia/hypoplasia and joint dysplasia. In a family with Fuhrmann syndrome and a family with AARRS, Woods et al. (2006) identified homozygous missense mutations in the WNT7A gene (601570.0001 and 601570.0002, respectively) and confirmed their functional significance in retroviral-mediated transfection of chicken mesenchyme cell cultures and developing limbs. The findings suggested that a partial loss of WNT7A function caused Fuhrmann syndrome (and a phenotype similar to mouse Wnt7a knockout), whereas the more severe limb truncation phenotypes observed in Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome result from functionally null mutations (and cause a phenotype similar to Shh knockout (600725) in the mouse). The findings illustrated the specific and conserved importance of WNT7A in multiple aspects of vertebrate limb development.
In 2 Thai sisters with AARRS, Kantaputra et al. (2010) identified homozygosity for a missense mutation in the WNT7A gene (R222W; 601570.0004).
In 3 affected individuals from 2 related consanguineous Saudi Arabian families with AARRS, Eyaid et al. (2011) identified homozygosity for a missense mutation in the WNT7A gene (G204S; 601570.0003).
In a child with the AARRS phenotype, Garavelli et al. (2011) identified homozygosity for a 214G-A transition in the WNT7A gene, resulting in a glu72-to-lys (E72K) substitution at a highly conserved residue.
Parr and McMahon (1998) showed that male mice lacking the signaling molecule Wnt7a failed to undergo regression of the mullerian duct as a result of the absence of the receptor for mullerian-inhibiting substance (600957). Wnt7a-deficient females were infertile because of abnormal development of the oviduct and uterus, both of which are mullerian duct derivatives. Therefore, Parr and McMahon (1998) proposed that signaling by Wnt7a allows sexually dimorphic development of the mullerian ducts. Normally in females, mullerian ducts develop into the oviduct, uterus, cervix, and upper vagina, whereas wolffian ducts regress. In males, testosterone promotes differentiation of wolffian ducts into the epididymis, vas deferens, and seminal vesicle. The Sertoli cells of the testes produce mullerian-inhibiting substance (also called mullerian-inhibiting factor or, preferably, anti-mullerian hormone, AMH), which stimulates mullerian duct regression in males. The receptor for mullerian-inhibiting substance is expressed by mesenchymal cells underlying the mullerian duct which are thought to mediate regression of the duct. Mutations that inactivate either mullerian-inhibiting substance or its receptor allow development of the female reproductive tract in males.
Woods et al. (2006) demonstrated a homozygous missense mutation in the WNT7A gene, arg292 to cys (R292C), in a consanguineous family in which 3 members had absent ulna and fibula with severe limb deficiency (276820), also known as Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome. The R292C mutation arose from an 1179C-T transition in exon 4.
In the family originally described by Kumar et al. (1997) with Fuhrmann syndrome (228930), Woods et al. (2006) found a 630G-A transition in exon 3 of the WNT7A gene that caused an ala109-to-thr (A109T) substitution. Two nonsynonymous single-nucleotide polymorphisms (SNPs), also in exon 3 of the WNT7A gene, were also found in affected individuals.
In an affected brother and sister and their female cousin with variable limb reduction phenotypes (276820), all born of consanguineous marriages within a Saudi Arabian family, Eyaid et al. (2011) identified homozygosity for a 610G-A transition in exon 4 of the WNT7A gene, predicted to result in a gly204-to-ser (G204S) substitution at a highly conserved residue within the Wnt signature motif. The unaffected parents were heterozygous carriers of the mutation, which was not found in 80 ethnically matched controls or in any public domain databases. All 3 patients had pelvic hypoplasia and truncated appendages replacing the lower limbs, but the upper limb phenotype ranged from absence of the ulna with a short radius and 1 missing digit per hand to a single bone with absence of elbow joint and only 2 digits per hand to total absence of the upper limbs (amelia).
In 2 Thai sisters with short and malformed long bones, absent fibulae, flexion contracture of digits, and hypoplastic/aplastic nails (276820), Kantaputra et al. (2010) identified homozygosity for a 664C-T transition in exon 4 of the WNT7A gene, resulting in an arg222-to-trp (R222W) substitution at a highly conserved residue. The unaffected parents were each heterozygous for the mutation, which was not found in an unaffected sister or 100 controls.
In a child with the AARRS phenotype (276820), Garavelli et al. (2011) identified homozygosity for a 214G-A transition in the WNT7A gene, resulting in a glu72-to-lys (E72K) substitution at a highly conserved residue. The mutation was not observed in over 200 Caucasian control alleles or in databases. Parental DNA was not available.
Adamson, M. C., Dennis, C., Delaney, S., Christiansen, J., Monkley, S., Kozak, C. A., Wainwright, B. Isolation and genetic mapping of two novel members of the murine Wnt gene family, Wnt11 and Wnt12, and the mapping of Wnt5a and Wnt7a. Genomics 24: 9-13, 1994. [PubMed: 7896292] [Full Text: https://doi.org/10.1006/geno.1994.1575]
Bui, T. D., Lako, M., Lejeune, S., Curtis, A. R. J., Strachan, T., Lindsay, S., Harris, A. L. Isolation of a full-length human WNT7A gene implicated in limb development and cell transformation, and mapping to chromosome 3p25. Gene 189: 25-29, 1997. [PubMed: 9161407] [Full Text: https://doi.org/10.1016/s0378-1119(96)00808-6]
Eyaid, W., Al-Qattan, M. M., Al Abdulkareem, I., Fetaini, N., Al Balwi, M. A novel homozygous missense mutation (c.610G-A, p.gly204ser) in the WNT7A gene causes tetra-amelia in two Saudi families. Am. J. Med. Genet. 155A: 599-604, 2011. [PubMed: 21344627] [Full Text: https://doi.org/10.1002/ajmg.a.33717]
Garavelli, L., Wischmeijer, A., Rosato, S., Gelmini, C., Reverberi, S., Sassi, S., Ferrari, A., Mari, F., Zabel, B., Lausch, E., Unger, S., Superti-Furga, A. Al-Awadi--Raas-Rothschild (limb/pelvis/uterus--hypoplasia/aplasia) syndrome and WNT7A mutations: genetic homogeneity and nosological delineation. Am. J. Med. Genet. 155A: 332-336, 2011. [PubMed: 21271649] [Full Text: https://doi.org/10.1002/ajmg.a.33793]
Gavin, B. J., McMahon, J. A., McMahon, A. P. Expression of multiple novel Wnt-1/int-1-related genes during fetal and adult mouse development. Genes Dev. 4: 2319-2332, 1990. [PubMed: 2279700] [Full Text: https://doi.org/10.1101/gad.4.12b.2319]
Ikegawa, S., Kumano, Y., Okui, K., Fujiwara, T., Takahashi, E., Nakamura, Y. Isolation, characterization and chromosomal assignment of the human WNT7A gene. Cytogenet. Cell Genet. 74: 149-152, 1996. [PubMed: 8893824] [Full Text: https://doi.org/10.1159/000134404]
Johnson, R. L., Tabin, C. J. Molecular models for vertebrate limb development. Cell 90: 979-990, 1997. [PubMed: 9323126] [Full Text: https://doi.org/10.1016/s0092-8674(00)80364-5]
Kantaputra, P. N., Mundlos, S., Sripathomsawat, W. A novel homozygous arg222trp missense mutation in WNT7A in two sisters with severe Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome. Am. J. Med. Genet. 152A: 2832-2837, 2010. [PubMed: 20949531] [Full Text: https://doi.org/10.1002/ajmg.a.33673]
Kumar, D., Duggan, M. B., Mueller, R. F., Karbani, G. Familial aplasia/hypoplasia of pelvis, femur, fibula, and ulna with abnormal digits in an inbred Pakistani Muslim family: a possible new autosomal recessive disorder with overlapping manifestations of the syndromes of Fuhrmann, Al-Awadi, and Raas-Rothschild. Am. J. Med. Genet. 70: 107-113, 1997. [PubMed: 9128926]
Li, S., Chiang, T.-C., Davis, G. R., Williams, R. M., Wilson, V. P., McLachlan, J. A. Decreased expression of Wnt7a mRNA is inversely associated with the expression of estrogen receptor-alpha in human uterine leiomyoma. J. Clin. Endocr. Metab. 86: 454-457, 2001. [PubMed: 11232041] [Full Text: https://doi.org/10.1210/jcem.86.1.7276]
Nusse, R., Varmus, H. E. Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome. Cell 31: 99-109, 1982. [PubMed: 6297757] [Full Text: https://doi.org/10.1016/0092-8674(82)90409-3]
Parr, B. A., McMahon, A. P. Sexually dimorphic development of the mammalian reproductive tract requires Wnt-7a. Nature 395: 707-710, 1998. [PubMed: 9790192] [Full Text: https://doi.org/10.1038/27221]
Stenman, J. M., Rajagopal, J., Carroll, T. J., Ishibashi, M., McMahon, J., McMahon, A. P. Canonical Wnt signaling regulates organ-specific assembly and differentiation of CNS vasculature. Science 322: 1247-1250, 2008. [PubMed: 19023080] [Full Text: https://doi.org/10.1126/science.1164594]
Woods, C. G., Stricker, S., Seemann, P., Stern, R., Cox, J., Sherridan, E., Roberts, E., Springell, K., Scott, S., Karbani, G., Sharif, S. M., Toomes, C., Bond, J., Kumar, D., Al-Gazali, L., Mundlos, S. Mutations in WNT7A cause a range of limb malformations, including Fuhrmann syndrome and Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome. Am. J. Hum. Genet. 79: 402-408, 2006. [PubMed: 16826533] [Full Text: https://doi.org/10.1086/506332]