Alternative titles; symbols
HGNC Approved Gene Symbol: FZD5
Cytogenetic location: 2q33.3 Genomic coordinates (GRCh38): 2:207,762,598-207,769,906 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q33.3 | Microphthalmia/coloboma 11 | 620731 | Autosomal dominant | 3 |
Wang et al. (1996) cloned and sequenced a large family of mammalian homologs of the Drosophila polarity gene 'frizzled' (see 600667). One of these was a human gene, termed 'frizzled 5,' isolated from a retina cDNA library. Wang et al. (1996) determined that this gene encodes a polypeptide of 585 amino acids.
Wang et al. (1996) used interspecific backcross analysis to map the gene to mouse chromosome 1 between the markers Ctla4 (123890) and Fn1 (135600), which is syntenic to human chromosome 2q33-q34.
He et al. (1997) showed that human frizzled 5 is the receptor for the Wnt5A (164975) ligand.
In 11 affected individuals from 2 branches of a large Mennonite pedigree with ocular coloboma and microphthalmia (MCOPCB11; 620731), Liu et al. (2016) identified heterozygosity for a deletion/insertion mutation in the FZD5 gene (601723.0001). The mutation showed high but incomplete penetrance (0.8), as it was also detected in 2 unaffected family members; it was not found in in-house exomes or in public variant databases. Functional analysis suggested that the mutant acts in a dominant non-cell-autonomous manner to repress FZD5 signaling.
Aubert-Mucca et al. (2021) screened a panel of 119 ocular developmental genes in a cohort of 50 individuals with ocular coloboma and identified 3 unrelated patients with heterozygous mutations in the FZD5 gene (see, e.g., 601723.0002 and 601723.0003).
Jiang et al. (2021) analyzed exome data from 5,845 Chinese probands with various eye conditions, and identified heterozygosity for 8 pathogenic or possibly pathogenic variants in the FZD5 gene in 9 families (see, e.g., 601723.0004-601723.0006). The variants cosegregated with closely related ocular phenotypes in 14 affected individuals in the 6 families for which segregation information was available. The authors noted that the phenotypes of the affected individuals were variable and included coloboma, inferior chorioretinal and/or optic disc hypoplasia, high myopia, and posterior microphthalmos, and overlapping associated phenotypes were present in different individuals within and among families, as well as in different eyes of the same individual.
Using morpholino knockdown, Liu et al. (2016) generated fzd5 zebrafish morphants and observed coloboma and microphthalmia phenotypes. Overexpression of FZD5-A219EfsTer49 (601723.0001) in zebrafish embryos also resulted in coloboma and microphthalmia, as did overexpression of wildtype FZD5. The authors suggested that precise FZD5 and/or WNT (see 164820) signaling dosage is critical for ocular development.
In 10 affected members over 3 generations of 2 branches (families 3483 and 111) of a large Mennonite pedigree with nonsyndromic ocular coloboma, some of whom also had microphthalmia (MCOPCB11; 620731), Liu et al. (2016) identified heterozygosity for a deletion/insertion mutation (c.656delCinsAG) in the FZD5 gene, causing a frameshift predicted to result in a premature termination codon (Ala219GlufsTer49). The authors referred to the effect of the mutation as Ala219XfsTer49. The mutation showed incomplete penetrance (0.8), as it was also detected in 2 unaffected family members and in 1 individual with unilateral optic disc/nerve pigmentary abnormality. The variant was not found in a UK10K internal database or in the ExAC, EVS, 1000 Genomes Project databases. Analysis of transfected HEK293 cells showed production of a truncated FZD5 protein as predicted, lacking the transmembrane domains. Live cell-surface immunofluorescence analysis confirmed that, in contrast to wildtype FZD5, the truncated protein did not localize to the outer cell membrane, but displayed punctate and/or irregular extracellular staining. Pulldown assay confirmed that truncated FZD5 lacked the ability to mediate both canonical and noncanonical WNT (see 164820) signaling activities. Coculture assays in transfected HEK293 and STF cells demonstrated dose-dependent non-cell-autonomous inhibition of FZD5-mediated canonical WNT activity with the mutant which could be reversed in a dose-dependent manner by increasing wildtype FZD5 expression. The authors concluded that the mutant protein functions in a dominant non-cell-autonomous manner to repress FZD5 signaling. Overexpression of the truncated mutant in zebrafish embryos resulted in coloboma and microphthalmia, and overexpression in cultured mouse retinal explants caused apical junction defects.
In a 10-year-old Algerian/Moroccan girl (patient 1) with right-sided iris, choroidal, and optic disc coloboma, and left-sided choroidal and optic disc coloboma (MCOPDB11; 620731), Aubert-Mucca et al. (2021) identified heterozygosity for a 1-bp deletion (c.830del, NM_003468.4) in the FZD5 gene, causing a frameshift predicted to result in a premature termination codon (Leu274CysfsTer73). The deletion was not found in the gnomAD database; the complete segregation pattern could not be established due to lack of DNA from her father.
In a French mother and daughter (patient 3) with coloboma (MCOPDB11; 620731), Aubert-Mucca et al. (2021) identified heterozygosity for a 66-bp deletion (c.1181_1246del, NM_003468.4) in the FZD5 gene, resulting in deletion of 22 highly conserved amino acids (Asn394_Gly415del) within the frizzled domain. The deletion was not found in the gnomAD database. The 26-year-old proband had bilateral iris and chorioretinal coloboma involving the macula and optic nerve, with secondary congenital nystagmus and high myopia, as well as a right-sided posterior cataract; her 52-year-old mother had bilateral optic disc colobomas.
In a 4-year-old Chinese boy (family 18739) with left optic disc hypoplasia and bilateral posterior microphthalmia (MCOPCB11; 620731), Jiang et al. (2021) identified heterozygosity for a c.1232A-G transition (c.1232A-G, NM_003468.4) in the FZD5 gene, resulting in a tyr411-to-cys (Y411C) substitution at a highly conserved residue within a transmembrane domain. His mother, who had bilateral inferior chorioretinal hypoplasia and right optic disc hypoplasia, was also heterozygous for the mutation, which was present at very low minor allele frequency (1/143,012) in the gnomAD database.
In a Chinese sister and brother and their affected father (family 9574) with coloboma (MCOPCB11; 620731), Jiang et al. (2021) identified heterozygosity for a 1-bp deletion (c.1428delG, NM_003468.4) in the FZD5 gene, causing a frameshift predicted to result in a premature termination codon (Ser477AlafsTer130). The 3-year-old sister exhibited photophobia and had bilateral coloboma; the 1-year-old brother had strabismus and left-sided inferior chorioretinal hypoplasia and right-sided coloboma; and their 32-year-old father had right-sided coloboma with visual acuity reduced to light perception, and left-sided optic disc hypoplasia with visual acuity of 20/15. The deletion was not found in the gnomAD database.
In a Chinese brother and sister and their affected father (family 5485) with coloboma (MCOPCB11; 620731), Jiang et al. (2021) identified heterozygosity for a 4-bp duplication (c.1403_1406dupACCT, NM_003468.4), causing a frameshift predicted to result in a premature termination codon (Tyr470ProfsTer130). Both sibs exhibited nystagmus and had bilateral uveal and iris coloboma, whereas their father had bilateral optic disc and inferior chorioretinal hypoplasia. The duplication was not found in the gnomAD database.
Aubert-Mucca, M., Pernin-Grandjean, J., Marchasson, S., Gaston, V., Habib, C., Meunier, I., Sigaudy, S., Kaplan, J., Roche, O., Denis, D., Bitoun, P., Haye, D., Verloes, A., Calvas, P., Chassaing, N., Plaisancie, J. Confirmation of FZD5 implication in a cohort of 50 patients with ocular coloboma. Europ. J. Hum. Genet. 29: 131-140, 2021. [PubMed: 32737437] [Full Text: https://doi.org/10.1038/s41431-020-0695-8]
He, X., Saint-Jeannet, J.-P., Wang, Y., Nathans, J., Dawid, I., Varmus, H. A member of the frizzled protein family mediating axis induction by Wnt-5A. Science 275: 1652-1654, 1997. [PubMed: 9054360] [Full Text: https://doi.org/10.1126/science.275.5306.1652]
Holt, R., Goudie, D., Verde, A. D., Gardham, A., Ramond, F., Putoux, A., Sarkar, A., Clowes, V., Clayton-Smith, J., Banka, S., Cortazar Galarza, L., Thuret, G., and 11 others. Individuals with heterozygous variants in the Wnt-signalling pathway gene FZD5 delineate a phenotype characterized by isolated coloboma and variable expressivity. Ophthalmic Genet. 43: 809-816, 2022. [PubMed: 36695497] [Full Text: https://doi.org/10.1080/13816810.2022.2144905]
Jiang, Y., Ouyang, J., Li, S., Xiao, X., Sun, W., Zhang, Q. Confirming and expanding the phenotypes of FZD5 variants: Coloboma, inferior chorioretinal hypoplasia, and high myopia. Molec. Vision 27: 50-60, 2021. [PubMed: 33633439]
Liu, C., Widen, S. A., Williamson, K. A., Ratnapriya, R., Gerth-Kahlert, C., Rainger, J., Alur, R. P., Strachan, E., Manjunath, S. H., Balakrishnan, A., Floyd, J. A., UK10K Consortium, Li, T., Waskiewicz, A., Brooks, B. P., Lehmann, O. J., FitzPatrick, D. R., Swaroop, A. A secreted WNT-ligand-binding domain of FZD5 generated by a frameshift mutation causes autosomal dominant coloboma. Hum. Molec. Genet. 25: 1382-1391, 2016. [PubMed: 26908622] [Full Text: https://doi.org/10.1093/hmg/ddw020]
Wang, Y., Macke, J. P., Abella, B. S., Andreasson, K., Worley, P., Gilbert, D. J., Copeland, N. G., Jenkins, N. A., Nathans, J. A large family of putative transmembrane receptors homologous to the product of the Drosophila tissue polarity gene frizzled. J. Biol. Chem. 271: 4468-4476, 1996. [PubMed: 8626800] [Full Text: https://doi.org/10.1074/jbc.271.8.4468]