FZD6 is a protein coding gene that comprises 8 exons extending for about 41 kb of genomic DNA. It is located on human chromosome 8q22.3, it has 7 transcripts, 82 orthologues, 12 paralogues and is associated with 3 phenotypes.

Six transcripts have been found for this gene (font: FZD6_transcript_ensembl)

Not identified.

The Frizzled (FZD) gene was initially isolated as a Drosophilla tissue polarity gene (Adler et al., 1990) and later was characterized the human FZD gene homologue (Zhao et al., 1995).
The Frizzled proteins are the receptors for WNT glycoproteins. Most of FZD are coupled with the β-catenin canonical signaling pathway, which leads to nuclear translocation of these effectors and activation of Wnt target genes. Others two non-canonical signaling pathways β-catenin-independent (Wnt-Ca2+ and planar cell polarity) involves PKC and intracellular calcium stores or the Rho family of GTPase, to regulate intracellular calcium levels or actin cytoskeleton reorganization.
The FZD6 gene encodes a 706 amino-acid protein with seven transmembrane domains (amino acids 202-222, 234-254, 284-305, 325-345, 371-391, 417-437, 474-494) with a highly conserved cystein-rich domain (cysteine-rich domain, CRD) in the N-terminal extracellular region (amino acids 1-18), which is necessary to the binding with Wnt-ligands. Almost all FZD receptors share a C-terminal portion (amino acids 495-706), spanning the KTxxxW motif, that is a binding site for the cytoplasmatic protein containing the PDZ domain (like a Dishevelled protein). However, unlike many other Fz family members (Tokuhara et al., 1998), FZD6 does not contain a C-terminal PDZ domain-binding motif.
The molecular mass of FZD6 protein is 79 kDa and alternative splicing results in multiple transcript variants, some of which are not involved in the encoding of proteins (see transcription section).

    Figure 4. FZD6 structure. The CRD is shaded in green, the 10 cysteine (C) residues forming five disulfide bonds is highlighted. DVL protein is also illustrated with DIX, PDZ and DEP domains and the non-interaction with FZD6 carboxyl tail is reported with a barred arrow.
Ψ= Potential N-glycosylation sites; ECL = extracellular loop; ICL = intracellular loop (MacDonald et al., 2012).

In Tokuhara's study (Tokuhara et al., 1998), 4,4 kb FZD6 mRNA was detected in several adult human tissues, like heart, brain, placenta, lung, liver, pancreas, kidney, thymus, colon, testis, ovary and other. In the fetus is expressed in brain, lung, liver and kidney. Furthermore, it was detected in many cancer cell lines among which MOLT4 (human acute T lymphoblastic leukaemia), A549 (lung cancer), SW480 (colon cancer), G361 (melanoma) and HeLa (cervical cancer) (Figure 5).
In Wagner's study (Wagner et al., 2004), the FZD6 gene overexpression was determined in slow-dividing fraction (SDF) of hematopoietic progenitor cells (HPCs) within the CD34+ /CD38- population.

    Figure 5. FZD6 mRNA expression analysis. (A) Adult human tissue. (B) Human cancer cell lines. The arrow indicates the FZD6 mRNA 4,4 kb position (Tokuhara et al., 1998).

 FZD6 is a multi-pass membrane protein, with seven transmembrane domains which have cysteine-rich domains (CRD) in N-terminal extracellular region and carboxyl tail in intracellular region. Trough the CRD, FZD6 receptor binds Wnt ligands in extracellular microenvironment.

Frizzled receptors mediate Wnt ligand signalling, which is crucially involved in regulating tissue development and differentiation, and is often deregulated in cancer.
Fzd6 is generally associated with PCP (planar cell polarity) signaling in epithelial cells: for example, it was shown that controls macroscopic hair patterning in the mouse. Both epithelial cells and melanocytes are FZD6 expression sites (Guo et al., 2004).
Data from Golan's study (Golan et al., 2004), suggest that human FZD6 activates the transforming growth factor-β-activated kinase-NEMO-like kinase ( NLK) pathway that blocks nuclear LEF1 (TCF/LEF, T cell factor/lymphoid enhancer factor) binding to target promoters, thus repressing the ability of CTNNB1 (β-catenin) to activate transcription of Wnt target genes. The FZD6 protein blocks canonical Wnt pathway through cross-talks with repressors Wnt signaling downstream of the β-catenin destruction complex. Indeed, human FZD6 does not change the cellular levels of β-catenin, suggesting that the ectopically expressed FZD6 does not destabilize the β-catenin. In this respect, the FZD6 does not interfere with nuclear translocation of β-catenin or theirs TCF-binding, but the repressive activity is mediated by inhibition of TCF/LEF binding and TCF/β-catenin complexes formation to target DNA.
Furthermore, Kilander's study (Kilander et al., 2014) identified FZD6 as a G-protein-coupled receptors ( GPCR) and Disheveled ( DVL1) protein as a master regulator of FZD6/G-protein coupling, which at high levels can also act as negative regulator of Wnt/FZD- induced G protein signaling. DIX domain of DVL is responsible for the negative regulation of FZD6-G-protein precoupling.
Frizzled-6 (Fzd6), regulates hematopoietic stem/progenitor cell (HSPC) expansion and survival in a hematopoietic cell-intrinsic manner.
Abidin's research (Abidin et al., 2015) showed that FZD6-/- HSCs are able to localize in the bone marrow but it does not reconstitute a lethally irradiated host. The FZD6 deficiency impaires the expansion and survival of HSCs, resulting in activation of caspase-3 ( CASP3) and weak HSCs engraftment after bone marrow transplant in C57BL/6 mice. The non-canonical Wnt receptor FZD6, is also necessary for HSC expansion during emergency hematopoiesis.
FZD6 is involved in the neural tube closure and plays a role in the regulation of the establishment of planar cell polarity (PCP), together with FZD3, particularly in the orientation of asymmetric bundles of stereocilia in a group of auditory and vestibular sensory cells located in the inner ear (De Marco et al., 2011).

The FZD6 gene is conserved in chimpanzee, Rhesus monkey, dog, cow, mouse, rat, chicken, zebrafish, and frog.

    De novo frameshift mutation c.1843_1844insA (p.Cys615X)= it introduces a premature stop codon and encodes for a truncated protein that lacks the last 51 amino-acids in carboxyl-terminal tail.
De novo frameshift mutation c.1843_1844insA (p.Cys615X)= it introduces a premature stop codon and encodes Missense changes c.1214G>A (p.Arg405Gln) = the mutation changes a positively charged residue into a hydrophilic uncharged residue. Its prediction suggests that it is probably a pathogenic protein.
Missense changes c.1531C>T (p.Arg511Cys)= this variant introduces a cysteine in a conserved region and may result in abnormal conformational changes of the protein.
Missense changes c.1532G>A (p.Arg511His)= the variant represents an exchange of two basic amino-acids in a conserved region.
Single nucleotide substitution (c.20C>T) = affecting the 3' UTR of the FZD6 gene. This substitution changed the target site for miR628, whichcould cause changes in FZD6 gene regulation.
Homozygous nonsense mutation c.1750G>T (p. Glu584X) = mutation involved in autosomal-recessive nail dysplasia. The G>T transition in exon 6 of FZD6 changes the codon GAA (encoding glutamic acid) to TAA (stop codon). This induces the truncated protein formation, lacking the C-terminus. To determine his functional effect, Naz' s group (Naz et al., 2012) carried out immunofluorescence analysis, which revealed the presence of a mutant FZD6 protein in the cell membrane. The KTxxxW motif is also present in FZD6 mutant form, so could be that Wnt ligands may still be able to bind to truncated protein, leading to recruitment of DVL protein but no of other cytoplasmic mediators such as G proteins (Figure 7).
Missense mutation c.1531C>T (p.Arg511Cys) = mutation involved in autosomal-recessive nail dysplasia. The changed arginine residue is conserved in several species, supporting the potential functional importance of this variant. It was observed that FZD6 changed protein with this mutation is confined to intracellular vesicles (lysosomes), where is probably degraded (Figure 7. Fröjmark et al., 2011). Then was also seen that FZD6-Arg511Cys mutation is incapable of G-protein precoupling, even though it still binds DVL (Kilander et al., 2014)
Missense mutation c.1266G>A (p.Gly422Asp) = mutation involved in autosomal-recessive nail dysplasia. The changed glycine residue is conserved in several species, supporting the potential functional importance of this variant. Variant is located in the sixth transmembrane domain of the mutant FZD6 protein, suggesting that FZD6 mutant can affect binding of Wnt ligand. It is highly likely that also this mutant FD6 is confined and degraded in the lysosome.(Figure 7. Raza et al., 2012).

 Figure 6. FZD6 variants. Schematic model of FZD6 gene (A) and protein (B) with the locations of the rare variants involved in Neural tube defects (NTDs). In red are framed FZD6 mutations which are absent in controls of NTDs and which are predicted to have a functional effect. CRD= cysteine-rich domain (De Marco et al., 2011).

 Figure 7. Representation of the human FZD6 protein domains. Positions of the FZD6 mutations involved in autosomal-recessive nail dysplasia are shown with an arrow.