HGNC Approved Gene Symbol: FLRT3
Cytogenetic location: 20p12.1 Genomic coordinates (GRCh38) : 20:14,322,985-14,337,612 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20p12.1 | Hypogonadotropic hypogonadism 21 with anosmia | 615271 | Autosomal dominant | 3 |
The FLRT3 gene encodes a transmembrane cell-adhesion protein that is characterized by a cluster of leucine-rich repeats and 1 fibronectin type III domain within its extracellular region. Its action promotes the activation of fibroblast growth factor (FGF) signaling by increasing extracellular signal-regulated kinase (ERK; see 176948) phosphorylation (summary by Miraoui et al., 2013).
The FLRT family of proteins structurally resembles small leucine-rich proteoglycans found in the extracellular matrix. By searching a human EST database with portions of the FLRT1 protein (604806) sequence, Lacy et al. (1999) identified an EST encoding FLRT3. They isolated the complete coding region of FLRT3 by screening a human skeletal muscle cDNA library. The predicted 649-amino acid FLRT3 protein contains a putative N-terminal signal sequence, 10 leucine-rich repeats (LRRs) flanked by N- and C-terminal cysteine-rich regions, a fibronectin-/collagen-like domain, a transmembrane domain, and an intracellular C-terminal tail. FLRT3 has 4 potential N-glycosylation sites in its extracellular region. FLRT3 shares 55% amino acid sequence identity with FLRT1 and 44% identity with FLRT2 (604807). Northern blot analysis of a variety of human adult tissues detected a 4.4-kb FLRT3 transcript that was expressed at high levels in kidney, skeletal muscle, lung, and brain, and at lower levels in pancreas, liver, placenta, and heart. Lacy et al. (1999) suggested that FLRT3 functions in cell adhesion and/or receptor signaling.
By YAC mapping, Lacy et al. (1999) localized the FLRT3 gene to chromosome 20p11.
Maas et al. (2007) stated that the FLRT3 gene is nested within intron 3 of the MACROD2 gene (611567).
Bottcher et al. (2004) found that Xenopus Flrt3 was coexpressed with fibroblast growth factors (FGFs; see 131220). Flrt3 expression was induced after activation and downregulated after inhibition of FGF signaling. Xenopus Flrt3 interacted directly with FGF receptors (see 136350) in several in vitro and in vivo binding assays. Flrt3 signaling through FGF resulted in Erk (601795) phosphorylation and could be blocked by Mapk phosphatase-1 (600714). Bottcher et al. (2004) concluded that FLRT3 is a transmembrane modulator of FGF-MAPK signaling in vertebrates.
Using the ectodomain of human LPHN3 (ADGRL3; 616417) for affinity chromatography, O'Sullivan et al. (2012) purified Flrt3 and Flrt2 from rat synaptosome extracts. The interactions were confirmed by pull-down assays of rat brain extracts and with HEK293 cells expressing mouse Flrt3. HEK293 cells expressing Flrt3 clustered with axons of cocultured mouse hippocampal neurons expressing Lphn3. Knockdown of Lphn3 or Flrt3 in cultured neurons via short hairpin RNA, or exposure of neurons to soluble Lphn3, reduced excitatory synapse density. Knockdown of Flrt3 in mice via in utero electroporation significantly reduced dendritic protrusion density, with attenuation of glutamatergic transmission onto granule cells. O'Sullivan et al. (2012) proposed a model whereby the ectodomain of presynaptic LPHN3 interacts with the ectodomain of postsynaptic FLRT3, stabilizing the synapse.
In 3 unrelated individuals with congenital hypogonadotropic hypogonadism (HH21; 615271) with anosmia, Miraoui et al. (2013) identified 4 missense mutations in the FLRT3 gene (604808.0001-604808.0004). One of the 3 probands belonged to a large consanguineous 10-generation French Canadian family with anosmic HH and cleft palate (see HH2, 147950), in which Tornberg et al. (2011) had identified missense mutations in both the FGFR1 (136350.0025) and HS6ST1 (604846.0002) genes; in that proband, Miraoui et al. (2013) also identified a missense mutation in another FGF-network gene, FGF17 (603725.0001). Another proband also carried a heterozygous mutation in FGFR1 (136350.0029). Miraoui et al. (2013) concluded that mutations in genes encoding components of the FGF pathway are associated with complex modes of congenital HH (CHH) inheritance and act primarily as contributors to an oligogenic genetic architecture underlying CHH.
Egea et al. (2008) found that knockout of Flrt3 in mice was embryonic lethal. At midgestation, Flrt3 -/- embryos showed a range of malformations, including cardia bifida, anterior neural tube closure defects, asymmetric development of the headfolds, and failure of embryonic turning and ventral body closure. In most severe cases, the embryos developed outside the yolk sac. Flrt3 -/- embryos showed a highly disorganized basement membrane in the region of the anterior visceral endoderm, which secretes factors involved in anterior-posterior axis formation. Adjacent anterior epiblast cells displayed an epithelial-to-mesenchymal transition (EMT)-like process characterized by loss of cell polarity, cell ingression, and upregulation of EMT and mesodermal marker genes.
In the female proband from a large consanguineous 10-generation French Canadian family with anosmic hypogonadotropic hypogonadism (HH21; 615271) and cleft palate, previously reported by White et al. (1983) and in whom Tornberg et al. (2011) had identified missense mutations in the FGFR1 (R250Q; 136350.0025) and HS6ST1 (R296W; 604846.0002) genes, Miraoui et al. (2013) also identified 2 mutations in exon 3 of the FLRT3 gene: a heterozygous c.290A-G transition, resulting in a glu97-to-gly (E97G) substitution, and a homozygous c.431G-T transversion, resulting in a ser144-to-ile (S144I; 604808.0002) substitution, both at highly conserved residues in the leucine-rich domain. In addition, the proband was heterozygous for a missense mutation in the FGF17 gene (I108T; 603725.0001). Three other affected family members also carried mutations in the FGFR1, HS6ST1, and FLRT3 genes, and 4 unaffected family members carried 1 or 2 mutations in those genes. Neither FLRT3 mutation was found in 155 controls or in the 1000 Genomes Project database.
See 604808.0001 and Miraoui et al. (2013).
In a female proband with congenital hypogonadotropic hypogonadism (HH21; 615271), who was anosmic and also had hearing loss and low bone mass, Miraoui et al. (2013) identified heterozygosity for a c.205C-A transversion in exon 3 of the FLRT3 gene, resulting in a gln69-to-lys (Q69K) substitution at a highly conserved residue in the leucine-rich domain. The mutation was not found in 155 controls or in the 1000 Genomes Project database. The patient was also heterozygous for a missense mutation in the FGFR1 gene (E670K; 136350.0029).
In a male proband with congenital hypogonadotropic hypogonadism (HH21; 615271), who was anosmic and underwent partial puberty, Miraoui et al. (2013) identified heterozygosity for a c.1016A-G transition in exon 3 of the FLRT3 gene, resulting in a lys339-to-arg (K339R) substitution at a highly conserved residue in the cysteine-rich domain. The mutation was not found in 155 controls or in the 1000 Genomes Project database.
Bottcher, R. T., Pollet, N., Delius, H., Niehrs, C. The transmembrane protein XFLRT3 forms a complex with FGF receptors and promotes FGF signalling. Nature Cell Biol. 6: 38-44, 2004. [PubMed: 14688794] [Full Text: https://doi.org/10.1038/ncb1082]
Egea, J., Erlacher, C., Montanez, E., Burtscher, I., Yamagishi, S., Hess, M., Hampel, F., Sanchez, R., Rodriguez-Manzaneque, M. T., Bosl, M. R., Fassler, R., Lickert, H., Klein, R. Genetic ablation of FLRT3 reveals a novel morphogenetic function for the anterior visceral endoderm in suppressing mesoderm differentiation. Genes Dev. 22: 3349-3362, 2008. [PubMed: 19056886] [Full Text: https://doi.org/10.1101/gad.486708]
Lacy, S. E., Bonnemann, C. G., Buzney, E. A., Kunkel, L. M. Identification of FLRT1, FLRT2, and FLRT3: a novel family of transmembrane leucine-rich repeat proteins. Genomics 62: 417-426, 1999. [PubMed: 10644439] [Full Text: https://doi.org/10.1006/geno.1999.6033]
Maas, N. M. C., Van de Putte, T., Melotte, C., Francis, A., Schrander-Stumpel, C. T. R. M., Sanlaville, D., Genevieve, D., Lyonnet, S., Dimitrov, B., Devriendt, K., Fryns, J.-P., Vermeesch, J. R. The C20orf133 gene is disrupted in a patient with Kabuki syndrome. J. Med. Genet. 44: 562-569, 2007. [PubMed: 17586838] [Full Text: https://doi.org/10.1136/jmg.2007.049510]
Miraoui, H., Dwyer, A. A., Sykiotis, G. P., Plummer, L., Chung, W., Feng, B., Beenken, A., Clarke, J., Pers, T. H., Dworzynski, P., Keefe, K., Niedziela, M., and 17 others. Mutations in FGF17, IL17RD, DUPS6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism. Am. J. Hum. Genet. 92: 725-743, 2013. [PubMed: 23643382] [Full Text: https://doi.org/10.1016/j.ajhg.2013.04.008]
O'Sullivan, M. L., de Wit, J., Savas, J. N., Comoletti, D., Otto-Hitt, S., Yates, J. R., III, Ghosh, A. FLRT proteins are endogenous latrophilin ligands and regulate excitatory synapse development. Neuron 73: 903-910, 2012. [PubMed: 22405201] [Full Text: https://doi.org/10.1016/j.neuron.2012.01.018]
Tornberg, J., Sykiotis, G. P., Keefe, K., Plummer, L., Hoang, X., Hall, J. E., Quinton, R., Seminara, S. B., Hughes, V., Van Vliet, G., Van Uum, S., Crowley, W. F., Habuchi, H., Kimata, K., Pitteloud, N., Bulow, H. E. Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism. Proc. Nat. Acad. Sci. 108: 11524-11529, 2011. [PubMed: 21700882] [Full Text: https://doi.org/10.1073/pnas.1102284108]
White, B. J., Rogol, A. D., Brown, K. S., Lieblich, J. M., Rosen, S. W. The syndrome of anosmia with hypogonadotropic hypogonadism: a genetic study of 18 new families and a review. Am. J. Med. Genet. 15: 417-435, 1983. [PubMed: 6881209] [Full Text: https://doi.org/10.1002/ajmg.1320150307]