Alternative titles; symbols
HGNC Approved Gene Symbol: IL17RD
Cytogenetic location: 3p14.3 Genomic coordinates (GRCh38) : 3:57,089,982-57,170,317 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3p14.3 | Hypogonadotropic hypogonadism 18 with or without anosmia | 615267 | Autosomal dominant; Autosomal recessive; Digenic dominant | 3 |
Fibroblast growth factors (FGFs; see 603726) are secreted proteins involved in cellular proliferation, migration, differentiation, and survival. FGF activity is negatively regulated by members of the 'sprouty' family (e.g., SPRY1, 602465). The SEF protein is a modulator of FGF signaling.
Genes expressed in similar complex groups are said to belong to synexpression groups. Such genes often encode proteins that function in a common pathway. Tsang et al. (2002) and Furthauer et al. (2002) identified a synexpression group in zebrafish that includes Sef (similar expression to FGFs). Sef is expressed with the zebrafish homologs of FGF3 (164950), FGF8 (600483), SPRY2 (602466), and SPRY4 (607984). The intracellular domain of Sef interacts with FGFR1 (136350) and FGFR2 (176943). EST database searching identified human, frog, and mouse homologs of Sef that show homology to the intracellular region of IL17R (605461).
By PCR of a human umbilical vein cell (HUVEC) cDNA library, Yang et al. (2003) cloned full-length human SEF. The deduced 739-amino acid protein has an N-terminal signal peptide, followed by an extracellular domain, a transmembrane domain, and a cytoplasmic domain. The extracellular domain contains 7 N-glycosylation sites and 8 cysteines that are conserved in mouse and zebrafish Sef homologs. Northern blot analysis detected major 8.5- and minor 4.4-kb transcripts in human tissues. Expression was highest in kidney, followed by heart, skeletal muscle, colon, and small intestine, and was barely detected in brain, spleen, liver, placenta, and lung. PCR analysis showed a similar expression pattern, with highest levels in ovary and breast. SEF was enriched in HUVECs, but showed low or no expression in other human cell lines examined. In situ hybridization revealed expression of SEF in ductal epithelial cells of various tissues and in breast cancer cells.
Miraoui et al. (2013) investigated the localization patterns of Il17rd in the nasal region of mouse embryos at embryonic day (E) 10.5 to E12.5, and observed that Il17rd immunoreactivity was highest in E10.5 epithelium of the developing olfactory placode, where Fgf8 is present, whereas it was much milder in the mesenchyme. Il17rd localized to the perinuclear compartment of the cell. At E12.5, Il17rd was no longer detectable in the olfactory epithelium, but was detected in the septal area and in the midbrain-hindbrain junction. Il17rd was undetectable in the brain of Fgf8 hypomorphic embryos. At E11.5, when GnRH (152760) neurons begin migrating from the olfactory placode to the developing olfactory bulb, Il17rd levels were dramatically decreased overall compared to E10.5, but Il17rd was present in a few GnRH neurons. Miraoui et al. (2013) suggested that IL17RD might have a role in the early stages of GnRH neuron fate specification.
Furthauer et al. (2002) determined that the IL17RD gene contains 13 exons.
By genomic sequence analysis, Furthauer et al. (2002) mapped the IL17RD gene to chromosome 3p14.3-p14.2.
By immunoprecipitation and Western blot analyses, Yang et al. (2003) showed that SEF formed homomeric complexes and interacted with FGFR1 in transfected human embryonic kidney cells. Overexpression of SEF suppressed FGF-induced signal transduction, and this inhibition was dependent on the intracellular IL17R-like domain of SEF. Yang et al. (2003) proposed that SEF is likely to play critical roles in proliferation, migration, and angiogenesis.
Torii et al. (2004) found that SEF localized mainly to the Golgi apparatus of transfected human embryonic kidney cells. After stimulation, some SEF proteins translocated to the plasma membrane region. In stimulated cells, activated MEK (see 176872) and activated ERK (600997) colocalized with SEF in both the Golgi apparatus and plasma membrane regions. SEF bound activated MEK and inhibited dissociation of the MEK-ERK complex, thus blocking nuclear translocation of activated ERK. SEF inhibited the stimulus-dependent phosphorylation of the nuclear ERK substrate ELK1 (311040), but it did not inhibit phosphorylation of the cytoplasmic ERK substrate RSK2 (300075). Downregulation of endogenous SEF by small interfering RNA enhanced the stimulus-dependent ERK nuclear translocation and ELK1 activation. Torii et al. (2004) concluded that SEF regulates the nuclear Ras/ERK signaling pathway by spatially blocking nuclear translocation of activated ERK.
Zisman-Rozen et al. (2007) found that SEF was highly expressed in epithelial cells of human breast, prostate, thyroid gland, and the ovarian surface. By comparison, SEF expression was substantially downregulated in the majority of tumors originating from these epithelia. The association of SEF downregulation and tumor progression was statistically significant. Ectopic expression of SEF suppressed proliferation of breast carcinoma cells, whereas inhibition of endogenous SEF expression accelerated FGF-dependent proliferation of cervical carcinoma cells. Zisman-Rozen et al. (2007) concluded that SEF functions as a tumor suppressor.
In 8 unrelated individuals with congenital hypogonadotropic hypogonadism (HH18; 615267), Miraoui et al. (2013) identified 7 missense mutations in the IL17RD gene (see, e.g., 606807.0001-606807.0005). Two of the patients were homozygous for IL17RD mutations, and in another 2 patients, their heterozygous IL17RD mutation was accompanied by a heterozygous mutation in another HH-associated gene, FGFR1 (see 136350.0026) and KISS1R (see 604161.0007), respectively. Miraoui et al. (2013) concluded that mutations in genes encoding components of the FGF pathway are associated with complex modes of CHH inheritance and act primarily as contributors to an oligogenic genetic architecture underlying CHH.
In 2 unrelated male patients with congenital hypogonadotropic hypogonadism (HH18; 615267), both anosmic, Miraoui et al. (2013) identified heterozygosity for a c.392A-C transversion in exon 6 of the IL17RD gene, resulting in a lys131-to-thr (K131T) substitution at a residue between the Ig-like and transmembrane domains. One of the patients had absent puberty whereas the other had partial puberty. The patient with partial puberty also displayed abnormal dentition, and had a sister of unknown genotype who had delayed puberty. Neither patient had hearing loss. Both sets of parents, for whom genotype was unknown, were unaffected. In a cell-based reporter-gene assay, the K131T mutant inhibited FGF8 (600483) to a significantly lesser degree than wildtype IL17RD, indicating loss of function. In addition, the mutant exhibited significantly decreased cell surface expression, at approximately 15% that of wildtype.
In a female patient with congenital hypogonadotropic hypogonadism (HH18; 615267) who was anosmic and also displayed hearing loss, abnormal dentition, and low bone mass, Miraoui et al. (2013) identified heterozygosity for a c.1136A-G transition in exon 13 of the IL17RD gene, resulting in a tyr379-to-cys (Y379C) substitution in the SEF/IL17R domain. The patient was also heterozygous for a missense mutation in the FGFR1 gene (G348R; 136350.0026). Her mother, who carried only a heterozygous Y379C mutation in IL17RD, was anosmic but had normal hearing and did not display features of hypogonadotropic hypogonadism. Neither mutation was found in the unaffected father or in 155 controls. In a cell-based reporter-gene assay, the Y379C mutant inhibited FGF8 (600483) to a lesser degree than wildtype IL17RD (75% relative to wildtype), indicating reduced function.
In a male patient with congenital hypogonadotropic hypogonadism (HH18; 615267) who was anosmic and also had hearing loss, Miraoui et al. (2013) identified heterozygosity for a c.2204C-T transition in exon 15 of the IL17RD gene, resulting in an ala735-to-val (A735V) substitution in the C terminus. The patient was also heterozygous for a missense mutation in the KISS1R gene (A194D; 604161.0007). The patient had a sister who also had anosmic hypogonadotropic hypogonadism, and their parents were unaffected; family member genotypes were unavailable. In COS-7 cells, the A735V mutant exhibited significantly decreased cell surface expression, at approximately 15% that of wildtype.
In a male patient with congenital hypogonadotropic hypogonadism (HH18; 615267) who was anosmic and also had absent puberty, hearing loss, and low bone mass, Miraoui et al. (2013) identified heterozygosity for a c.1403C-T transition in exon 14 of the IL17RD gene, resulting in a ser468-to-leu (S468L) substitution in the SEF/IL17R domain. The patient had a twin brother with hearing loss and anosmia who did not carry the mutation; their mother, who had anosmia and delayed puberty, was heterozygous for the mutation. The mutation was not found in their unaffected father or in 155 controls. In a cell-based reporter-gene assay, the S468L mutant inhibited FGF8 (600483) to a significantly lesser degree than wildtype IL17RD, indicating loss of function. In addition, the mutant exhibited significantly decreased cell-surface expression, at approximately 50% that of wildtype.
In a twin brother and sister with congenital hypogonadotropic hypogonadism (HH18; 615267), who were both anosmic and also had hearing loss, Miraoui et al. (2013) identified homozygosity for a c.1730C-A transversion in exon 14 of the L17RD gene, resulting in a pro577-to-gln (P577Q) substitution in the SEF/IL17R domain. The brother also displayed abnormal dentition. Their mother, who had delayed puberty, was heterozygous for the mutation; their unaffected father's genotype was unavailable. The mutation was not found in 155 controls.
Furthauer, M., Lin, W., Ang, S.-L., Thisse, B., Thisse, C. Sef is a feedback-induced antagonist of Ras/MAPK-mediated FGF signalling. Nature Cell Biol. 4: 170-174, 2002. [PubMed: 11802165] [Full Text: https://doi.org/10.1038/ncb750]
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]
Torii, S., Kusakabe, M., Yamamoto, T., Maekawa, M., Nishida, E. Sef is a spatial regulator for Ras/MAP kinase signaling. Dev. Cell 7: 33-44, 2004. [PubMed: 15239952] [Full Text: https://doi.org/10.1016/j.devcel.2004.05.019]
Tsang, M., Friesel, R., Kudoh, T., Dawid, I. B. Identification of Sef, a novel modulator of FGF signalling. Nature Cell Biol. 4: 165-169, 2002. [PubMed: 11802164] [Full Text: https://doi.org/10.1038/ncb749]
Yang, R.-B., Ng, C. K. D., Wasserman, S. M., Komuves, L. G., Gerritsen, M. E., Topper, J. N. A novel interleukin-17 receptor-like protein identified in human umbilical vein endothelial cells antagonizes basic fibroblast growth factor-induced signaling. J. Biol. Chem. 278: 33232-33238, 2003. [PubMed: 12807873] [Full Text: https://doi.org/10.1074/jbc.M305022200]
Zisman-Rozen, S., Fink, D., Ben-Izhak, O., Fuchs, Y., Brodski, A., Kraus, M. H., Bejar, J., Ron, D. Downregulation of Sef, an inhibitor of receptor tyrosine kinase signaling, is common to a variety of human carcinomas. Oncogene 26: 6093-6098, 2007. [PubMed: 17420726] [Full Text: https://doi.org/10.1038/sj.onc.1210424]