Alternative titles; symbols
HGNC Approved Gene Symbol: SEMA3E
Cytogenetic location: 7q21.11 Genomic coordinates (GRCh38): 7:83,363,238-83,649,139 (from NCBI)
SEMA3E is a secreted class 3 semaphorin that triggers repulsion of endothelial cells in specific vascular beds and modulates axonal growth and synaptic connectivity for the correct wiring of the central nervous system. SEMA3E is a neurotrophic factor that is essential for development of hypothalamic neurons that produce gonadotropin-releasing hormone (GNRH; 152760) (Cariboni et al., 2015).
By sequencing clones obtained from a size-fractionated brain cDNA library, Nagase et al. (1997) cloned SEMA3E, which they designated KIAA0331. The 3-prime untranslated region of the transcript contains an Alu repetitive element. The deduced 775-amino acid protein has a calculated molecular mass of about 95 kD. SEMA3E shares 87.4% identity with mouse Sema3e. RT-PCR detected highest expression in brain and prostate, followed by small intestine, thymus, and lung. Little to no expression was detected in other tissues examined.
By differential display of metastatic and nonmetastatic mouse cell lines, Christensen et al. (1998) cloned 2 splice variants of mouse Sema3e, which they called Semah. Both variants encode the same 775-amino acid protein, which contains an N-terminal signal sequence followed by a large semaphorin domain, a C2 immunoglobulin-like domain, and a positively charged C terminus. Semah also has 13 conserved cysteines and 3 potential N-glycosylation sites. Northern blot analysis detected transcripts of 7.0, 4.5, and 4.0 kb expressed at highest levels in adult mouse brain and lung; RT-PCR determined that the 5-prime ends of the 4.5- and 4.0-kb transcripts were identical. All 3 transcripts were detected in whole mouse embryos and in 12 of 12 metastatic cell lines, but they were detected in only 2 of 6 nonmetastatic cells. Expression was not detected in immortalized mouse fibroblasts. In situ hybridization of embryonic mice detected expression in developing lungs and skeletal elements and in the ventral horns of the developing neural tube.
By radiation hybrid analysis, Nagase et al. (1997) mapped the SEMA3E gene to chromosome 7.
Lalani et al. (2004) mapped the SEMA3E gene to chromosome 7q21.11.
Gu et al. (2005) found that signaling by semaphorin-3E and its receptor plexin-D1 (604282) controls endothelial cell positioning and the patterning of developing vasculature in the mouse. Sema3e is highly expressed in developing somites, where it acts as a repulsive cue for plexin-D1-expressing endothelial cells of adjacent intersomitic vessels. Sema3e-plexin-D1 signaling did not require neuropilins (see 602069), which had been presumed to be obligate Sema3 coreceptors. Moreover, genetic ablation of Sema3e or plexin-D1 but not neuropilin-mediated Sema3 signaling disrupted vascular patterning. Gu et al. (2005) concluded that their results reveal an unexpected semaphorin signaling pathway and define a mechanism for controlling vascular patterning.
Pecho-Vrieseling et al. (2009) showed that a recognition system of a specific sensory motor connection involving expression of the class 3 semaphorin Sema3e by selected motor neuron pools, and its high-affinity receptor plexin D1 (PLXND1; 604282) by proprioceptive sensory neurons, is a critical determinant of synaptic specificity in sensory motor circuits in mice. Changing the profile of Sema3e-Plxnd1 signaling in sensory or motor neurons results in functional and anatomic rewiring of monosynaptic connections, but does not alter motor pool specificity. Pecho-Vrieseling et al. (2009) concluded that patterns of monosynaptic connectivity in this prototypic central nervous system circuit are constructed through a recognition program based on repellent signaling.
Using GN11 and GT1-7 cells as established models of immature migrating and maturing hypothalamic GnRH neurons, respectively, Cariboni et al. (2015) observed that SEMA3E did not affect guidance or survival in GN11 neurons, but in GT1-7 cells, serum starvation-induced death was dramatically reduced by SEMA3E, suggesting a survival function for SEMA3E in hypothalamic GnRH neurons. Blocking the SEMA3E receptor PLXND1 abolished the protective effect of SEMA3E on GT1-7 cells but did not affect GN11 cells, supporting the notion that SEMA3E protects the survival of maturing hypothalamic, but not immature, GnRH neurons in a PLXND1-dependent fashion. Treatment with the PI3K (see 171834) inhibitor LY294 prevented the SEMA3E-mediated protection of GT1-7 cells, as did treatment with a function-blocking antibody for the PLXND1 coreceptor KDR (191306). Cariboni et al. (2015) suggested that SEMA3E signals through PLXND1 in a KDR-dependent fashion to promote PI3 kinase activation in maturing GnRH neurons.
Reclassified Variants
The S703L variant (608166.0001) reported by Lalani et al. (2004) has been reclassified as a variant of unknown significance. In a patient originally described by Martin et al. (2001) with CHARGE syndrome (214800) and a de novo balanced translocation involving chromosomes 2 and 7, Lalani et al. (2004) mapped the translocation breakpoints and identified the SEMA3E gene within 200 kb of the breakpoint on 7q21.11. Screening of patients with CHARGE syndrome for mutations in the SEMA3E gene revealed a de novo mutation in an unrelated patient (S703L; 608166.0001).
Associations Pending Confirmation
For discussion of a possible association between mutation in the SEMA3E gene and hypogonadotropic hypogonadism with anosmia (see 147950), see 608166.0002.
For discussion of a possible association between mutation in the SEMA3E gene and an intellectual developmental disorder with cognitive regression, see 608166.0003.
In Sema3e-null mice, Cariboni et al. (2015) performed immunohistochemical staining of mouse heads at embryonic day 14.5 and observed a significant reduction in the numbers of GnRH (152760) neurons compared to wildtype littermates. In addition, residual neurons in the medial preoptic area appeared collapsed, and neuron loss was pronounced in the forebrain but not the nose. Cariboni et al. (2015) noted the similarity to the phenotype of mice lacking PLXND1 (604282) or KDR (191306), and suggested that SEMA3E serves as a ligand for a PLXND1/KDR coreceptor complex to promote the survival of GnRH neurons in the developing brain. In addition, the authors observed a markedly reduced number of GnRH-positive neurites at the median eminence in adult Sema3e-null mice compared to wildtype males, and the testes of adult male mice lacking Sema3e were smaller than those of wildtype littermates.
This variant, formerly titled CHARGE SYNDROME, has been reclassified as a variant of unknown significance based on the findings of Suspitsin et al. (2020) and a review of the gnomAD database by Hamosh (2022).
In a patient with CHARGE syndrome (214800), Lalani et al. (2004) identified a 2108C-T transition in the SEMA3E gene resulting in a ser703-to-leu (S703L) substitution. The mutation was not found in either parent or in 338 ethnically matched control chromosomes. The authors noted that ser703 is conserved in human, mouse, and rat.
Suspitsin et al. (2020) sequenced 344 immunity-related genes in 333 patients with inborn errors of immunity. They identified identical twins with a de novo occurrence of the c.2108C-T S703L variant. While the twins had destructive pneumonia, atopic dermatitis, recurrent respiratory infections, oral candidiasis, and molluscum contagiosum, all consistent with an inborn error of immunity, they had no features of CHARGE syndrome.
Hamosh (2022) found the S703L variant in 7 of 282,814 alleles in the gnomAD database, in heterozygosity only. This frequency suggests that the S703L variant is not pathogenic for CHARGE syndrome, which manifests in the neonatal period with multiple congenital anomalies.
This variant is classified as a variant of unknown significance because its contribution to hypogonadotropic hypogonadism with anosmia (Kallmann syndrome; see 147950) has not been confirmed.
Cariboni et al. (2015) performed exome sequencing in 121 patients with Kallmann syndrome and identified 2 affected brothers with heterozygosity for a c.1855C-T transition (c.1855C-T, ENST00000307792.3) in exon 16 of the SEMA3E gene, resulting in an arg619-to-cys (R619C) substitution at a residue that is highly conserved in mammals. Analysis of their exome data for mutation in known Kallmann syndrome-associated genes revealed that both brothers were also heterozygous for an F1019C substitution in the hypogonadotropic hypogonadism-5 (HH5; 612370)-associated CHD7 gene (608892). Parental DNA was unavailable for study. The brothers were diagnosed at ages 15 and 17 years, respectively, with anosmia, prepubertal testes, and GnRH deficiency in the setting of hypogonadal testosterone levels. The SEMA3E mutation was not found in the 1000 Genomes Project database, and occurred at a very low minor allele frequency (0.0004%) in the NHLBI GO Exome Sequencing Project database in European ancestry samples, whereas the CHD7 mutation was not found in either database. Ligand-binding assays demonstrated that both wildtype SEMA3E and the R619C mutant bound GT1-7 cells (maturing hypothalamic GnRH neurons, see 152760), although the mutant failed to protect the cells from serum starvation-induced death. In addition, the mutant was ineffective in AKT (164730) activation in serum-starved GT1-7 cells. Cariboni et al. (2015) suggested that SEMA3E-mediated survival signaling in maturing GnRH neurons is compromised by the R619C mutation.
This variant is classified as a variant of unknown significance because its contribution to an intellectual developmental disorder with cognitive regression has not been confirmed.
In a patient with severely impaired intellectual development and cognitive regression, Paganoni et al. (2022) identified a de novo heterozygous 1-bp deletion (c.621delG, NM_012431.3) in exon 6 of the SEMA3E gene, resulting in a frameshift and premature stop codon 15 amino acids downstream of the deletion (Arg208AspfsTer15). The affected residue is partially conserved across species. The variant was not found in the 1000 Genomes project, ExAC, and gnomAD (April 2022) databases. The affected residue is partially conserved across species. In vitro and ex vivo experiments showed that the variant impairs protein secretion and hampers binding to embryonic mouse neuronal cells and tissues. The authors noted that SEMA3E is expressed during human brain development.
Cariboni, A., Andre, V., Chauvet, S., Cassatella, D., Davidson, K., Caramello, A., Fantin, A., Bouloux, P., Mann, F., Ruhrberg, C. Dysfunctional SEMA3E signaling underlies gonadotropin-releasing hormone neuron deficiency in Kallmann syndrome. J. Clin. Invest. 125: 2413-2428, 2015. [PubMed: 25985275] [Full Text: https://doi.org/10.1172/JCI78448]
Christensen, C. R. L., Klingelhofer, J., Tarabykina, S., Hulgaard, E. F., Kramerov, D., Lukanidin, E. Transcription of a novel mouse semaphorin gene, M-semaH, correlates with the metastatic ability of mouse tumor cell lines. Cancer Res. 58: 1238-1244, 1998. [PubMed: 9515811]
Gu, C., Yoshida, Y., Livet, J., Reimert, D. V., Mann, F., Merte, J., Henderson, C. E., Jessell, T. M., Kolodkin, A. L., Ginty, D. D. Semaphorin 3E and plexin-D1 control vascular pattern independently of neuropilins. Science 307: 265-268, 2005. [PubMed: 15550623] [Full Text: https://doi.org/10.1126/science.1105416]
Hamosh, A. Personal Communication. Baltimore, Md. 10/14/2022.
Lalani, S. R., Safiullah, A. M., Molinari, L. M., Fernbach, S. D., Martin, D. M., Belmont, J. W. SEMA3E mutation in a patient with CHARGE syndrome. J. Med. Genet. 41: e94, 2004. Note: Electronic Article. [PubMed: 15235037] [Full Text: https://doi.org/10.1136/jmg.2003.017640]
Martin, D. M., Sheldon, S., Gorski, J. L. CHARGE association with choanal atresia and inner ear hypoplasia in a child with a de novo chromosome translocation t(2;7)(p14;q21.11). Am. J. Med. Genet. 99: 115-119, 2001. [PubMed: 11241468] [Full Text: https://doi.org/10.1002/1096-8628(2000)9999:999<00::aid-ajmg1126>3.0.co;2-8]
Nagase, T., Ishikawa, K., Nakajima, D., Ohira, M., Seki, N., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. VII. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro. DNA Res. 4: 141-150, 1997. [PubMed: 9205841] [Full Text: https://doi.org/10.1093/dnares/4.2.141]
Paganoni, A. J. J., Amoruso, F., Porta Pelayo, J., Calleja-Perez, B., Vezzoli, V., Duminuco, P., Caramello, A., Oleari, R., Fernandez-Jaen, A., Cariboni, A. A novel loss-of-function SEMA3E mutation in a patient with severe intellectual disability and cognitive regression. Int. J. Molec. Sci. 23: 5632, 2022. [PubMed: 35628442] [Full Text: https://doi.org/10.3390/ijms23105632]
Pecho-Vrieseling, E., Sigrist, M., Yoshida, Y., Jessell, T. M., Arber, S. Specificity of sensory-motor connections encoded by Sema3e-Plxnd1 recognition. Nature 459: 842-846, 2009. [PubMed: 19421194] [Full Text: https://doi.org/10.1038/nature08000]
Suspitsin, E. N., Guseva, M. N., Kostik, M. M., Sokolenko, A. P., Skripchenko, N. V., Levina, A. S., Goleva, O. V., Dubko, M. F., Tumakova, A. V., Makhova, M. A., Lyazina, L. V., Bizin, I. V., Sokolova, N. E., Gabrusskaya, T. V., Ditkovskaya, L. V., Kozlova, O. P., Vahliarskaya, S. S., Kondratenko, I. V., Imyanitov, E. N. Next generation sequencing analysis of consecutive Russian patients with clinical suspicion of inborn errors of immunity. Clin. Genet. 98: 231-239, 2020. [PubMed: 32441320] [Full Text: https://doi.org/10.1111/cge.13789]