Alt. symbols: SEMAH | M-SemaK | KIAA0331 | coll-5

Approved name: semaphorin 3E
Alt. names: sema domain, immunoglobulin domain (Ig), short basic domain, secreted, (semaphorin) 3E | M-sema H

Location: 7q21.11: 83363238 - 83649139 (-)
Gene type: protein_coding, 6 transcripts.

Scores: LoFtool: 0.718000 | pLI: 0.03044787 | LOEUF: 0.679

HGNC: 10727

NCBI: 9723, RefSeq: NG_021242.2

Ensembl: ENSG00000170381.15

LRG_1287 | Status: public

OMIM: 608166

Expression | ProteinAtlas

SEMA3E encodes a semaphorin with important roles in developmental signaling. It is required for normal vascular patterning during embryogenesis and continues to regulate angiogenesis postnatally. It is also thought to play an important role in ensuring the specificity of synapse formation, partly via reorganization of the actin cytoskeleton, leading to the retraction of cell projections. Semaphorin 3E is also thought to play an important role (via plexinD1 receptor) in directing maturing thymocyte migration in response to chemokine gradients (PMID: 19027330). More recently, Semaphorin 3E produced by immature dendritic cells (iDCs) was reported to regulate NK-DC crosstalk by limiting activated NK cell migration towards iDCs (PMID: 29867980).

Monoallelic mutations in SEMA3E are reported to be associated with CHARGE syndrome and potentially also Kallmann syndrome, both of which are also associated with mutations in CHD7. CHARGE syndrome is an autosomal dominant multiple congenital anomalies syndrome featuring choanal atresia and malformations of the heart, inner ear, and retina, as well as immune defects. Lalani et al. (2004) first reported a de novo heterozygous missense SEMA3E variant c.2108C>T (p.S703L) in a patient with clinical f eatures of CHARGE syndrome [MIM:214800]. More recently, Suspitsin et al. (2020) identified this same variant, also found to be de novo, in identical twins who lacked the congenital anomalies associated with CHARGE syndrome but had severe immunodeficiency presenting as a history of destructive pneumonia, recurrent respiratory infections, atopic dermatitis, allergic rhinitis, bronchial asthma, frequent episodes of subfebrile fever, oral candidiasis and molluscum contagiosum (PMID: 32441320). Song et al. (2020) reported another de novo heterozygous missense variant (c.1327G>A; p. Ala443Thr) in a fetus with prenatal features concerning for CHARGE syndrome and no evidence of mutations in other CHARGE-associated genes such as CHD7, but did not report any functional studies (PMID: 31691538). Additionally, Cariboni et al. (2015) performed exome sequencing in 121 patients with Kallmann syndrome and identified 2 affected brothers heterozygous for another SEMA3E missense variant c.1855C>T (p.R619C), found at very low minor allele frequencies and affecting a highly conserved residue (PMID: 25985275). However, both brothers were also heterozygous for a rare CHD7 missense variant (F1019C). The authors showed via ligand-binding assays that both wildtype and mutant SEMA3E bound GT1-7 cells (maturing hypothalamic GnRH neurons), but only the mutant was ineffective in AKT activation in serum-starved GT1-7 cells and failed to protect these cells from serum starvation-induced death, suggesting that SEMA3E-mediated survival signaling in maturing GnRH neurons may be compromised by the R619C mutation. Immunodeficiency in CHARGE syndrome has mostly been studied in patients harboring CHD7 mutations. Immune defects overall are thought to be rare and attributed to impaired thymic development, the extent of which appears to determine the severity of the immunophenotype (PMID: 29159871). Complete thymic aplasia, although very rare, results in severe combined immunodeficiency with complete/near complete absence of T-cells, abnormal B-cell function and associated hypogammaglobulinemia, while partial thymic aplasia may result in no detectable defect at all, mildly reduced T-cell count with no clinical consequences, or a more significant reduction in T-cells with impaired B-cell function leading to inadequate vaccine responses and recurrent infections. Pure B-cell or antibody defects have been rarely described in CHARGE syndrome. Though autoimmune phenomena have not yet been reported in association with SEMA3E, Martire et al. (2016) reported the identification of a previously known CHARGE-associated heterozygous CHD7 variant c.1153C>T (p.Q385X) in a girl who developed CVID-like features including persistent, relapsing Evans syndrome, lymphadenopathy,and granulomatous lymphocytic interstitial lung disease (GLILD), along with hypogammaglobulinemia and poor vaccine responses (PMID: 27062223). [Load More]