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SEMAPHORIN 6B; SEMA6B

SEMAPHORIN 6B; SEMA6B

HGNC Approved Gene Symbol: SEMA6BCytogenetic location: 19p13.3 Genomic coordinates (GRCh38): 19:4,542,592-4,559,683 (from NCBI)▼ DescriptionSEMA3B is a neura...

HGNC Approved Gene Symbol: SEMA6B

Cytogenetic location: 19p13.3 Genomic coordinates (GRCh38): 19:4,542,592-4,559,683 (from NCBI)

▼ Description
SEMA3B is a neural repellent protein that signals through plexin-A receptors (e.g., PLXNA4; 604280) (Tawarayama et al., 2010).

▼ Cloning and Expression
By searching a breast tumor EST database for sequences similar to rat and mouse Sema6b, followed by RT-PCR of a breast tumor cDNA library, Correa et al. (2001) cloned SEMA6B. The deduced protein contains 517 amino acids. By database analysis, they identified 2 additional SEMA6B splice variants that encode deduced proteins of 687 and 888 amino acids that differ in their C-terminal halves. These larger proteins contain a putative transmembrane domain and a cytoplasmic domain. Northern blot analysis detected a 4.5-kb transcript expressed at higher levels in brain and heart and at lower levels in spleen, placenta, and lung. Expression was also detected in 2 human glioblastoma cell lines.

Using in situ hybridization analysis, Tawarayama et al. (2010) showed that Sema6b was expressed in CA3 pyramidal cells of neonatal mice. Further analysis showed that Sema6b localized on dendrites of transfected pyramidal cells.

Hamanaka et al. (2020) found expression of the SEMA6B gene in mouse and human brain tissue during development. Immunostaining localized expression to neurons in multiple brain regions, including the cerebral cortex, cerebellar Purkinje cells, and interneurons; specific cell types included excitatory and GABAergic inhibitory neurons.

▼ Gene Structure
Correa et al. (2001) determined that the SEMA6B gene contains 17 exons. Collet et al. (2004) identified a PPAR (see PPARA, 170998)-binding site in the upstream sequence.

▼ Mapping
By analyzing a human/hamster hybrid cell line, Correa et al. (2001) mapped the SEMA6B gene to chromosome 19.

Stumpf (2020) mapped the SEMA6B gene to chromosome 19p13 based on an alignment of the SEMA6B sequence (GenBank AF293363) with the genomic sequence (GRCh38).

▼ Gene Function
Correa et al. (2001) found that all-trans retinoic acid downregulated expression of SEMA6B in 2 human glioblastoma cell lines.

Collet et al. (2004) found that PPARA agonists downregulated expression of SEMA6B in glioblastoma cells.

Using in vivo analyses in knockout mice, Tawarayama et al. (2010) showed that Sema6a (605885) and Sema6b functioned as repellents for mossy fibers to prevent abnormal projections. Repulsive activities of Sema6a and Sema6b were additive and were mediated by Plxna4. Sema6b suppressed innervation of mossy fibers into the suprapyramidal region in a dosage-dependent manner. Plxna2 (601054) attenuated mossy fiber repulsion by Sema6a and promoted growth of mossy fibers.

By analyzing knockout mice, Matsuoka et al. (2013) showed that, despite expression during postnatal development of mouse retina, Sema6b, Sema6c (609294), and Sema6d (609295) were not involved in neurite stratification of inner and outer retinal neurons and did not affect morphology and process extension of Muller glia cells.

▼ Molecular Genetics
In 4 unrelated patients with progressive myoclonic epilepsy-11 (EPM11; 618876), Hamanaka et al. (2020) identified de novo heterozygous frameshift mutations in the last exon of the SEMA6B gene (608873.0001-608873.0003). The mutations, which were found by a sequencing technique using enrichment analysis for mutations predicted to escape nonsense-mediated mRNA decay, were confirmed by Sanger sequencing. The mutations were predicted to result in the production of truncated proteins lacking the intracellular domain. Truncating variants in this region of the gene were not observed in the gnomAD database, although truncating variants in other regions of the gene were observed in gnomAD. RNA analysis of lymphoblastoid cells derived from 1 patient showed that a truncated protein was produced. Cells from the other patients were not available, and functional studies of the variants were not performed. The authors postulated a dominant-negative or gain-of-function effect rather than haploinsufficiency. The patients were ascertained from several large cohorts of patients, totaling over 6,000 individuals, with variable developmental disorders who underwent genetic testing.

▼ Animal Model
Hamanaka et al. (2020) found that zebrafish with distal truncating variants affecting the intracellular domain of sema6b orthologs which escaped nonsense-mediated mRNA decay had defective brain development and were more susceptible to seizures compared to wildtype. In addition, zebrafish with loss-of-function mutations had less severe abnormalities compared to those with distal truncating mutations, indicating that the truncating mutations exert a more detrimental toxic effect than loss-of-function mutations.

▼ ALLELIC VARIANTS ( 3 Selected Examples):

.0001 EPILEPSY, PROGRESSIVE MYOCLONIC, 11
SEMA6B, 20-BP DUP, NT1950
In a 22-year-old Japanese man (patient 1) with progressive myoclonic epilepsy-11 (EPM11; 618876), Hamanaka et al. (2020) identified a de novo 20-bp duplication (c.1950_1969dup, NM_032108.4) in the last exon of the SEMA6B gene, predicted to result in a frameshift and premature termination (Arg657ProfsTer35). The mutation, which was found by a sequencing technique using enrichment analysis for mutations predicted to escape nonsense-mediated mRNA decay, was confirmed by Sanger sequencing. Functional studies of the variant were not performed, but the mutant transcript was predicted to produce a truncated protein lacking the intracellular domain.

.0002 EPILEPSY, PROGRESSIVE MYOCLONIC, 11
SEMA6B, 7-BP DEL, NT1976
In a 28-year-old Japanese woman (patient 2) with progressive myoclonic epilepsy-11 (EPM11; 618876), Hamanaka et al. (2020) identified a de novo 7-bp deletion (c.1976_1982del, NM_032108.4) in the last exon of the SEMA6B gene, predicted to result in a frameshift and premature termination (Ala659ValfsTer24). The mutation, which was found by a sequencing technique using enrichment analysis for mutations predicted to escape nonsense-mediated mRNA decay, was confirmed by Sanger sequencing. RNA analysis of lymphoblastoid cells derived from the patient showed that a truncated protein was produced; additional functional studies were not performed.

.0003 EPILEPSY, PROGRESSIVE MYOCLONIC, 11
SEMA6B, 1-BP DEL, NT1991
In 2 unrelated patients, a 14-year-old boy of Israeli descent (patient 3) and an 11-year-old girl of Malaysian descent (patient 4), both with progressive myoclonic epilepsy-11 (EPM11; 618876), Hamanaka et al. (2020) identified a de novo 1-bp deletion (c.1991del, NM_032108.4) in the last exon of the SEMA6B gene, predicted to result in a frameshift and premature termination (Gly664AlafsTer21). The mutation, which was found by a sequencing technique using enrichment analysis for mutations predicted to escape nonsense-mediated mRNA decay, was confirmed by Sanger sequencing. Functional studies of the variant were not performed, but the mutant transcript was predicted to produce a truncated protein lacking the intracellular domain.

Tags: 19p13.3