Alternative titles; symbols
HGNC Approved Gene Symbol: SEC31A
Cytogenetic location: 4q21.22 Genomic coordinates (GRCh38): 4:82,818,509-82,900,569 (from NCBI)
Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
---|---|---|---|---|
4q21.22 | ?Halperin-Birk syndrome | 618651 | Autosomal recessive | 3 |
The SEC31A gene encodes a subunit of the coat protein complex II (COPII), which is essential for cellular trafficking of proteins from the endoplasmic reticulum (ER) to the Golgi apparatus (Jin et al., 2012, summary by Halperin et al., 2019).
By sequencing clones obtained from a size-fractionated adult brain cDNA library, Nagase et al. (1998) cloned SEC31L1, which they designated KIAA0905. The deduced protein contains 1,220 amino acids. RT-PCR detected moderate expression in all adult and fetal tissues and specific brain regions examined.
By searching EST databases for sequences similar to yeast Sec31, followed by screening a pancreas cDNA library, Tang et al. (2000) cloned SEC31L1, which they called SEC31A. The deduced 1,218-amino acid protein shares 25.8% identity with yeast Sec31. It contains 5 WD40 or WD40-like repeats at its N terminus and a proline-rich region in its C-terminal half. Northern blot analysis detected a 4-kb transcript that was abundantly and ubiquitously expressed. In rat kidney cells, Sec31a colocalized with Sec13 (SEC13L1; 600152) in vesicular-tubular structures characteristic of endoplasmic reticulum (ER) exit sites.
During zebrafish embryogenesis, sec31a is highly expressed in the notochord, optic tectum, otic vesicle, cleithrum, and fin, suggesting an important role in neuronal and craniofacial development (summary by Halperin et al., 2019).
By immunostaining for Sec31a in intact and permeabilized rat kidney cells, Tang et al. (2000) found that Sec31a was not tightly associated with the membrane. Binding of Sec31a to specific membrane structures was restored by incubating washed cells with cytosol, indicating that Sec31a was recruited to membranes. The membrane association of Sec31a was greatly enhanced in the presence of a nonhydrolyzable GTP analog. Tang et al. (2000) demonstrated that Sec31A and Sec13 coimmunoprecipitated and that the proteins existed in a 600- to 700-kD complex. Immunodepletion studies showed that rat Sec31a was required for ER-to-Golgi vesicular transport.
Jin et al. (2012) found that monoubiquitination of Sec31 in mouse embryonic stem cells by Klhl12 (614522) and the Cul3 (603136) E3 ubiquitin ligase complex was required for COPII vesicle expansion to accommodate large cargo proteins, such as procollagens (see 120150). A Sec31-binding mutant of Klhl12 neither colocalized with Sec31 at intracellular vesicles nor induced formation of large vesicles. Disruption of KLHL12-CUL3 function in human HT1080 fibrosarcoma cells impaired COPII vesicle expansion and collagen export, but it had no effect on export of smaller cargo by small COPII vesicles. Jin et al. (2012) concluded that KLHL12-CUL3 monoubiquitination of SEC31 is required for COPII vesicle expansion to accommodate large or bulky cargo molecules.
By radiation hybrid analysis, Nagase et al. (1998) mapped the SEC31L1 gene to chromosome 4.
In 2 sibs, born of consanguineous Bedouin parents, with Halperin-Birk syndrome (HLBKS; 618651), Halperin et al. (2019) identified a homozygous frameshift mutation in the SEC31A gene (610257.0001). The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing, segregated with the disorder in the family. Analysis of parental cells carrying the mutation showed that it resulted in nonsense-mediated mRNA decay and a complete loss of function. Knockdown of the gene in Drosophila recapitulated the phenotype (see ANIMAL MODEL). CRISPR/Cas9-mediated knockdown of the SEC31A gene in human SH-SY5Y neuroblastoma cells resulted in failure of the cells to expand to generate viable clones. Knockdown of the gene in HEK293 cells resulted in increased susceptibility to ER stress compared to controls.
Halperin et al. (2019) found that complete loss of sec31a in Drosophila was embryonically lethal and associated with defects in eye and brain development, consistent with abnormal neurodevelopment.
In 2 sibs, born of consanguineous Bedouin parents, with Halperin-Birk syndrome (HLBKS; 618651), Halperin et al. (2019) identified a homozygous 2-bp duplication (c.2776_2777dupTA, NM_001318120) in exon 22 of the SEC31A gene, resulting in a frameshift and premature termination (Ala927fsTer61). The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing, segregated with the disorder in the family. It was not found in the 1000 Genomes Project, Exome Sequencing Project, or gnomAD databases, or in 250 in-house Bedouin control samples. Analysis of parental cells carrying the mutation showed that it resulted in nonsense-mediated mRNA decay and a complete loss of function.
Halperin, D., Kadir, R., Perez, Y., Drabkin, M., Yogev, Y., Wormser, O., Berman, E. M., Eremenko, E., Rotblat, B., Shorer, Z., Gradstein, L., Shelef, I., Birk, R., Abdu, U., Flusser, H., Birk, O. S. SEC31A mutation affects ER homeostasis, causing a neurologic syndrome. J. Med. Genet. 56: 139-148, 2019. [PubMed: 30464055] [Full Text: https://doi.org/10.1136/jmedgenet-2018-105503]
Jin, L., Pahuja, K. B., Wickliffe, K. E., Gorur, A., Baumgartel, C., Schekman, R., Rape, M. Ubiquitin-dependent regulation of COPII coat size and function. Nature 482: 495-500, 2012. [PubMed: 22358839] [Full Text: https://doi.org/10.1038/nature10822]
Nagase, T., Ishikawa, K., Suyama, M., Kikuno, R., Hirosawa, M., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Oharo, O. Prediction of the coding sequences of unidentified human genes. XII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 5: 355-364, 1998. [PubMed: 10048485] [Full Text: https://doi.org/10.1093/dnares/5.6.355]
Tang, B. L., Zhang, T., Low, D. Y. H., Wong, E. T., Horstmann, H., Hong, W. Mammalian homologues of yeast Sec31p: an ubiquitously expressed form is localized to endoplasmic reticulum (ER) exit sites and is essential for ER-Golgi transport. J. Biol. Chem. 275: 13597-13604, 2000. [PubMed: 10788476] [Full Text: https://doi.org/10.1074/jbc.275.18.13597]