Alternative titles; symbols
HGNC Approved Gene Symbol: SEL1L
Cytogenetic location: 14q31.1 Genomic coordinates (GRCh38) : 14:81,471,547-81,533,853 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 14q31.1 | ?Neurodevelopmental disorder with poor growth, absent speech, progressive ataxia, and dysmorphic facies | 621067 | 3 | |
| Neurodevelopmental disorder with hypotonia, poor growth, dysmorphic facies, and agammaglobulinemia | 621068 | 3 |
Misfolded proteins that have entered the endoplasmic reticulum (ER) are transported back into the cytosol, where they are degraded by the proteasome in a ubiquitin-dependent manner. SEL1L is a component of a protein complex required for retrotranslocation or dislocation of misfolded proteins from the ER lumen to the cytosol (Mueller et al., 2008).
Biunno et al. (1997) isolated a novel cDNA, designated SEL1L by them, that shows sequence similarities to sel-1, a gene identified as an extragenic suppressor of the lin-12 hypomorphic mutant from C. elegans (Grant and Greenwald (1996, 1997)). SEL1L exhibited a tissue-specific pattern of expression: high levels of a single 7.5-kb transcript were detected only in the pancreas of healthy individuals, whereas low to undetectable levels were observed in other adult tissues and in some fetal tissues.
Using differential display to identify transcripts highly expressed in pancreas, followed by screening and 5-prime RACE of a pancreas cDNA library, Harada et al. (1999) cloned human SEL1L. The deduced 794-amino acid protein has a calculated molecular mass of 88.8 kD. It has an N-terminal signal sequence and 2 putative transmembrane domains near its C terminus. Human SEL1L shares 46% and 92% amino acid identity with C. elegans Sel1 and murine Sel1l, respectively. Northern blot analysis detected high expression of a major transcript of 7.8 kb and minor transcripts of 4.0, 3.5, 1.5, and 0.8 kb in pancreas. The 7.8-kb transcript was also weakly expressed in most other tissues examined.
Cattaneo et al. (2004) determined that the deduced 794-amino acid SEL1L protein contains an N-terminal signal sequence, followed by a fibronectin (FN1; 135600) type II domain, 11 tandem SEL1L repeats of about 34 amino acids each, a transmembrane domain, and a proline-rich C terminus. SEL1L repeats, which are related to tetratricopeptide (TPR) repeats, contain 2 alpha helices separated by a variable number of amino acids. The last SEL1L repeat also has a motif similar to one found in S. cerevisiae Hrd3. Cattaneo et al. (2004) stated that SEL1L is expressed in normal breast tissue, as well as pancreas.
Harada et al. (1999) determined that the SEL1L gene contains at least 20 coding exons.
By somatic cell hybrid analysis and fluorescence in situ hybridization, Biunno et al. (1997) mapped the SEL1L gene to chromosome 14q31. Donoviel and Bernstein (1999) localized the gene to chromosome 14q24.3-q31 by FISH and radiation hybrid analysis. Independently, Harada et al. (1999) mapped the SEL1L gene to chromosome 14q24.3-q31 by radiation hybrid analysis and FISH.
Biunno et al. (1997) found that 17% of human adenocarcinomas of the pancreas did not express SEL1L to a detectable level; however, no gross genomic alterations were apparent within a few hundred kb of the relevant region.
Cattaneo et al. (2004) stated that overexpression of SEL1L in MCF-7 breast cancer cells reduces their proliferative activity and aggressive behavior. They found that deletion of the SEL1L C-terminal domain after residue 658 completely restored the ability of MCF-7 cells to form anchorage-dependent and -independent colonies. This deletion removed the C-terminal SEL1L repeat containing the HRD3 motif, the transmembrane domain, and the proline-rich C terminus.
In a study comparing the binding of transcriptional regulators to promoter regions across species (human and mouse), Odom et al. (2007) demonstrated that HNF1A (142410) bound strongly to SEL1L in human liver, but that this binding was entirely absent in mouse.
Kaneko et al. (2007) found that HRD1 (SYVN1; 608046) and SEL1L were induced by distinct pathways following ER stress in HEK293 cells. HRD1 was induced by both ATF6 (605537) and XBP1 (194355), whereas SEL1L was induced by ATF6, but not XBP1. Induction of HRD1 was dependent upon an ER stress response element (ERSE) type I within its promoter region. In contrast, the SEL1L promoter region contains 2 ESRE I-like motifs but no classic ERSE.
Using human cell lines, Mueller et al. (2008) showed that SEL1L immunoprecipitated with a protein complex required for the retrotranslocation or dislocation of misfolded proteins from the ER lumen to the cytosol. Other proteins associated with the dislocation complex included HRD1, derlin-2 (DERL2; 610304), the ATPase p97 (VCP; 601023), PDI (P4HB; 176790), BIP (HSPA5; 138120), calnexin (CANX; 114217), AUP1 (602434), UBXD8 (FAF2), UBC6E (UBE2J1; 616175), and OS9 (609677).
Zhou et al. (2020) used 3-dimensional high-resolution imaging to investigate the formation of pleomorphic 'megamitochondria' with altered mitochondria-associated membranes in brown adipocytes lacking the Sel1L-Hrd1 protein complex of ER-associated protein degradation (ERAD). Mice with ERAD deficiency in brown adipocytes were cold-sensitive and exhibited mitochondrial dysfunction. ERAD deficiency affected ER-mitochondria contacts and mitochondrial dynamics at least in part by regulating the turnover of the mitochondria-associated membrane protein SigmaR1 (601978). Zhou et al. (2020) concluded that their study provided molecular insights into ER-mitochondrial crosstalk and expanded understanding of the physiologic importance of Sel1L-Hrd1 ERAD.
Neurodevelopmental Disorder With Poor Growth, Absent Speech, Progressive Ataxia, And Dysmorphic Facies
In 4 sibs (P2-P5), born of consanguineous Moroccan parents (family B), with neurodevelopmental disorder with poor growth, absent speech, progressive ataxia, and dysmorphic facies (NEDGSAF; 621067) Wang et al. (2024) identified a homozygous missense mutation in the SEL1L gene (M528R; 602329.0001). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation was not found in public genetic databases, including gnomAD. Patient cells were not available for study, but expression of the M528R mutation in HEK293 cells generated using CRISPR/Cas9 caused impaired ERAD function and accumulation of endogenous substrates that formed aggregates, consistent with it being a hypomorphic allele. M528R HEK293 cells had reduced SEL1L and HRD1 (608046) protein levels by about 80% and 60%, respectively, suggesting reduced protein stability of the ERAD complex components. There was no evidence of an unfolded protein response. The authors also reported a 14-year-old boy (P1), born of consanguineous Saudi parents (family A), with a similar neurodevelopmental disorder associated with a homozygous missense variant (G585D) in a predicted substrate-binding groove. The variant, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in public genetic databases, including gnomAD. Expression of G585D in HEK293 cells resulted in mildly decreased SEL1L and HRD1 protein levels (by about 20 to 30%). P1 also carried a presumably de novo heterozygous missense variant (T2497R) in the FRYL gene (620798), which is associated with a different neurodevelopmental disorder (PCBS; 621049).
Neurodevelopmental Disorder With Hypotonia, Poor Growth, Dysmorphic Facies, And Agammaglobulinemia
In 5 patients from a consanguineous Slovakian kindred with neurodevelopmental disorder with hypotonia, poor growth, dysmorphic facies, and agammaglobulinemia (NEDHGFA; 621068), Weis et al. (2024) identified a homozygous missense mutation in the SEL1L gene (C141Y; 602329.0002). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Structural modeling indicated that cys141 forms a disulfide bridge with cys168. Fibroblasts derived from P5 and HEK293 cells expressing the mutation generated using CRISPR/Cas9 had significantly reduced SEL1L and HRD1 protein levels compared to controls, whereas ERAD substrates IRE1A (ERN1; 608046) and CD147 (BSG; 109480) were increased. These changes were more prominent compared to the M528R mutation reported by Wang et al. (2024), indicating that C141Y causes more severe ERAD dysfunction, which was consistent with the more severe phenotype. There was no evidence of an overt unfolded protein response in C141Y cells.
Associations Pending Confirmation
For discussion of a possible association between variation in the promoter region of the SEL1L gene and a branchial cleft syndrome involving hypertelorism, preauricular sinus, punctal pits, and deafness, see HPPD (614187).
Francisco et al. (2011) stated that Sel1l -/- mice develop systemic ER stress and die during midgestation. They found that Sel1l +/- mice appeared normal and maintained normal glycemia when fed a regular diet. However, when fed a high-fat diet, Sel1l -/- mice developed glucose intolerance and showed impaired compensatory pancreatic beta-cell growth compared with controls. RT-PCR of cultured Sel1l +/- islets and Western blot analysis of liver from Sel1l +/- mice revealed upregulation of ER stress-induced genes compared with controls. Sel1l +/- pancreatic islets cultured in the presence of high glucose showed elevated expression of unfolded protein response genes. Mouse and rat insulinoma cells stably expressing a dominant-negative form of Sel1l exhibited impaired protein secretion and cell growth. Francisco et al. (2011) concluded that haploinsufficiency of Sel1l predisposes mice to high-fat-induced hyperglycemia.
Ji et al. (2023) found that mice homozygous for myeloid cell-specific Sel1l deletion had normal appearance, immune cell composition, and survival. Hrd1 protein levels were significantly decreased in the macrophages of mutant mice. However, the mutant mice had intact lipopolysaccharide response and intact major histocompatibility complex antigen presentation in macrophages, and they did not show diet-induced obesity. Sel1w deficiency increased cGas (613973)-Sting (STING1; 612374) signalling in macrophages, as Sting protein was stabilized in the absence of ERAD. The authors found that basal-state Sting was degraded in the ER via Sel1l-Hrd1 ERAD, in contrast with active Sting, which is degraded in endolysosomes independent of macroautophagy. The effect of ERAD on Sting was uncoupled from the unfolded protein response (UPR) and its ER-resident sensor, Ire1-alpha (ERN1; 604033). Instead, basal-state Sing interacted with and was ubiquitinated by Hrd1 and functioned as an endogenous substrate of Sel1l-Hrd1 ERAD, which controlled the amount of Sting that could be activated. Further analysis demonstrated that myeloid-specific Sel1l-Hrd1 ERAD limited Sting signaling against DNA viruses and tumor growth.
Song et al. (2024) found that Sel1l-Hrd1 ERAD deficiency due to hepatocyte-specific deletion of Sel1l in mice led to the formation of inclusion bodies in liver, which progressively enlarged with age. Induction of Crebh (CREB3L3; 611998) or Fgf21 (609436) or deficiency of Ire1-alpha was insufficient to induce formation of hepatic inclusion bodies. Inclusion bodies in Sel1l-deficient hepatocytes were single membrane-bound structures in the cytosol and contained fibrinogen (see 134820). Fibrinogen within the inclusion bodies was physically associated with various ER chaperones, suggesting a misfolded or folding intermediate stage. Moreover, all 3 fibrinogen chains accumulated, aggregated, and were retained in the ER instead of being secreted in hepatocytes with Sel1l deficiency, leading to formation of hepatic inclusion bodies. Fibrinogen chains were endogenous ERAD substrates. Misfolded nascent fibrinogen chains were ubiquitinated and degraded by Sel1l-Hrd1 ERAD, whereas correctly assembled fibrinogen chains were protected from degradation by Sel1l-Hrd1 ERAD. Further analysis revealed that Sel1l-Hrd1 ERAD degraded fibrinogen-gamma (FGG; 134850) disease mutants, suggesting that Sel1l-Hrd1 ERAD negatively controls pathogenicity of fibrinogen-gamma mutants.
Ji et al. (2016) found that B cell-specific loss of Sel1l in mice resulted in impaired B cell development, causing a severe block at the transition from large to small pre-B cells. The authors demonstrated that the Sel1l/Hrd1 ERAD complex manages a key checkpoint in B cell development that targets the pre-B cell receptor (BCR) for proteasomal degradation, thus terminating pre-BCR signaling.
In 4 sibs (P2-P5), born of consanguineous Moroccan parents (family B), with neurodevelopmental disorder with poor growth, absent speech, progressive ataxia, and dysmorphic facies (NEDGSAF; 621067), Wang et al. (2024) identified a homozygous c.1583T-G transversion (c.1583T-G, NM_005065) in exon 16 of the SEL1L gene, resulting in a met528-to-arg (M528R) substitution at a conserved residue in the SLR-M domain, predicted to disrupt the alpha-helical structure and destabilize the protein. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation was not found in public genetic databases, including gnomAD. Patient cells were not available for study, but expression of the M528R mutation in HEK293 cells generated using CRISPR/Cas9 caused impaired ERAD function and accumulation of endogenous substrates that formed aggregates, consistent with it being a hypomorphic allele. M528R HEK293 cells had reduced SEL1L and HRD1 (608046) protein levels by about 80% and 60%, respectively, suggesting reduced protein stability of the ERAD complex components. There was no evidence of an unfolded protein response.
In 5 patients from a consanguineous Slovakian kindred with neurodevelopmental disorder with hypotonia, poor growth, dysmorphic facies, and agammaglobulinemia (NEDHGFA; 621068), Weis et al. (2024) identified a homozygous c.422G-A transition (c.422G-A, NM_005065.6) in exon 4 of the SEL1L gene, resulting in a cys141-to-tyr (C141Y) substitution at a conserved residue in the luminal N-terminal fibronectin type II (FNII) domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Structural modeling indicated that cys141 forms a disulfide bridge with cys168. Fibroblasts derived from P5 and HEK293 cells expressing the mutation generated using CRISPR/Cas9 had significantly reduced SEL1L and HRD1 (608046) protein levels compared to controls, whereas ERAD substrates IRE1A (604033) and CD147 (109480) were increased. These changes were more prominent compared to the M528R mutation (602329.0001) reported by Wang et al. (2024), indicating that C141Y causes more severe ERAD dysfunction, which was consistent with the more severe phenotype. There was no evidence of an overt unfolded protein response in C141Y cells. Further studies suggested that the disulfide bonds in the FNII domain (C141-C168 and C127-C153) are essential for ERAD complex stability and that the C141Y variant caused proteasome-mediated self-destruction of the SEL1L-HRD1 ERAD complex. Of note, ERAD function was retained in HEK293 cells lacking the FNII domain, suggesting that the C141Y variant causes dysfunction by adversely affecting ERAD complex stability.
Biunno, I., Appierto, V., Cattaneo, M., Leone, B. E., Balzano, G., Socci, C., Saccone, S., Letizia, A., Valle, G. D., Sgaramella, V. Isolation of a pancreas-specific gene located on human chromosome 14q31: expression analysis in human pancreatic ductal carcinomas. Genomics 46: 284-286, 1997. [PubMed: 9417916] [Full Text: https://doi.org/10.1006/geno.1997.5018]
Cattaneo, M., Canton, C., Albertini, A., Biunno, I. Identification of a region within SEL1L protein required for tumour growth inhibition. Gene 326: 149-156, 2004. [PubMed: 14729273] [Full Text: https://doi.org/10.1016/j.gene.2003.10.021]
Donoviel, D. B., Bernstein, A. SEL-1L maps to human chromosome 14, near the insulin-dependent diabetes mellitus locus 11. Genomics 56: 232-233, 1999. [PubMed: 10051412] [Full Text: https://doi.org/10.1006/geno.1998.5534]
Francisco, A. B., Singh, R., Sha, H., Yan, X., Qi, L., Lei, X., Long, Q. Haploid insufficiency of suppressor enhancer Lin12 1-like (SEL1L) protein predisposes mice to high fat diet-induced hyperglycemia. J. Biol. Chem. 286: 22275-22282, 2011. [PubMed: 21536682] [Full Text: https://doi.org/10.1074/jbc.M111.239418]
Grant, B., Greenwald, I. The Caenorhabditis. elegans sel-1 gene, a negative regulator of lin-12 and glp-1, encodes a predicted extracellular protein. Genetics 143: 237-247, 1996. [PubMed: 8722778] [Full Text: https://doi.org/10.1093/genetics/143.1.237]
Grant, B., Greenwald, I. Structure, function and expression of SEL-1, a negative regulator of LIN-12 and GLP-1 in C. elegans. Development 124: 637-644, 1997. [PubMed: 9043078] [Full Text: https://doi.org/10.1242/dev.124.3.637]
Harada, Y., Ozaki, K., Suzuki, M., Fujiwara, T., Takahashi, E., Nakamura, Y., Tanigami, A. Complete cDNA sequence and genomic organization of a human pancreas-specific gene homologous to Caenorhabditis elegans sel-1. J. Hum. Genet. 44: 330-336, 1999. [PubMed: 10496078] [Full Text: https://doi.org/10.1007/s100380050171]
Ji, Y., Kim, H., Yang, L., Sha, H., Roman, C. A., Long, Q., Qi, L. The Sel1L-Hrd1 endoplasmic reticulum-associated degradation complex manages a key checkpoint in B cell development. Cell Rep. 16: 2630-2640, 2016. [PubMed: 27568564] [Full Text: https://doi.org/10.1016/j.celrep.2016.08.003]
Ji, Y., Luo, Y., Wu, Y., Sun, Y., Zhao, L., Xue, Z., Sun, M., Wei, X., He, Z., Wu, S. A., Lin, L. L., Lu, Y., and 12 others. SEL1L-HRD1 endoplasmic reticulum-associated degradation controls STING-mediated innate immunity by limiting the size of the activable STING pool. Nature Cell Biol. 25: 726-739, 2023. [PubMed: 37142791] [Full Text: https://doi.org/10.1038/s41556-023-01138-4]
Kaneko, M., Yasui, S., Niinuma, Y., Arai, K., Omura, T., Okuma, Y., Nomura, Y. A different pathway in the endoplasmic reticulum stress-induced expression of human HRD1 and SEL1 genes. FEBS Lett. 581: 5355-5360, 2007. [PubMed: 17967421] [Full Text: https://doi.org/10.1016/j.febslet.2007.10.033]
Mueller, B., Klemm, E. J., Spooner, E., Claessen, J. H., Ploegh, H. L. SEL1L nucleates a protein complex required for dislocation of misfolded glycoproteins. Proc. Nat. Acad. Sci. 105: 12325-12330, 2008. [PubMed: 18711132] [Full Text: https://doi.org/10.1073/pnas.0805371105]
Odom, D. T., Dowell, R. D., Jacobsen, E. S., Gordon, W., Danford, T. W., MacIsaac, K. D., Rolfe, P. A., Conboy, C. M., Gifford, D. K., Fraenkel, E. Tissue-specific transcriptional regulation has diverged significantly between human and mouse. Nature Genet. 39: 730-732, 2007. [PubMed: 17529977] [Full Text: https://doi.org/10.1038/ng2047]
Song, Z., Thepsuwan, P., Hur, W. S., Torres, M., Wu, S. A., Wei, X., Tushi, N. J., Wei, J., Ferraresso, F., Paton, A. W., Paton, J. C., Zheng, Z., Zhang, K., Fang, D., Kastrup, C. J., Jaiman, S., Flick, M. J., Sun, S. Regulation of hepatic inclusions and fibrinogen biogenesis by SEL1L-HRD1 ERAD. Nature Commun. 15: 9244, 2024. [PubMed: 39455574] [Full Text: https://doi.org/10.1038/s41467-024-53639-x]
Wang, H. H., Lin, L. L., Li, Z. J., Wei, X., Askander, O., Cappuccio, G., Hashem, M. O., Hubert, L., Munnich, A., Alqahtani, M., Pang, Q., Burmeister, M., Lu, Y., Poirier, K., Besmond, C., Sun, S., Brunetti-Pierri, N., Alkuraya, F. S., Qi, L. Hypomorphic variants of SEL1L-HRD1 ER-associated degradation are associated with neurodevelopmental disorders. J. Clin. Invest. 134: e170054, 2024. [PubMed: 37943610] [Full Text: https://doi.org/10.1172/JCI170054]
Weis, D., Lin, L. L., Wang, H. H., Li, Z. J., Kusikova, K., Ciznar, P., Wolf, H. M., Leiss-Piller, A., Wang, Z., Wei, X., Weis, S., Skalicka, K., Hrckova, G., Danisovic, L., Soltysova, A., Yang, T. T., Feichtinger, R. G., Mayr, J. A., Qi, L. Biallelic cys141tyr variant of SEL1L is associated with neurodevelopmental disorders, agammaglobulinemia, and premature death. J. Clin. Invest. 134: e170882, 2024. [PubMed: 37943617] [Full Text: https://doi.org/10.1172/JCI170882]
Zhou, Z., Torres, M., Sha, H., Halbrook, C. J., Van den Bergh, F., Reinert, R. B., Yamada, T., Wang, S., Luo, Y., Hunter, A. H., Wang, C., Sanderson, T. H., Liu, M., Taylor, A., Sesaki, H., Lyssiotis, C. A., Wu, J., Kersten, S., Beard, D. A., Qi, L. Endoplasmic reticulum-associated degradation regulates mitochondrial dynamics in brown adipocytes. Science 368: 54-60, 2020. [PubMed: 32193362] [Full Text: https://doi.org/10.1126/science.aay2494]