Alternative titles; symbols
HGNC Approved Gene Symbol: SEC61A1
Cytogenetic location: 3q21.3 Genomic coordinates (GRCh38) : 3:128,051,641-128,071,683 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3q21.3 | ?Neutropenia, severe congenital, 11, autosomal dominant | 620674 | Autosomal dominant | 3 |
| Immunodeficiency, common variable, 15 | 620670 | Autosomal dominant | 3 | |
| Tubulointerstitial kidney disease, autosomal dominant, 5 | 617056 | Autosomal dominant | 3 |
SEC61A1 is a subunit of the heteromeric SEC61 complex, which also contains beta (SEC61B; 609214) and gamma (SEC61G; 609215) subunits. The SEC61 complex forms the core of the mammalian endoplasmic reticulum (ER) translocon, a transmembrane channel for the translocation of proteins across the ER membrane (Greenfield and High, 1999). Genes encoding the SEC61 complex are involved in the unfolded protein response (UPR) in the ER. The SEC61 complex also acts as a passive calcium leakage channel between the ER and the cytoplasm (summary by Schubert et al., 2018).
Schubert et al. (2018) found that the relative abundance of SEC61A protein in plasmablasts from human peripheral blood was about 2-fold higher when compared to naive and memory B cells. This is consistent with a SEC61A1 being a target gene of XBP1 (194355) during plasma cell differentiation. XBP1 induces the transcription of genes encoding mediators of protein synthesis, transport, folding, and degradation, and plays a role in activation of the UPR during ER stress.
The SEC61 complex is an essential translocation component that can associate with either ribosomes or the SEC62 (602173)/SEC63 (608648) complex to perform cotranslational or posttranslational transport, respectively (Wiertz et al., 1996). It was originally thought to have a role only in translocation of proteins from the cytosol into the ER. However, Wiertz et al. (1996), Bebok et al. (1998), Chen et al. (1998), and Petaja-Repo et al. (2001) presented evidence suggesting that the human SEC61 complex can also function in retrograde transport of multidomain integral membrane proteins from the ER to the cytosol for proteasomal degradation.
By immunolocalization of fluorescence-tagged canine Sec61a transfected into COS-1 cells, Greenfield and High (1999) determined that the Sec61 complex distributed to both the ER and the ER-Golgi intermediate compartment, but not to the trans-Golgi network. Endogenous Sec61b and Sec61g showed the same distribution. Another translocon component, the glycoprotein Tram (see 605190) was also present in post-ER compartments, suggesting that the core components of the mammalian ER translocon are not permanently resident in the ER, but rather they are maintained in the ER by a specific retrieval mechanism.
Hessa et al. (2005) challenged the endoplasmic reticulum Sec61 translocon with an extensive set of designed polypeptide segments and determined the basic features of the code for recognition of transmembrane helices, including a 'biological' hydrophobicity scale. They found that membrane insertion depends strongly on the position of polar residues within transmembrane segments, adding a new dimension to the problem of predicting transmembrane helices from amino acid sequences. Hessa et al. (2005) concluded that direct protein-lipid interactions are critical during translocon-mediated membrane insertion.
Transmembrane alpha-helices in integral membrane proteins are recognized cotranslationally and inserted into the membrane of the endoplasmic reticulum by the Sec61 translocon. Using in vitro translation of a model protein in the presence of dog pancreas rough microsomes to analyze a large number of systematically designed hydrophobic segments, Hessa et al. (2007) presented a quantitative analysis of the position-dependent contribution of all 20 amino acids to membrane insertion efficiency, as well as of the effects of transmembrane segment length and flanking amino acids. The resulting picture of translocon-mediated transmembrane helix assembly is simple, with the critical sequence characteristics mirroring the physical properties of the lipid bilayer.
Mycolactone is an immunosuppressive and cytotoxic virulence factor of Mycobacterium ulcerans, the causative agent of Buruli ulcer (610446). By competitive binding analyses, Baron et al. (2016) showed that mycolactone bound tightly to SEC61A and had a slow dissociation rate. Screening of SEC61A mutants expressed in embryonic kidney cells revealed that mutations at arg66 or ser82 conferred resistance to cytotoxicity and mycolactone-mediated blockade of protein secretion and translocation. These mutations are located near the luminal plug of SEC61A. Proteomic analysis and in vitro translation experiments showed that a broad spectrum of proteins, particularly secreted proteins (e.g., IFNG; 147570) and single-pass type I/II membrane proteins (e.g., TNF; 191160), as well as the ER-resident protein BIP (HSPA5; 138120), were affected by mycolactone inhibition of SEC61A. Mycolactone inhibition of wildtype, but not mutant, Sec61 activity prevented production of Ifng by mouse T cells and responsiveness to Ifng through Ifngr (see 107470) in mouse macrophages. Mycolactone also affected Sec61-dependent Cd62l (153240) expression and Cd62l-dependent lymphocyte homing in mice. Baron et al. (2016) concluded that mycolactone inhibition of SEC61 prevents the production of key mediators of innate and adaptive immune responses against intracellular pathogens.
Cryoelectron Microscopy
Becker et al. (2009) determined subnanometer-resolution cryoelectron microscopy structures of eukaryotic ribosome-Sec61 complexes. In combination with biochemical data, they found that in both idle and active states, the Sec complex is not oligomeric and interacts mainly via 2 cytoplasmic loops with the universal ribosomal adaptor site. In the active state, the ribosomal tunnel and a central pore of the monomeric protein-conducting channel were occupied by the nascent chain, contacting loop 6 of the Sec complex. Becker et al. (2009) concluded that this provides a structural basis for the activity of a solitary Sec complex in cotranslational protein translocation.
Gogala et al. (2014) presented cryoelectron microscopy structures of ribosome-bound SEC61 complexes engaged in translocation or membrane insertion of nascent peptides. The data showed that a hydrophilic peptide can translocate through the SEC complex with an essentially closed lateral gate and an only slightly rearranged central channel. Membrane insertion of a hydrophobic domain seems to occur with the SEC complex opening the proposed lateral gate while rearranging the plug to maintain an ion permeability barrier. Gogala et al. (2014) provided a structural model for the basic activities of the SEC61 complex as a protein-conducting channel.
Stumpf (2024) mapped the SEC61A1 gene to chromosome 3q21.3 based on an alignment of the SEC61A1 sequence (GenBank BC156688) with the genomic sequence (GRCh38).
Autosomal Dominant Tubulointerstitial Kidney Disease 5
In affected members of 2 unrelated families with autosomal dominant tubulointerstitial kidney disease-5 (ADTKD5; 617056), Bolar et al. (2016) identified 2 different heterozygous missense mutations in the SEC61A1 gene (T185A, 609213.0001 and V67G, 609213.0002). The mutation in the first family was found by a combination of linkage analysis and whole-exome sequencing, whereas the mutation in the second family was found by custom gene panel sequencing of 46 unrelated probands with a renal disorder; the mutations segregated with the disorder in both families. The mutations affected the selectivity and permeability of the pore of the translocon channel. Transfection of the mutations into HEK293 cells resulted in decreased protein levels compared to wildtype, and both mutant proteins formed intracellular clumps that were localized in the endoplasmic reticulum and partially in the Golgi apparatus. The findings suggested that the mutant proteins were subjected to endoplasmic-reticulum-associated degradation (ERAD) and increased ER stress. The mutant T185A protein was unable to rescue the tubular atrophy phenotype in zebrafish embryos with morpholino knockdown of the sec61a1 ortholog, suggesting that this mutation results in a complete loss of function. The V67G protein showed partial rescue of the zebrafish phenotype. The findings suggested that SEC61A1 is necessary for proper tubular organization of the nephron, and that the disorder results from protein translocation defects across the endoplasmic reticulum membrane.
In a 4-year-old girl with ADTKD5 and CD4+ T cell lymphopenia, Espino-Hernandez et al. (2021) identified a de novo heterozygous T185A mutation in the SEC61A1 gene. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant were not performed. Neutrophil count and immunoglobulin levels were normal. Espino-Hernandez et al. (2021) noted that ADTKD5 may manifest as a syndromic form of progressive chronic kidney disease.
Common Variable Immunodeficiency 15
In 10 affected members of a family of northern European descent (family 1) with common variable immunodeficiency-15 (CVID15; 620670), Schubert et al. (2018) identified a heterozygous missense mutation in the SEC61A1 gene (V85D; 609213.0003). The mutation, which was found by a combination of linkage analysis and whole-exome sequencing, segregated with the disorder in the family. Subsequent targeted next-generation sequencing of more than 200 patients with primary antibody deficiencies identified a second family in which 3 members had a heterozygous nonsense mutation in the SEC61A1 gene (E381X; 609213.0004). Patient-derived B cells from both families showed reduced SEC61A1 mRNA and protein levels and significantly reduced immunoglobulin secretion compared to controls. Studies of patient B cells and in vitro studies of transfected cells (including plasma cell-specific multiple myeloma cell lines) showed that the V85D mutation exerted a dominant-negative effect with increased ER/cytosolic calcium leakage depleting the calcium gradient, impaired protein translocation, increased ER stress, and activation of the terminal UPR pathway with increased levels of XBP1 (194355), CHOP (126337), and ATF4 (604064). Although the E381X mutation resulted in haploinsufficiency with a loss-of-function effect, the effect was similar: an inability to maintain ER homeostasis in times of stress, such as immunoglobulin production. Of note, the disorder in the second family showed incomplete penetrance and variable expressivity. Affected individuals from both families had early onset of recurrent infections associated with possibly transient antibody deficiency (IgM, IgG, and IgA), but normal numbers and subsets of peripheral B cells, T cells, and NK cells. Patient B cells did not differentiate into plasma cells in vitro, indicating a specific impairment of plasma cell homeostasis. Schubert et al. (2018) noted that studies in mice in which Xbp1 was conditionally deleted in B cells resulted in reduced immunoglobulin production by plasma cells and reduced expression of the Xbp1 target gene Sec61a1 (see, e.g., Reimold et al., 2001 and Taubenheim et al., 2012).
Autosomal Dominant Severe Congenital Neutropenia 11
In a 19-year-old woman, born of unrelated Belgian parents, with autosomal dominant severe congenital neutropenia-11 (SCN11; 620674), Van Nieuwenhove et al. (2020) identified a de novo heterozygous missense mutation in the SEC61A1 gene (Q92R; 609213.0005). The mutation, which was found by whole-exome sequencing, was not present in public databases. Patient peripheral blood mononuclear cells and fibroblasts showed decreased SEC61A1 protein expression that correlated with decreased SEC61-dependent protein translocation across the ER. Detailed in vitro studies in patient cells and HL-60 promyeloblasts showed that the mutation increased calcium leakage causing neutralization of the ER/cytosolic calcium gradient, increased ER stress, activation of the UPR, and increased susceptibility to apoptosis under ER stress conditions compared to controls. Patient CD34+ cells showed defective myeloid differentiation and neutrophil maturation in vitro. The patient had normal B-cell numbers, but there was maturation arrest of B-cell precursors at the transitional B-cell stage. However, she had increased plasmablasts and hypergammaglobulinemia. NK cells also showed a maturation defect. Thus, although the primary presentation of the patient was consistent with severe congenital neutropenia, the mutation also affected other leukocyte populations. The findings indicated that the mutation resulted in a combined quantitative and functional SEC61A1 protein defect. The authors stated that the clinical diversity in patients with SEC61A1 mutations is unclear, and that phenotypes cannot be predicted on the basis of location or nature of the mutation, as the effects are cell-intrinsic and cell-specific. However, a common disease mechanism appears to be that impaired SEC61A1 function leads to disrupted calcium flux, increased ER stress, and activation of the UPR.
Lloyd et al. (2010) described a recessive diabetic mouse mutant resulting from a homozygous Y344H mutation in the Sec61a1 gene. In addition to diabetes and hyperglycemia due to insulin insufficiency, the mice had poor growth, hyperlipidemia, hypercholesterolemia, and hepatosteatosis. Cirrhosis was apparent in older mice. The associated hypoinsulinemia indicated pancreatic beta-cell failure. Immunohistochemical studies of wildtype mice showed high Sec61a1 expression in beta-cells in the pancreas, and the pancreas of mutant mice contained multiple apoptotic beta-cells resulting from increased ER stress.
Bolar et al. (2016) found that morpholino knockdown of the zebrafish sec61a1 ortholog in zebrafish embryos resulted in increased frequency of absence or decreased convolution of the pronephric tubules compared to wildtype, consistent with tubular atrophy.
In 7 affected members of a 3-generation family with autosomal dominant tubulointerstitial kidney disease-5 (ADTKD5; 617056) Bolar et al. (2016) identified a heterozygous c.553A-G transition (c.553A-G, NM_013336.3) in the SEC61A1 gene, resulting in a thr185-to-ala (T185A) substitution at a conserved residue in transmembrane helix 5 that may affect the structural integrity of the channel. The mutation, which was found by a combination of linkage analysis and whole-exome sequencing, segregated with the disorder in the family and was not found in the 1000 Genomes Project, Exome Variant Server, or ExAC databases, in 204 Belgian control chromosomes, or in several in-house exome databases. Immunohistochemical staining of a patient-derived kidney biopsy showed abnormal intracellular localization and aggregation of the mutant protein, with coarse granular cytoplasmic staining in tubules and collecting ducts. There was also absence of REN (179820) immunostaining in juxtaglomerular cells. The mutant protein was unable to rescue the tubular atrophy phenotype in zebrafish embryos with morpholino knockdown of the sec61a1 ortholog, suggesting that the mutation results in a complete loss of function.
In a 4-year-old girl with ADTKD5, Espino-Hernandez et al. (2021) identified a de novo heterozygous T185A mutation in the SEC61A1 gene. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant were not performed. She presented in infancy with poor overall growth, elevated uric acid, and mild anemia. Urinary concentrating ability was reduced and kidneys were at the lower limit of normal size. She also had mild psychomotor delay. She did not have recurrent infections, but immunologic work-up showed CD4+ T cell lymphopenia. Neutrophil count and immunoglobulin levels were normal. Espino-Hernandez et al. (2021) noted that ADTKD5 may manifest as a syndromic form of progressive chronic kidney disease.
In a father and daughter with autosomal dominant tubulointerstitial kidney disease-5 (ADTKD5; 617056), Bolar et al. (2016) identified a heterozygous c.200T-G transversion (c.200T-G, NM_013336.3) in the SEC61A1 gene, resulting in a val67-to-gly (V67G) substitution at a conserved residue in the translocon pore; the residue is part of a plug domain that seals and stabilizes the pore during the closed state. The mutation, which was found by custom gene panel sequencing of 46 unrelated probands with a similar disorder, was not found in the 1000 Genomes Project, Exome Variant Server, or several in-house exome databases, but was found once in the ExAC database (1 of 121,410 alleles). Transfection of the mutation into HEK293 cells resulted in decreased protein levels compared to wildtype, and the mutant protein formed intracellular clumps that were localized in the endoplasmic reticulum and partially in the Golgi apparatus. The mutant protein was unable to fully rescue the tubular atrophy phenotype in zebrafish embryos with morpholino knockdown of the sec61a1 ortholog, suggesting that the mutation results in a partial loss of function.
In 10 affected members of a family of northern European descent (family 1) with common variable immunodeficiency-15 (CVID15; 620670), Schubert et al. (2018) identified a heterozygous c.254T-A transversion in the SEC61A1 gene, resulting in a val85-to-asp (V85D) substitution at a highly conserved residue that forms the pore ring of the Sec61 channel. The mutation, which was found by a combination of linkage analysis and whole-exome sequencing, segregated with the disorder in the family. Patient-derived B cells showed reduced SEC61A1 mRNA and protein levels and had significantly reduced immunoglobulin secretion compared to controls. Expression of the V85D mutation in HeLa cells caused increased ER/cytosol calcium leakage, impaired protein translocation, and increased ER stress. Multiple myeloma cells expressing the V85D mutation showed selectively impaired survival of plasma cells and strong activation of the terminal UPR. The V85D mutation showed a dominant-negative effect in the in vitro studies. Patient B cells did not differentiate into plasma cells in vitro, indicating a specific impairment of plasma cell homeostasis. Affected individuals had early onset of recurrent infections associated with antibody deficiency (IgM, IgG, and IgA), but normal levels of peripheral B cells, T cells, and NK cells.
In 3 members of a 3-generation family (family 2) with common variable immunodeficiency-15 (CVID15; 620670), Schubert et al. (2018) identified a heterozygous c.1325G-T transversion in the SEC61A1 gene, resulting in a glu381-to-ter (E381X) substitution. The mutation, which was found by targeted next-generation sequencing of more than 200 patients with primary antibody deficiencies and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation was not present in the gnomAD database. SEC61A1 protein levels were decreased in patient naive B cells, but normal in patient CD8+ T cells. SEC61A1 mRNA levels were decreased in patient-derived B cells, and a truncated protein was not detected, suggesting that the mutation results in nonsense-mediated mRNA decay and haploinsufficiency. Patient B cells showed significantly reduced immunoglobulin secretion compared to controls. Affected individuals had early onset of recurrent infections associated with possibly transient antibody deficiency (IgM, IgG, and IgA), but normal numbers and subsets of peripheral B cells, T cells, and NK cells. Patient B cells did not differentiate into plasma cells in vitro, indicating a specific impairment of plasma cell homeostasis. However, the authors noted that the phenotype in this family showed variable expressivity and incomplete penetrance, likely due to SEC61A1 haploinsufficiency.
In a 19-year-old woman, born of unrelated Belgian parents, with autosomal dominant severe congenital neutropenia-11 (SCN11; 620674), Van Nieuwenhove et al. (2020) identified a de novo heterozygous c.275A-G transition (c.275A-G, NM_013336) in the SEC61A1 gene, resulting in a gln92-to-arg (Q92R) substitution at a conserved residue in transmembrane 2. The mutation, which was found by whole-exome sequencing, was not present in public databases. Patient peripheral blood mononuclear cells and fibroblasts showed decreased SEC61A1 protein expression, although mRNA levels were normal. The reduced protein expression correlated with decreased SEC61-dependent protein translocation across the ER. Patient CD34+ cells showed defective myeloid differentiation and neutrophil maturation in vitro. Patient bone marrow biopsy showed myeloid maturation arrest, and transcriptome analysis was consistent with decreased progenitor subsets of several populations, including B cells, common lymphoid progenitors, and granulocyte/myeloid progenitors. The macrophage/monocyte cluster demonstrated the most differentially expressed genes. There was also evidence of upregulation of the UPR and mitochondrial dysfunction. Accordingly, patient cells showed upregulation of the ER stress mechanism and increased susceptibility to apoptosis under ER stress conditions compared to controls. Similar cellular abnormalities, including arrested neutrophil differentiation, elevated ER stress, and activation of the UPR, were observed in HL-60 cells transduced with the mutation; this was associated with increased calcium leakage causing neutralization of the ER/cytosolic calcium gradient. The patient had normal B-cell numbers, but there was maturation arrest of B-cell precursors at the transitional B-cell stage. However, she had increased plasmablasts and hypergammaglobulinemia. NK cells also showed a maturation defect. Thus, although the primary presentation of the patient was consistent with severe congenital neutropenia, the mutation also affected other leukocyte populations. The findings indicated that the mutation resulted in a combined quantitative and functional SEC61A1 protein defect.
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