SEC61A1 deficiency is an autosomal dominant disorder caused by heterozygous, often de novo, variants in SEC61A1, which encodes the pore-forming alpha subunit of the Sec61 translocon in the endoplasmic reticulum membrane. The Sec61 channel moves nascent secretory and membrane proteins into the endoplasmic reticulum and also acts as a passive calcium leak channel. Reported variants reduce protein abundance, impair cotranslational translocation, and disturb endoplasmic reticulum calcium homeostasis, which pushes highly secretory cells into a terminal unfolded protein response. Three clinical presentations have been described, sometimes overlapping within a family or a patient: autosomal dominant tubulointerstitial kidney disease with glomerular cysts, hyperuricemia and congenital anemia (ADTKD-SEC61A1, also familial juvenile hyperuricemic nephropathy type 4); a primary antibody deficiency with an intrinsic failure of B cells to become plasma cells (common variable immunodeficiency 15); and severe congenital neutropenia with maturation arrest of granulopoiesis. Neutropenia, growth retardation, cleft palate and cognitive impairment have been reported with the kidney form. A single family with polycystic liver disease carries a further missense variant, and one child had epilepsy, microcephaly and hypomagnesemia. Fewer than thirty patients have been published.
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name: SEC61A1 Deficiency
creation_date: "2026-10-22T20:30:00Z"
category: Mendelian
synonyms:
- SEC61A1-related disease
disease_term:
preferred_term: SEC61A1 deficiency
term:
id: MONDO:0100337
label: SEC61A1 deficiency
parents:
- Autosomal Dominant Tubulointerstitial Kidney Disease
- Inborn Error of Immunity
- Severe Congenital Neutropenia
description: >-
SEC61A1 deficiency is an autosomal dominant disorder caused by heterozygous,
often de novo, variants in SEC61A1, which encodes the pore-forming alpha
subunit of the Sec61 translocon in the endoplasmic reticulum membrane. The
Sec61 channel moves nascent secretory and membrane proteins into the
endoplasmic reticulum and also acts as a passive calcium leak channel.
Reported variants reduce protein abundance, impair cotranslational
translocation, and disturb endoplasmic reticulum calcium homeostasis, which
pushes highly secretory cells into a terminal unfolded protein response.
Three clinical presentations have been described, sometimes overlapping
within a family or a patient: autosomal dominant tubulointerstitial kidney
disease with glomerular cysts, hyperuricemia and congenital anemia
(ADTKD-SEC61A1, also familial juvenile hyperuricemic nephropathy type 4); a
primary antibody deficiency with an intrinsic failure of B cells to become
plasma cells (common variable immunodeficiency 15); and severe congenital
neutropenia with maturation arrest of granulopoiesis. Neutropenia, growth
retardation, cleft palate and cognitive impairment have been reported with
the kidney form. A single family with polycystic liver disease carries a
further missense variant, and one child had epilepsy, microcephaly and
hypomagnesemia. Fewer than thirty patients have been published.
notes: >-
ClinGen lumped the kidney, antibody deficiency and neutropenia presentations
into one entity, autosomal dominant SEC61A1 deficiency (MONDO:0100337), and
classified the gene-disease relationship as Moderate; this entry follows that
decision and carries the three presentations as subtypes. Common variable
immunodeficiency 15 is also listed as a subtype of
Common_Variable_Immunodeficiency, because MONDO files that term under both
parents.
The polycystic liver disease family (p.Arg236Cys, PMID:36478640) is recorded
as a phenotype rather than a subtype: it is one family, and it has no
separate MONDO term.
No GeneReviews chapter covers SEC61A1 or ADTKD-SEC61A1.
Frequencies are omitted throughout. The literature is a set of single
families and case reports, and no series gives a denominator.
inheritance:
- name: Autosomal dominant
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
description: >-
Heterozygous variants segregate with disease in multigenerational families
(kidney and antibody deficiency presentations) or arise de novo (several
kidney and neutropenia cases). Penetrance of the nonsense allele p.Glu381*
for the antibody deficiency was incomplete, with variable expressivity, in
the family that carried it.
evidence:
- reference: CGGV:assertion_1ff61d15-19f9-42a2-8dc4-0a4071b562eb-2021-07-27T154837.287Z
reference_title: "SEC61A1 / SEC61A1 deficiency (Moderate)"
supports: SUPPORT
evidence_source: OTHER
snippet: "SEC61A1 | HGNC:18276 | SEC61A1 deficiency | MONDO:0100337 | AD | Moderate"
explanation: ClinGen records autosomal dominant inheritance for this gene-disease pair.
- reference: PMID:27392076
reference_title: Heterozygous Loss-of-Function SEC61A1 Mutations Cause Autosomal-Dominant Tubulo-Interstitial and Glomerulocystic Kidney Disease with Anemia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "A three-generation family (family 1; Figure 1A) presented with autosomal-dominant progressive chronic kidney disease associated with congenital anemia and intrauterine and postnatal growth retardation (Table 1)."
explanation: Dominant transmission over three generations in the first founding kidney family.
- reference: PMID:28782633
reference_title: Plasma cell deficiency in human subjects with heterozygous mutations in Sec61 translocon alpha 1 subunit (SEC61A1).
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We suggest that SEC61A1 haploinsufficincy is causing (possibly transient) hypogammaglobulinemia with variable expressivity and incomplete penetrance in Family II."
explanation: >-
Incomplete penetrance and variable expressivity of the nonsense allele.
The misspelling "haploinsufficincy" is in the source.
- reference: PMID:32325141
reference_title: Defective Sec61α1 underlies a novel cause of autosomal dominant severe congenital neutropenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We identified a novel de novo missense mutation in SEC61A1 (c.A275G;p.Q92R) in a patient with SCN who was born to nonconsanguineous Belgian parents."
explanation: De novo heterozygous origin in the neutropenia presentation.
prevalence:
- population: Worldwide, published cases
measure_type: CASES_IN_LITERATURE
prevalence_class: ULTRA_RARE
notes: >-
A 2026 review counted fifteen published patients with the kidney
presentation. The antibody deficiency report adds eleven patients from two
families, and two patients with severe congenital neutropenia have been
reported.
evidence:
- reference: PMID:41850665
reference_title: "De novo SEC61A1 mutation in congenital anemia and early-onset kidney disease: Case report and review of the literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "So far fifteen patients with SEC61A1-related ADTKD have been reported, most of whom presented with early-onset chronic kidney disease and hyperuricemia."
explanation: Published case count for the kidney presentation.
- reference: PMID:28782633
reference_title: Plasma cell deficiency in human subjects with heterozygous mutations in Sec61 translocon alpha 1 subunit (SEC61A1).
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We identified a novel genetic defect and studied its pathologic mechanism in 11 patients from 2 unrelated families with PADs."
explanation: Case count for the antibody deficiency presentation.
- reference: PMID:42056350
reference_title: Identification of a Novel De Novo Heterozygous SEC61A1 Variant in a Patient With Severe Congenital Neutropenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "This is the second reported SEC61A1 variant associated with SCN11, expanding the genetic and phenotypic spectrum of SCN."
explanation: Case count for the neutropenia presentation.
has_subtypes:
- name: ADTKD-SEC61A1
display_name: Autosomal dominant tubulointerstitial kidney disease, SEC61A1-related (HNFJ4)
subtype_term:
preferred_term: hyperuricemic nephropathy, familial juvenile type 4
term:
id: MONDO:0014891
label: hyperuricemic nephropathy, familial juvenile type 4
genes:
- preferred_term: SEC61A1
term:
id: hgnc:18276
label: SEC61A1
description: >-
Early-onset, slowly progressive chronic kidney disease with tubular
atrophy, interstitial fibrosis, glomerular and tubular cysts, small
dysplastic kidneys and hyperuricemia, usually with congenital
erythropoietin-responsive anemia. Gout, growth retardation, low renin and
aldosterone with hyperkalemia and hypotension, neutropenia, cleft palate
and cognitive impairment occur in some patients.
evidence:
- reference: PMID:27392076
reference_title: Heterozygous Loss-of-Function SEC61A1 Mutations Cause Autosomal-Dominant Tubulo-Interstitial and Glomerulocystic Kidney Disease with Anemia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We report on two families with ADTKD and congenital anemia accompanied by either intrauterine growth retardation or neutropenia."
explanation: Founding description of the kidney presentation.
- reference: PMID:41850665
reference_title: "De novo SEC61A1 mutation in congenital anemia and early-onset kidney disease: Case report and review of the literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The extrarenal features included growth retardation, hematological abnormalities, cognitive impairment, and immunological abnormalities."
explanation: Extrarenal features summarized across fifteen published kidney cases.
- name: CVID15
display_name: Common variable immunodeficiency 15 (SEC61A1 plasma cell deficiency)
subtype_term:
preferred_term: immunodeficiency, common variable, 15
term:
id: MONDO:0958013
label: immunodeficiency, common variable, 15
genes:
- preferred_term: SEC61A1
term:
id: hgnc:18276
label: SEC61A1
description: >-
Early-onset hypogammaglobulinemia involving IgG, IgA and IgM with severe
recurrent bacterial respiratory infections. Peripheral B and T cell
subsets are normal, but B cells fail to differentiate into plasma cells.
Kidney disease was not reported in these families.
evidence:
- reference: PMID:28782633
reference_title: Plasma cell deficiency in human subjects with heterozygous mutations in Sec61 translocon alpha 1 subunit (SEC61A1).
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We investigated 2 families with patients with hypogammaglobulinemia, severe recurrent respiratory tract infections, and normal peripheral B- and T-cell subpopulations."
explanation: Defining clinical description of the antibody deficiency presentation.
- name: SCN11
display_name: Severe congenital neutropenia 11 (SEC61A1-related)
subtype_term:
preferred_term: neutropenia, severe congenital, 11, autosomal dominant
term:
id: MONDO:0958017
label: neutropenia, severe congenital, 11, autosomal dominant
genes:
- preferred_term: SEC61A1
term:
id: hgnc:18276
label: SEC61A1
description: >-
Severe congenital neutropenia with maturation arrest of granulopoiesis at
the promyelocyte and myelocyte stage and recurrent bacterial infections.
Two patients with de novo variants have been reported.
evidence:
- reference: PMID:32325141
reference_title: Defective Sec61α1 underlies a novel cause of autosomal dominant severe congenital neutropenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Specific mutations in SEC61A1 cause SCN through dysregulation of the UPR."
explanation: Defines the neutropenia presentation.
- reference: PMID:42056350
reference_title: Identification of a Novel De Novo Heterozygous SEC61A1 Variant in a Patient With Severe Congenital Neutropenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "A novel de novo pathogenic SEC61A1 variant (c.1135 T > C; p.Trp379Arg) was identified."
explanation: Second patient with the neutropenia presentation.
pathophysiology:
- name: Heterozygous SEC61A1 Variants
biological_scale: MOLECULAR
description: >-
Germline heterozygous missense and nonsense variants in SEC61A1. Missense
variants in the plug and pore ring regions (p.Val67Gly, p.Thr185Ala,
p.Val85Asp, p.Gln92Arg) reduce protein stability or mislocalize the
protein to the Golgi; the nonsense variant p.Glu381* acts by
haploinsufficiency. Some missense variants are proposed to act in a
dominant-negative way on calcium leak, so the net effect is a functional
haploinsufficiency of the translocon.
molecular_functions:
- preferred_term: protein-conducting channel activity of Sec61 alpha
modifier: DECREASED
term:
id: GO:0008320
label: transmembrane protein transporter activity
genes:
- preferred_term: SEC61A1
term:
id: hgnc:18276
label: SEC61A1
modifier: DECREASED
genetic_context:
description: >-
Germline heterozygous variants, inherited or de novo. Missense variants
predominate; one nonsense variant is reported.
allelic_events:
- MISSENSE_VARIANT
- NONSENSE_VARIANT
variant_origin: GERMLINE
zygosity: HETEROZYGOUS
functional_impact_category: LOSS_OF_FUNCTION
evidence:
- reference: PMID:27392076
reference_title: Heterozygous Loss-of-Function SEC61A1 Mutations Cause Autosomal-Dominant Tubulo-Interstitial and Glomerulocystic Kidney Disease with Anemia.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Both transiently expressed SEC6A1A variants are delocalized to the Golgi, a finding confirmed in a renal biopsy from an affected individual."
explanation: >-
The two kidney-disease missense variants mislocalize the protein. The
typo "SEC6A1A" is in the source.
- reference: PMID:32325141
reference_title: Defective Sec61α1 underlies a novel cause of autosomal dominant severe congenital neutropenia.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Structural predictions and transient in vitro expression of other reported missense mutations indicate that these other mutations also have a detrimental impact on protein stability, further implicating haploinsufficiency as a disease mechanism."
explanation: Reduced protein stability across reported missense variants supports haploinsufficiency.
- reference: PMID:28782633
reference_title: Plasma cell deficiency in human subjects with heterozygous mutations in Sec61 translocon alpha 1 subunit (SEC61A1).
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "In contrast, a dominant negative mutation in SEC61A1 resulting in a functional haploinsufficiency in combination with a dominant negative disturbance of the calcium homeostasis may be responsible for the fully penetrant PAD in Family I ranging from transient hypogammaglobulinemia and specific antibody deficiency to CVID."
explanation: Proposed dominant-negative action of the p.Val85Asp missense variant, giving functional haploinsufficiency.
downstream:
- target: Defective Sec61 Cotranslational Protein Translocation
causal_link_type: DIRECT
evidence:
- reference: PMID:28782633
reference_title: Plasma cell deficiency in human subjects with heterozygous mutations in Sec61 translocon alpha 1 subunit (SEC61A1).
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "SEC61A1-V85D was deficient in cotranslational protein translocation, and it disturbed the cellular calcium homeostasis in HeLa cells."
explanation: A patient missense variant impairs translocation in a cell-based assay.
- reference: PMID:32325141
reference_title: Defective Sec61α1 underlies a novel cause of autosomal dominant severe congenital neutropenia.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "The mutation results in diminished protein expression, disturbed protein translocation, and an increase in calcium leakage from the endoplasmic reticulum."
explanation: The neutropenia variant reduces protein abundance and translocation.
- target: Increased Endoplasmic Reticulum Calcium Leak
causal_link_type: DIRECT
evidence:
- reference: PMID:28782633
reference_title: Plasma cell deficiency in human subjects with heterozygous mutations in Sec61 translocon alpha 1 subunit (SEC61A1).
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Since these experiments were carried out in cells overexpressing SEC61A1-V85D without prior silencing of endogenous SEC61A1, we conclude that the effect on the ER/cytosol Ca2+ gradient is a dominant effect of SEC61A1-V85D."
explanation: The antibody deficiency variant disturbs the endoplasmic reticulum calcium gradient dominantly.
- reference: PMID:32325141
reference_title: Defective Sec61α1 underlies a novel cause of autosomal dominant severe congenital neutropenia.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "The mutation results in diminished protein expression, disturbed protein translocation, and an increase in calcium leakage from the endoplasmic reticulum."
explanation: The neutropenia variant increases calcium leak from the endoplasmic reticulum.
- name: Defective Sec61 Cotranslational Protein Translocation
biological_scale: MOLECULAR
description: >-
Reduced or defective Sec61 channel limits the cotranslational transport of
signal-peptide-bearing secretory and membrane proteins into the
endoplasmic reticulum. Substrates differ in their sensitivity: in cellular
models of the kidney variants, transport of renin was impaired, and the
polycystic liver variant reduced polycystin-2 biosynthesis. Substrate
selectivity is a proposed reason why different variants give different
clinical presentations.
biological_processes:
- preferred_term: SRP-dependent cotranslational protein targeting to membrane, translocation
term:
id: GO:0006616
label: SRP-dependent cotranslational protein targeting to membrane, translocation
modifier: DECREASED
protein_complexes:
- preferred_term: Sec61 translocon complex
term:
id: GO:0005784
label: Sec61 translocon complex
evidence:
- reference: PMID:28782633
reference_title: Plasma cell deficiency in human subjects with heterozygous mutations in Sec61 translocon alpha 1 subunit (SEC61A1).
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "SEC61A1-V85D was deficient in cotranslational protein translocation, and it disturbed the cellular calcium homeostasis in HeLa cells."
explanation: Direct measurement of defective translocation by a patient variant.
- reference: PMID:32325141
reference_title: Defective Sec61α1 underlies a novel cause of autosomal dominant severe congenital neutropenia.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Protein translocation of Sec61α1-dependent substrates may be differentially affected by the different mutations driving cell type-specific defects."
explanation: Proposes substrate-selective translocation defects as the reason for distinct presentations.
downstream:
- target: Impaired Renin Biosynthesis in Juxtaglomerular Cells
causal_link_type: DIRECT
evidence:
- reference: PMID:35064074
reference_title: Phenylbutyrate rescues the transport defect of the Sec61α mutations V67G and T185A for renin.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Using cellular disease models for ADTKD-SEC61A1, we identified an impaired protein transport of the renal secretory protein renin and a reduced abundance of regulatory calcium transporters, including SERCA2."
explanation: The kidney-disease variants impair translocation of renin in cellular models.
- target: Tubulointerstitial and Glomerulocystic Kidney Injury
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:27392076
reference_title: Heterozygous Loss-of-Function SEC61A1 Mutations Cause Autosomal-Dominant Tubulo-Interstitial and Glomerulocystic Kidney Disease with Anemia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: "We highlight protein translocation defects across the endoplasmic reticulum membrane, the principal role of the SEC61 complex, as a contributory pathogenic mechanism for ADTKD."
explanation: Authors' conclusion linking the translocation defect to the kidney disease; the intermediate steps in the tubule are not established.
- reference: PMID:27392076
reference_title: Heterozygous Loss-of-Function SEC61A1 Mutations Cause Autosomal-Dominant Tubulo-Interstitial and Glomerulocystic Kidney Disease with Anemia.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: INDIRECT
snippet: "Suppression or CRISPR-mediated deletions of sec61al2 in zebrafish embryos induced convolution defects of the pronephric tubules but not the pronephric ducts, consistent with the tubular atrophy observed in the affected individuals."
explanation: Loss of the zebrafish ortholog disturbs pronephric tubule development, a model of the tubular atrophy.
- target: Endoplasmic Reticulum Stress and Terminal Unfolded Protein Response
causal_link_type: DIRECT
evidence:
- reference: PMID:28782633
reference_title: Plasma cell deficiency in human subjects with heterozygous mutations in Sec61 translocon alpha 1 subunit (SEC61A1).
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "We show that SEC61A1-V85D overexpression boosts ER stress due to an increased Ca2+ leakage and impaired protein translocation in HeLa cells, and activates the terminal UPR in multiple myeloma (MM) cell lines."
explanation: Names impaired translocation, alongside calcium leak, as a cause of the ER stress produced by a patient variant.
- reference: PMID:32325141
reference_title: Defective Sec61α1 underlies a novel cause of autosomal dominant severe congenital neutropenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Specific mutations in SEC61A1 cause SCN through dysregulation of the UPR."
explanation: The neutropenia study places the unfolded protein response downstream of the defective translocon.
- target: Polycystic liver disease
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:36478640
reference_title: A SEC61A1 variant is associated with autosomal dominant polycystic liver disease.
supports: SUPPORT
evidence_source: IN_VITRO
directness: INDIRECT
snippet: "We further demonstrate that mutant SEC61A1 results in enhanced proteasomal degradation and impaired biosynthesis of PC2."
explanation: The liver-cyst variant lowers polycystin-2 biosynthesis, linking the translocon defect to the cystic pathway in one family.
- target: Cognitive impairment
causal_link_type: UNKNOWN
evidence:
- reference: PMID:27392076
reference_title: Heterozygous Loss-of-Function SEC61A1 Mutations Cause Autosomal-Dominant Tubulo-Interstitial and Glomerulocystic Kidney Disease with Anemia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: "Likewise, we speculate that the SEC61A1 alleles probably contribute to some of the additional phenotypes (e.g., cognitive impairment, neutropenia) found in the two families, though further laboratory investigation will be required to confirm this."
explanation: The authors attribute extrarenal features to the variant only speculatively; no mechanism is proposed.
- name: Increased Endoplasmic Reticulum Calcium Leak
biological_scale: CELLULAR
description: >-
The open Sec61 channel is permeable to calcium and is a passive leak
pathway from the endoplasmic reticulum to the cytosol. Patient variants in
the pore ring and plug increase this leak, and cellular models of the
kidney variants show reduced SERCA2. The resulting imbalance in
endoplasmic reticulum calcium is one of the two proposed routes to
endoplasmic reticulum stress.
biological_processes:
- preferred_term: endoplasmic reticulum calcium ion homeostasis
term:
id: GO:0032469
label: endoplasmic reticulum calcium ion homeostasis
modifier: DYSREGULATED
evidence:
- reference: PMID:21406962
reference_title: Sec61 complexes form ubiquitous ER Ca2+ leak channels.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Thus, the Sec61 complexes that are present in the ER membrane of nucleated cells form calcium leak channels that may play a crucial role in calcium homeostasis."
explanation: Establishes the Sec61 complex as an endoplasmic reticulum calcium leak channel.
- reference: PMID:35064074
reference_title: Phenylbutyrate rescues the transport defect of the Sec61α mutations V67G and T185A for renin.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Using cellular disease models for ADTKD-SEC61A1, we identified an impaired protein transport of the renal secretory protein renin and a reduced abundance of regulatory calcium transporters, including SERCA2."
explanation: The kidney variants also lower calcium transporters in cellular models.
downstream:
- target: Endoplasmic Reticulum Stress and Terminal Unfolded Protein Response
causal_link_type: DIRECT
evidence:
- reference: CGGV:assertion_1ff61d15-19f9-42a2-8dc4-0a4071b562eb-2021-07-27T154837.287Z
reference_title: "SEC61A1 / SEC61A1 deficiency (Moderate)"
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "ER stress and increased calcium leak are reported as disease pathomechanism and are demonstrated in patients as well as experimental systems (PMID: 32325141)."
explanation: ClinGen summary pairing increased calcium leak with endoplasmic reticulum stress as the disease mechanism.
- reference: PMID:32325141
reference_title: Defective Sec61α1 underlies a novel cause of autosomal dominant severe congenital neutropenia.
supports: SUPPORT
evidence_source: IN_VITRO
directness: INDIRECT
snippet: "The disturbed Ca2+ homeostasis associated with mutant Sec61α1 can thus potentially impede the ability of mitochondria to restore ATP levels in the ER, thereby inducing apoptosis."
explanation: Authors' proposed route from disturbed calcium homeostasis to stress-induced cell death; not directly tested.
- name: Endoplasmic Reticulum Stress and Terminal Unfolded Protein Response
biological_scale: CELLULAR
description: >-
Cells with mutant SEC61A1 upregulate BiP and the pro-apoptotic
transcription factor CHOP, with activation of the PERK and ATF4 branch of
the unfolded protein response. The effect is strongest in cells with a
high secretory load that depend on the translocon, such as plasma cells
and differentiating myeloid precursors.
biological_processes:
- preferred_term: endoplasmic reticulum unfolded protein response
term:
id: GO:0030968
label: endoplasmic reticulum unfolded protein response
modifier: INCREASED
- preferred_term: PERK-mediated unfolded protein response
term:
id: GO:0036499
label: PERK-mediated unfolded protein response
modifier: INCREASED
evidence:
- reference: PMID:32325141
reference_title: Defective Sec61α1 underlies a novel cause of autosomal dominant severe congenital neutropenia.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "In the index patient, primary fibroblasts demonstrated upregulation of both DDIT3, encoding CCAAT/enhancer-binding protein homologous protein (CHOP), and HSPA5, encoding immunoglobulin heavy chain binding protein (BiP), with primary PBMCs showing a similar fold increase for CHOP (Fig 5, B and C)."
explanation: Patient-derived cells show unfolded protein response activation.
- reference: PMID:28782633
reference_title: Plasma cell deficiency in human subjects with heterozygous mutations in Sec61 translocon alpha 1 subunit (SEC61A1).
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Moreover, SEC61A1-V85D triggered the terminal unfolded protein response in multiple myeloma cell lines."
explanation: A patient variant triggers the terminal unfolded protein response in plasma cell lines.
- reference: PMID:28782633
reference_title: Plasma cell deficiency in human subjects with heterozygous mutations in Sec61 translocon alpha 1 subunit (SEC61A1).
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Notably, the PERK/ATF4 pathway, which acts upstream of the apoptosis-inducing transcription factor CHOP, seemed to be activated."
explanation: Activation of the PERK branch with a patient variant.
- reference: PMID:32325141
reference_title: Defective Sec61α1 underlies a novel cause of autosomal dominant severe congenital neutropenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: "Although the UPR is a feature of all cell types, the reoccurring theme of SCN in patients with mutated UPR genes indicates that the differentiating myeloid progenitor is highly susceptible to ER stress, a feature shared with plasma cells, pancreatic β-cells, and the developing kidney."
explanation: Authors' explanation of why the disease is confined to secretory cell types.
downstream:
- target: Impaired Plasma Cell Differentiation and Survival
causal_link_type: DIRECT
evidence:
- reference: PMID:28782633
reference_title: Plasma cell deficiency in human subjects with heterozygous mutations in Sec61 translocon alpha 1 subunit (SEC61A1).
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Taken together, these observations indicate that SEC61A1-V85D production selectively impairs the survival of plasma cell lines."
explanation: Mutant SEC61A1 reduces plasma cell line survival.
- target: Granulocytic Maturation Arrest
causal_link_type: DIRECT
evidence:
- reference: PMID:32325141
reference_title: Defective Sec61α1 underlies a novel cause of autosomal dominant severe congenital neutropenia.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "A potential mechanism for this defect is the uncontrolled initiation of the unfolded protein stress response, with single-cell analysis of primary bone marrow revealing perturbed UPR in myeloid precursors and in vitro differentiation of primary CD34+ cells revealing upregulation of CCAAT/enhancer-binding protein homologous protein and immunoglobulin heavy chain binding protein UPR-response genes."
explanation: Links unfolded protein response activation in myeloid precursors to the granulopoiesis defect.
- name: Impaired Plasma Cell Differentiation and Survival
biological_scale: CELLULAR
description: >-
SEC61A1 is a target of spliced XBP1 and is strongly induced as B cells
become plasma cells. Patient B cells are present in normal numbers and
subsets but fail to form plasmablasts and plasma cells on stimulation,
and secrete less IgG and IgA. This is the cellular basis of the antibody
deficiency.
cell_types:
- preferred_term: B cell
term:
id: CL:0000236
label: B cell
- preferred_term: plasma cell
term:
id: CL:0000786
label: plasma cell
biological_processes:
- preferred_term: plasma cell differentiation
term:
id: GO:0002317
label: plasma cell differentiation
modifier: DECREASED
subtypes:
- CVID15
evidence:
- reference: PMID:28782633
reference_title: Plasma cell deficiency in human subjects with heterozygous mutations in Sec61 translocon alpha 1 subunit (SEC61A1).
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "On in vitro stimulation, B cells showed an intrinsic deficiency to develop into PCs."
explanation: Patient B cells fail to become plasma cells ex vivo.
- reference: PMID:28782633
reference_title: Plasma cell deficiency in human subjects with heterozygous mutations in Sec61 translocon alpha 1 subunit (SEC61A1).
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: BACKGROUND
snippet: "SEC61A1 is a target gene of spliced X-box binding protein 1 and strongly induced during plasma cell (PC) differentiation."
explanation: Explains why plasma cells are especially dependent on SEC61A1.
downstream:
- target: Decreased circulating immunoglobulin concentration
causal_link_type: DIRECT
evidence:
- reference: PMID:28782633
reference_title: Plasma cell deficiency in human subjects with heterozygous mutations in Sec61 translocon alpha 1 subunit (SEC61A1).
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We describe a monogenic defect leading to a specific PC deficiency in human subjects, expanding our knowledge about the pathogenesis of antibody deficiencies."
explanation: The plasma cell deficiency is the cause of the antibody deficiency.
- target: Decreased circulating IgG concentration
causal_link_type: DIRECT
- target: Decreased circulating IgA concentration
causal_link_type: DIRECT
- target: Decreased circulating IgM concentration
causal_link_type: DIRECT
- target: Recurrent respiratory infections
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: Antibody deficiency leaves patients susceptible to bacterial respiratory infections.
- target: Recurrent bacterial infections
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: Granulocytic Maturation Arrest
biological_scale: CELLULAR
description: >-
In the neutropenia presentation, bone marrow granulopoiesis arrests at the
promyelocyte and myelocyte stage. Patient CD34+ cells reproduce the arrest
in culture, and transduction of the patient variant into HL-60 cells
reduces their differentiation into mature neutrophils. Circulating
neutrophils that do appear on G-CSF remain immature with hyposegmented
nuclei.
cell_types:
- preferred_term: promyelocyte
term:
id: CL:0000836
label: promyelocyte
- preferred_term: neutrophil
term:
id: CL:0000775
label: neutrophil
biological_processes:
- preferred_term: neutrophil differentiation
term:
id: GO:0030223
label: neutrophil differentiation
modifier: DECREASED
subtypes:
- SCN11
evidence:
- reference: PMID:32325141
reference_title: Defective Sec61α1 underlies a novel cause of autosomal dominant severe congenital neutropenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Bone marrow analysis before G-CSF treatment showed a maturation arrest in granulopoiesis at the level of the promyelocytes and myelocytes (Fig 1, B)."
explanation: Maturation arrest in the patient's bone marrow.
- reference: PMID:32325141
reference_title: Defective Sec61α1 underlies a novel cause of autosomal dominant severe congenital neutropenia.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "In vitro differentiation of CD34+ cells recapitulated the patient's clinical arrest in granulopoiesis."
explanation: The arrest is intrinsic to patient hematopoietic progenitors.
- reference: PMID:42056350
reference_title: Identification of a Novel De Novo Heterozygous SEC61A1 Variant in a Patient With Severe Congenital Neutropenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Bone marrow showed granulocytic hyperplasia with maturation arrest and nuclear abnormalities."
explanation: Maturation arrest in a second, unrelated patient.
- reference: PMID:32325141
reference_title: Defective Sec61α1 underlies a novel cause of autosomal dominant severe congenital neutropenia.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Our data support genotype-specific effects contributing to the clinical presentation, with only the neutropenia-associated mutations and not the CVID-associated mutation showing defects in our HL-60 model of neutrophilic maturation."
explanation: Only neutropenia-associated variants block myeloid maturation in this model, supporting genotype-specific presentations.
downstream:
- target: Congenital agranulocytosis
causal_link_type: DIRECT
- target: Decreased total neutrophil count
causal_link_type: DIRECT
- target: Recurrent abscess formation
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: Neutropenia predisposes to bacterial skin and soft-tissue abscesses.
- name: Impaired Renin Biosynthesis in Juxtaglomerular Cells
biological_scale: CELLULAR
description: >-
Renin is a signal-peptide-dependent secretory protein made by the granular
cells of the juxtaglomerular apparatus. The kidney variants impair its
translocation in cellular models, and a patient biopsy lacked renin
staining in juxtaglomerular cells. Low renin and aldosterone explain the
hyperkalemia and hypotension seen in some patients, which corrected with
a mineralocorticoid. The chemical chaperone phenylbutyrate restored renin
transport in cellular models, but has not been tested in patients.
cell_types:
- preferred_term: kidney granular cell
term:
id: CL:0000648
label: kidney granular cell
biological_processes:
- preferred_term: renin secretion into blood stream
term:
id: GO:0002001
label: renin secretion into blood stream
modifier: DECREASED
subtypes:
- ADTKD-SEC61A1
evidence:
- reference: PMID:27392076
reference_title: Heterozygous Loss-of-Function SEC61A1 Mutations Cause Autosomal-Dominant Tubulo-Interstitial and Glomerulocystic Kidney Disease with Anemia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In the affected kidney, we observed absence of renin staining in juxtaglomerular granular cells, which was accompanied by mild granular positivity of renin staining in the cytoplasm of tubular cells (Figure 2E)."
explanation: Patient kidney biopsy lacks renin in juxtaglomerular granular cells.
- reference: PMID:35064074
reference_title: Phenylbutyrate rescues the transport defect of the Sec61α mutations V67G and T185A for renin.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Treatment with the molecular chaperone phenylbutyrate reversed the defective protein transport of renin and the imbalanced calcium homeostasis."
explanation: Renin transport defect in cellular models, reversible by a chemical chaperone.
downstream:
- target: Decreased circulating renin concentration
causal_link_type: DIRECT
- target: Decreased circulating aldosterone concentration
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
evidence:
- reference: PMID:39135939
reference_title: Hypoaldosteronism due to a novel SEC61A1 variant successfully treated with fludrocortisone.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "As the renin-angiotensin system promotes aldosterone release, and the patient had repeatedly undetectable aldosterone levels, the SEC61A1 variant presumably contributed to severe hypotension."
explanation: Low renin-angiotensin drive explains low aldosterone.
- target: Tubulointerstitial and Glomerulocystic Kidney Injury
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:35064074
reference_title: Phenylbutyrate rescues the transport defect of the Sec61α mutations V67G and T185A for renin.
supports: SUPPORT
evidence_source: IN_VITRO
directness: INDIRECT
snippet: "Similarly, dominant mutations in the signal peptide of renin also cause ADTKD and point to impaired transport of this renal hormone as important pathogenic feature for ADTKD-SEC61A1 patients as well."
explanation: By analogy with REN signal-peptide variants, impaired renin transport is proposed to contribute to the tubulointerstitial disease.
- name: Tubulointerstitial and Glomerulocystic Kidney Injury
biological_scale: TISSUE
description: >-
Kidneys are small and dysplastic, with tubular atrophy, interstitial
fibrosis, cystic dilatation of Bowman's spaces with rudimentary glomerular
tufts, and secondary glomerulosclerosis. Proteinuria is absent or minimal
and urinary sediment is bland. Function declines slowly from childhood,
and kidney failure has been reported from the first year of life to late
adulthood.
cell_types:
- preferred_term: epithelial cell of nephron
term:
id: CL:1000449
label: epithelial cell of nephron
subtypes:
- ADTKD-SEC61A1
evidence:
- reference: PMID:27392076
reference_title: Heterozygous Loss-of-Function SEC61A1 Mutations Cause Autosomal-Dominant Tubulo-Interstitial and Glomerulocystic Kidney Disease with Anemia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Ultrasound and kidney biopsy revealed small dysplastic kidneys with cysts and tubular atrophy with secondary glomerular sclerosis, respectively."
explanation: Imaging and histology of the kidney lesion.
- reference: PMID:27392076
reference_title: Heterozygous Loss-of-Function SEC61A1 Mutations Cause Autosomal-Dominant Tubulo-Interstitial and Glomerulocystic Kidney Disease with Anemia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Glomerular changes were dominated by cystic dilatation of Bowmann's spaces with collapsed or rudimentary glomerular tufts and often filled with precipitate of plasma proteins (Figure 2B)."
explanation: Glomerulocystic histology. The spelling "Bowmann" is in the source.
- reference: PMID:39135939
reference_title: Hypoaldosteronism due to a novel SEC61A1 variant successfully treated with fludrocortisone.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "A patient is described that presented at 1 year of age with failure-to-thrive, kidney failure (glomerular filtration rate, GFR, 18 ml/min/1.73m2), hyperkalemia and acidosis."
explanation: Kidney failure from the first year of life in a de novo case.
downstream:
- target: Chronic kidney disease
causal_link_type: DIRECT
- target: Renal tubular atrophy
causal_link_type: DIRECT
- target: Multiple glomerular cysts
causal_link_type: DIRECT
- target: Renal cyst
causal_link_type: DIRECT
- target: Renal dysplasia
causal_link_type: DIRECT
- target: Hyperuricemia
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Normocytic anemia
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:27392076
reference_title: Heterozygous Loss-of-Function SEC61A1 Mutations Cause Autosomal-Dominant Tubulo-Interstitial and Glomerulocystic Kidney Disease with Anemia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: "Significant laboratory findings included normochromic, normocytic anemia that was responsive to erythropoietin, elevated serum creatinine levels, mild hyperuricemia, and the absence of proteinuria."
explanation: >-
Response to erythropoietin points to deficient renal erythropoietin
production. The anemia is congenital and can precede measurable loss of
kidney function, so the intermediate steps are not established.
phenotypes:
- category: Renal
name: Chronic kidney disease
subtype: ADTKD-SEC61A1
description: >-
Early-onset and slowly progressive. A 2026 review of fifteen patients
found early-onset chronic kidney disease in most.
phenotype_term:
preferred_term: Chronic kidney disease
term:
id: HP:0012622
label: Chronic kidney disease
evidence:
- reference: PMID:41850665
reference_title: "De novo SEC61A1 mutation in congenital anemia and early-onset kidney disease: Case report and review of the literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "So far fifteen patients with SEC61A1-related ADTKD have been reported, most of whom presented with early-onset chronic kidney disease and hyperuricemia."
explanation: Chronic kidney disease in most published kidney-presentation patients.
- reference: PMID:27392076
reference_title: Heterozygous Loss-of-Function SEC61A1 Mutations Cause Autosomal-Dominant Tubulo-Interstitial and Glomerulocystic Kidney Disease with Anemia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Both affected relatives suffered from congenital anemia and neutropenia, gout in the second decade of life, and chronic kidney disease."
explanation: Chronic kidney disease in the second founding family.
sequelae:
- target: Gout
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- category: Renal
name: Renal tubular atrophy
subtype: ADTKD-SEC61A1
phenotype_term:
preferred_term: Renal tubular atrophy
term:
id: HP:0000092
label: Renal tubular atrophy
evidence:
- reference: PMID:27392076
reference_title: Heterozygous Loss-of-Function SEC61A1 Mutations Cause Autosomal-Dominant Tubulo-Interstitial and Glomerulocystic Kidney Disease with Anemia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Ultrasound and kidney biopsy revealed small dysplastic kidneys with cysts and tubular atrophy with secondary glomerular sclerosis, respectively."
explanation: Tubular atrophy on biopsy.
- category: Renal
name: Multiple glomerular cysts
subtype: ADTKD-SEC61A1
phenotype_term:
preferred_term: Multiple glomerular cysts
term:
id: HP:0100611
label: Multiple glomerular cysts
evidence:
- reference: PMID:27392076
reference_title: Heterozygous Loss-of-Function SEC61A1 Mutations Cause Autosomal-Dominant Tubulo-Interstitial and Glomerulocystic Kidney Disease with Anemia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Glomerular changes were dominated by cystic dilatation of Bowmann's spaces with collapsed or rudimentary glomerular tufts and often filled with precipitate of plasma proteins (Figure 2B)."
explanation: Glomerular cysts on biopsy.
- category: Renal
name: Renal cyst
subtype: ADTKD-SEC61A1
phenotype_term:
preferred_term: Renal cyst
term:
id: HP:0000107
label: Renal cyst
evidence:
- reference: PMID:41850665
reference_title: "De novo SEC61A1 mutation in congenital anemia and early-onset kidney disease: Case report and review of the literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The evaluation suggested elevated serum creatinine, hyperuricemia, bland urinary sediment, the absence of proteinuria, and renal cysts."
explanation: Renal cysts in a de novo case.
- category: Renal
name: Renal dysplasia
subtype: ADTKD-SEC61A1
description: Small dysplastic kidneys on ultrasound.
phenotype_term:
preferred_term: Small dysplastic kidneys
term:
id: HP:0000110
label: Renal dysplasia
evidence:
- reference: PMID:27392076
reference_title: Heterozygous Loss-of-Function SEC61A1 Mutations Cause Autosomal-Dominant Tubulo-Interstitial and Glomerulocystic Kidney Disease with Anemia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Ultrasound and kidney biopsy revealed small dysplastic kidneys with cysts and tubular atrophy with secondary glomerular sclerosis, respectively."
explanation: Small dysplastic kidneys on ultrasound.
- category: Metabolic
name: Hyperuricemia
subtype: ADTKD-SEC61A1
phenotype_term:
preferred_term: Hyperuricemia
term:
id: HP:0002149
label: Hyperuricemia
evidence:
- reference: PMID:41850665
reference_title: "De novo SEC61A1 mutation in congenital anemia and early-onset kidney disease: Case report and review of the literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "So far fifteen patients with SEC61A1-related ADTKD have been reported, most of whom presented with early-onset chronic kidney disease and hyperuricemia."
explanation: Hyperuricemia in most published kidney-presentation patients.
sequelae:
- target: Gout
causal_link_type: DIRECT
- category: Musculoskeletal
name: Gout
subtype: ADTKD-SEC61A1
phenotype_term:
preferred_term: Gout
term:
id: HP:0001997
label: Gout
evidence:
- reference: PMID:27392076
reference_title: Heterozygous Loss-of-Function SEC61A1 Mutations Cause Autosomal-Dominant Tubulo-Interstitial and Glomerulocystic Kidney Disease with Anemia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Both affected relatives suffered from congenital anemia and neutropenia, gout in the second decade of life, and chronic kidney disease."
explanation: Gout in the second decade in the second founding family; it was absent in the first.
- category: Hematologic
name: Normocytic anemia
description: >-
Congenital normocytic normochromic anemia, responsive to erythropoietin,
in the kidney presentation; mild intermittent anemia in a neutropenia
patient.
phenotype_term:
preferred_term: Congenital normocytic anemia
term:
id: HP:0001897
label: Normocytic anemia
evidence:
- reference: PMID:27392076
reference_title: Heterozygous Loss-of-Function SEC61A1 Mutations Cause Autosomal-Dominant Tubulo-Interstitial and Glomerulocystic Kidney Disease with Anemia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Significant laboratory findings included normochromic, normocytic anemia that was responsive to erythropoietin, elevated serum creatinine levels, mild hyperuricemia, and the absence of proteinuria."
explanation: Erythropoietin-responsive normocytic anemia in the founding family.
- reference: PMID:41850665
reference_title: "De novo SEC61A1 mutation in congenital anemia and early-onset kidney disease: Case report and review of the literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "He had normocytic normochromic anemia since early childhood and was recently found to have agranulocytosis."
explanation: Anemia from early childhood in a de novo case.
- category: Hematologic
name: Decreased total neutrophil count
description: >-
Reported in the kidney presentation as well as the neutropenia
presentation; it did not respond to G-CSF in one kidney-presentation
patient.
phenotype_term:
preferred_term: Neutropenia
term:
id: HP:0001875
label: Decreased total neutrophil count
evidence:
- reference: PMID:27392076
reference_title: Heterozygous Loss-of-Function SEC61A1 Mutations Cause Autosomal-Dominant Tubulo-Interstitial and Glomerulocystic Kidney Disease with Anemia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The affected individual had persistent granulocyte stimulating factor-unresponsive neutropenia and recurrent admissions for cutaneous abscesses."
explanation: G-CSF-unresponsive neutropenia in a kidney-presentation patient.
- reference: PMID:41850665
reference_title: "De novo SEC61A1 mutation in congenital anemia and early-onset kidney disease: Case report and review of the literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "He had normocytic normochromic anemia since early childhood and was recently found to have agranulocytosis."
explanation: Agranulocytosis in a kidney-presentation patient.
- category: Hematologic
name: Congenital agranulocytosis
subtype: SCN11
description: Severe congenital neutropenia.
phenotype_term:
preferred_term: Severe congenital neutropenia
term:
id: HP:0005541
label: Congenital agranulocytosis
evidence:
- reference: PMID:32325141
reference_title: Defective Sec61α1 underlies a novel cause of autosomal dominant severe congenital neutropenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We identified a novel de novo missense mutation in SEC61A1 (c.A275G;p.Q92R) in a patient with SCN who was born to nonconsanguineous Belgian parents."
explanation: Severe congenital neutropenia in the index patient.
- reference: PMID:42056350
reference_title: Identification of a Novel De Novo Heterozygous SEC61A1 Variant in a Patient With Severe Congenital Neutropenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We report an 11-year-old boy with decreased neutrophils and lymphocytes, and elevated proportions of monocytes and eosinophils."
explanation: Neutropenia in the second patient.
- category: Immunologic
name: Recurrent abscess formation
description: Cutaneous and deep abscesses, including Escherichia coli abscesses with septicemia.
phenotype_term:
preferred_term: Recurrent abscess formation
term:
id: HP:0002722
label: Recurrent abscess formation
evidence:
- reference: PMID:27392076
reference_title: Heterozygous Loss-of-Function SEC61A1 Mutations Cause Autosomal-Dominant Tubulo-Interstitial and Glomerulocystic Kidney Disease with Anemia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The affected individual had persistent granulocyte stimulating factor-unresponsive neutropenia and recurrent admissions for cutaneous abscesses."
explanation: Recurrent cutaneous abscesses with neutropenia.
- reference: PMID:32325141
reference_title: Defective Sec61α1 underlies a novel cause of autosomal dominant severe congenital neutropenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Following an Escherichia coli abscess in her facial region at the age of 15 years and septicemia secondary to a gluteal E coli abscess a year later, she began receiving daily G-CSF."
explanation: Recurrent abscesses in the neutropenia index patient.
- category: Immunologic
name: Decreased circulating immunoglobulin concentration
subtype: CVID15
description: Hypogammaglobulinemia, present from birth in some patients and transient in others.
phenotype_term:
preferred_term: Hypogammaglobulinemia
term:
id: HP:0004313
label: Decreased circulating immunoglobulin concentration
evidence:
- reference: PMID:28782633
reference_title: Plasma cell deficiency in human subjects with heterozygous mutations in Sec61 translocon alpha 1 subunit (SEC61A1).
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We investigated 2 families with patients with hypogammaglobulinemia, severe recurrent respiratory tract infections, and normal peripheral B- and T-cell subpopulations."
explanation: Hypogammaglobulinemia in both families.
- category: Immunologic
name: Decreased circulating IgG concentration
subtype: CVID15
phenotype_term:
preferred_term: Decreased circulating IgG concentration
term:
id: HP:0004315
label: Decreased circulating IgG concentration
evidence:
- reference: PMID:28782633
reference_title: Plasma cell deficiency in human subjects with heterozygous mutations in Sec61 translocon alpha 1 subunit (SEC61A1).
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We investigated 10 individuals in Family I (Figure 1A), who had antibody isotype deficiencies involving IgM, IgG and IgA (Table S1) and who suffered from severe recurrent bacterial infections such as tonsillitis, otitis, sinusitis, pneumonias and gastrointestinal infections."
explanation: IgG deficiency in the larger family.
- category: Immunologic
name: Decreased circulating IgA concentration
subtype: CVID15
phenotype_term:
preferred_term: Decreased circulating IgA concentration
term:
id: HP:0002720
label: Decreased circulating IgA concentration
evidence:
- reference: PMID:28782633
reference_title: Plasma cell deficiency in human subjects with heterozygous mutations in Sec61 translocon alpha 1 subunit (SEC61A1).
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We investigated 10 individuals in Family I (Figure 1A), who had antibody isotype deficiencies involving IgM, IgG and IgA (Table S1) and who suffered from severe recurrent bacterial infections such as tonsillitis, otitis, sinusitis, pneumonias and gastrointestinal infections."
explanation: IgA deficiency in the larger family.
- category: Immunologic
name: Decreased circulating IgM concentration
subtype: CVID15
phenotype_term:
preferred_term: Decreased circulating IgM concentration
term:
id: HP:0002850
label: Decreased circulating total IgM
evidence:
- reference: PMID:28782633
reference_title: Plasma cell deficiency in human subjects with heterozygous mutations in Sec61 translocon alpha 1 subunit (SEC61A1).
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We investigated 10 individuals in Family I (Figure 1A), who had antibody isotype deficiencies involving IgM, IgG and IgA (Table S1) and who suffered from severe recurrent bacterial infections such as tonsillitis, otitis, sinusitis, pneumonias and gastrointestinal infections."
explanation: IgM deficiency in the larger family.
- category: Immunologic
name: Recurrent respiratory infections
subtype: CVID15
description: Tonsillitis, otitis, sinusitis and pneumonia, with onset mostly in the first year of life.
phenotype_term:
preferred_term: Recurrent respiratory infections
term:
id: HP:0002205
label: Recurrent respiratory infections
evidence:
- reference: PMID:28782633
reference_title: Plasma cell deficiency in human subjects with heterozygous mutations in Sec61 translocon alpha 1 subunit (SEC61A1).
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We investigated 2 families with patients with hypogammaglobulinemia, severe recurrent respiratory tract infections, and normal peripheral B- and T-cell subpopulations."
explanation: Severe recurrent respiratory infections in both families.
- category: Immunologic
name: Recurrent bacterial infections
subtype: CVID15
phenotype_term:
preferred_term: Recurrent bacterial infections
term:
id: HP:0002718
label: Recurrent bacterial infections
evidence:
- reference: PMID:28782633
reference_title: Plasma cell deficiency in human subjects with heterozygous mutations in Sec61 translocon alpha 1 subunit (SEC61A1).
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We investigated 10 individuals in Family I (Figure 1A), who had antibody isotype deficiencies involving IgM, IgG and IgA (Table S1) and who suffered from severe recurrent bacterial infections such as tonsillitis, otitis, sinusitis, pneumonias and gastrointestinal infections."
explanation: Severe recurrent bacterial infections in the larger family.
- category: Endocrine
name: Decreased circulating renin concentration
subtype: ADTKD-SEC61A1
phenotype_term:
preferred_term: Decreased circulating renin concentration
term:
id: HP:0003351
label: Decreased circulating renin concentration
evidence:
- reference: PMID:39135939
reference_title: Hypoaldosteronism due to a novel SEC61A1 variant successfully treated with fludrocortisone.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Plasma renin was low or normal, aldosterone was low or undetectable and uromodulin was low."
explanation: Low or normal renin in a de novo case.
- category: Endocrine
name: Decreased circulating aldosterone concentration
subtype: ADTKD-SEC61A1
phenotype_term:
preferred_term: Hypoaldosteronism
term:
id: HP:0004319
label: Decreased circulating aldosterone concentration
evidence:
- reference: PMID:39135939
reference_title: Hypoaldosteronism due to a novel SEC61A1 variant successfully treated with fludrocortisone.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Plasma renin was low or normal, aldosterone was low or undetectable and uromodulin was low."
explanation: Low or undetectable aldosterone.
sequelae:
- target: Hyperkalemia
causal_link_type: DIRECT
- target: Hypotension
causal_link_type: DIRECT
evidence:
- reference: PMID:39135939
reference_title: Hypoaldosteronism due to a novel SEC61A1 variant successfully treated with fludrocortisone.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The patient experienced extreme fatigue due to severe hypotension attributed to hypoaldosteronism and at 8 years of age fludrocortisone treatment was initiated with marked improvement in her well-being."
explanation: The authors attribute the hypotension to hypoaldosteronism.
- category: Metabolic
name: Hyperkalemia
subtype: ADTKD-SEC61A1
phenotype_term:
preferred_term: Hyperkalemia
term:
id: HP:0002153
label: Hyperkalemia
evidence:
- reference: PMID:39135939
reference_title: Hypoaldosteronism due to a novel SEC61A1 variant successfully treated with fludrocortisone.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "A patient is described that presented at 1 year of age with failure-to-thrive, kidney failure (glomerular filtration rate, GFR, 18 ml/min/1.73m2), hyperkalemia and acidosis."
explanation: Hyperkalemia at presentation.
- reference: PMID:27392076
reference_title: Heterozygous Loss-of-Function SEC61A1 Mutations Cause Autosomal-Dominant Tubulo-Interstitial and Glomerulocystic Kidney Disease with Anemia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "At age 28, she was diagnosed with hypotension (systolic blood pressure readings in the high 80s) and hyperkalemia (serum potassium 5.7 mEq/L)."
explanation: Hyperkalemia in an adult from a founding family.
- category: Cardiovascular
name: Hypotension
subtype: ADTKD-SEC61A1
phenotype_term:
preferred_term: Hypotension
term:
id: HP:0002615
label: Hypotension
evidence:
- reference: PMID:27392076
reference_title: Heterozygous Loss-of-Function SEC61A1 Mutations Cause Autosomal-Dominant Tubulo-Interstitial and Glomerulocystic Kidney Disease with Anemia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "At age 28, she was diagnosed with hypotension (systolic blood pressure readings in the high 80s) and hyperkalemia (serum potassium 5.7 mEq/L)."
explanation: Hypotension in an adult from a founding family.
- reference: PMID:39135939
reference_title: Hypoaldosteronism due to a novel SEC61A1 variant successfully treated with fludrocortisone.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The patient experienced extreme fatigue due to severe hypotension attributed to hypoaldosteronism and at 8 years of age fludrocortisone treatment was initiated with marked improvement in her well-being."
explanation: Severe hypotension in a child.
- category: Growth
name: Intrauterine growth retardation
subtype: ADTKD-SEC61A1
phenotype_term:
preferred_term: Intrauterine growth retardation
term:
id: HP:0001511
label: Intrauterine growth retardation
evidence:
- reference: PMID:27392076
reference_title: Heterozygous Loss-of-Function SEC61A1 Mutations Cause Autosomal-Dominant Tubulo-Interstitial and Glomerulocystic Kidney Disease with Anemia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "A three-generation family (family 1; Figure 1A) presented with autosomal-dominant progressive chronic kidney disease associated with congenital anemia and intrauterine and postnatal growth retardation (Table 1)."
explanation: Intrauterine growth retardation in the first founding family.
- category: Growth
name: Postnatal growth retardation
subtype: ADTKD-SEC61A1
phenotype_term:
preferred_term: Postnatal growth retardation
term:
id: HP:0008897
label: Postnatal growth retardation
evidence:
- reference: PMID:27392076
reference_title: Heterozygous Loss-of-Function SEC61A1 Mutations Cause Autosomal-Dominant Tubulo-Interstitial and Glomerulocystic Kidney Disease with Anemia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "A three-generation family (family 1; Figure 1A) presented with autosomal-dominant progressive chronic kidney disease associated with congenital anemia and intrauterine and postnatal growth retardation (Table 1)."
explanation: Postnatal growth retardation in the first founding family.
- reference: PMID:41850665
reference_title: "De novo SEC61A1 mutation in congenital anemia and early-onset kidney disease: Case report and review of the literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The extrarenal features included growth retardation, hematological abnormalities, cognitive impairment, and immunological abnormalities."
explanation: Growth retardation across published kidney-presentation patients.
- category: Craniofacial
name: Cleft palate
subtype: ADTKD-SEC61A1
description: Cleft palate or bifid uvula in two members of the first founding family.
phenotype_term:
preferred_term: Cleft palate
term:
id: HP:0000175
label: Cleft palate
evidence:
- reference: PMID:27392076
reference_title: Heterozygous Loss-of-Function SEC61A1 Mutations Cause Autosomal-Dominant Tubulo-Interstitial and Glomerulocystic Kidney Disease with Anemia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Variable findings on physical examination included cleft palate or bifid uvula (1-I:2 and 1-II:6), velopharyngeal insufficiency (1-II:6), pre-axial polydactyly (1-II:6), and mild cognitive impairment (1-II:1, 1-II:3, 1-II:5, and 1-II:6)."
explanation: Cleft palate or bifid uvula as a variable finding.
- category: Neurological
name: Cognitive impairment
subtype: ADTKD-SEC61A1
description: Mild cognitive impairment in four members of the first founding family and in other published patients.
phenotype_term:
preferred_term: Cognitive impairment
term:
id: HP:0100543
label: Cognitive impairment
evidence:
- reference: PMID:27392076
reference_title: Heterozygous Loss-of-Function SEC61A1 Mutations Cause Autosomal-Dominant Tubulo-Interstitial and Glomerulocystic Kidney Disease with Anemia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Variable findings on physical examination included cleft palate or bifid uvula (1-I:2 and 1-II:6), velopharyngeal insufficiency (1-II:6), pre-axial polydactyly (1-II:6), and mild cognitive impairment (1-II:1, 1-II:3, 1-II:5, and 1-II:6)."
explanation: Mild cognitive impairment in four family members.
- reference: PMID:41850665
reference_title: "De novo SEC61A1 mutation in congenital anemia and early-onset kidney disease: Case report and review of the literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The extrarenal features included growth retardation, hematological abnormalities, cognitive impairment, and immunological abnormalities."
explanation: Cognitive impairment among published extrarenal features.
- category: Metabolic
name: Hypomagnesemia
subtype: ADTKD-SEC61A1
description: Reported in one child with the p.Thr185Ser variant.
phenotype_term:
preferred_term: Hypomagnesemia
term:
id: HP:0002917
label: Hypomagnesemia
evidence:
- reference: PMID:42730770
reference_title: "Rare forms of autosomal dominant tubulointerstitial kidney disease in children: a retrospective case series from Oman."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "A 16-year-old girl with a SEC61A1 variant (c.554C > G; p.Thr185Ser) presented with epilepsy, microcephaly, hypomagnesemia, and CKD."
explanation: Hypomagnesemia in a single reported child.
- category: Neurological
name: Seizure
subtype: ADTKD-SEC61A1
description: Epilepsy in one child with the p.Thr185Ser variant; the authors note it had not been reported before with this gene.
phenotype_term:
preferred_term: Seizure
term:
id: HP:0001250
label: Seizure
evidence:
- reference: PMID:42730770
reference_title: "Rare forms of autosomal dominant tubulointerstitial kidney disease in children: a retrospective case series from Oman."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "A 16-year-old girl with a SEC61A1 variant (c.554C > G; p.Thr185Ser) presented with epilepsy, microcephaly, hypomagnesemia, and CKD."
explanation: Epilepsy in a single reported child.
- category: Neurological
name: Microcephaly
subtype: ADTKD-SEC61A1
description: Reported in one child with the p.Thr185Ser variant.
phenotype_term:
preferred_term: Microcephaly
term:
id: HP:0000252
label: Microcephaly
evidence:
- reference: PMID:42730770
reference_title: "Rare forms of autosomal dominant tubulointerstitial kidney disease in children: a retrospective case series from Oman."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "A 16-year-old girl with a SEC61A1 variant (c.554C > G; p.Thr185Ser) presented with epilepsy, microcephaly, hypomagnesemia, and CKD."
explanation: Microcephaly in a single reported child.
- category: Hepatic
name: Polycystic liver disease
description: >-
One family with the p.Arg236Cys variant. Kidney disease was absent in the
proband; her mother had an atypical polycystic kidney phenotype with
severe renal failure.
phenotype_term:
preferred_term: Polycystic liver disease
term:
id: HP:0006557
label: Polycystic liver disease
evidence:
- reference: PMID:36478640
reference_title: A SEC61A1 variant is associated with autosomal dominant polycystic liver disease.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Our data expand the allelic and clinical spectrum for SEC61A1, adding PLD as a new and the major phenotypic trait in the family described."
explanation: Polycystic liver disease in one family.
genetic:
- name: SEC61A1
gene_term:
preferred_term: SEC61A1
term:
id: hgnc:18276
label: SEC61A1
variant_origin: GERMLINE
association: >-
Heterozygous loss-of-function and possibly dominant-negative variants;
ClinGen Moderate gene-disease validity.
gene_disease_validity:
- validity_classification: MODERATE
classified_by: CLINGEN
external_id: CGGV:assertion_1ff61d15-19f9-42a2-8dc4-0a4071b562eb-2021-07-27T154837.287Z
evidence:
- reference: CGGV:assertion_1ff61d15-19f9-42a2-8dc4-0a4071b562eb-2021-07-27T154837.287Z
reference_title: "SEC61A1 / SEC61A1 deficiency (Moderate)"
supports: SUPPORT
evidence_source: OTHER
snippet: "SEC61A1 | HGNC:18276 | SEC61A1 deficiency | MONDO:0100337 | AD | Moderate"
explanation: ClinGen gene-disease validity record filed against MONDO:0100337, copied as recorded.
notes: >-
relationship_type is left unset because the schema reserves CAUSATIVE for
a ClinGen Definitive or Strong classification and ClinGen rates this pair
Moderate. Variants reported in the cited literature include p.Val67Gly and
p.Thr185Ala (kidney), p.Val85Asp and p.Glu381* (antibody deficiency),
p.Gln92Arg and p.Trp379Arg (neutropenia), p.Ser71Pro, p.Thr185Ser and
p.Phe458Val (kidney, de novo), and p.Arg236Cys (polycystic liver disease).
evidence:
- reference: CGGV:assertion_1ff61d15-19f9-42a2-8dc4-0a4071b562eb-2021-07-27T154837.287Z
reference_title: "SEC61A1 / SEC61A1 deficiency (Moderate)"
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: "Therefore, all of the disease entities have been lumped into one disease entity, autosomal dominant SEC61A1 deficiency."
explanation: ClinGen's lumping of the kidney, antibody deficiency and neutropenia presentations into one entity.
- reference: PMID:27392076
reference_title: Heterozygous Loss-of-Function SEC61A1 Mutations Cause Autosomal-Dominant Tubulo-Interstitial and Glomerulocystic Kidney Disease with Anemia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Here, we present evidence that mutations in SEC61A1 with complete or partial loss of function compared to wild-type can cause autosomal-dominant progressive tubulo-interstitial and glomerulocystic kidney disorder with anemia."
explanation: Founding gene-disease report for the kidney presentation.
diagnosis:
- name: Monitoring of kidney function in all variant carriers
description: >-
Kidney disease may appear later than the immune or hematologic
presentation, so carriers identified through antibody deficiency or
neutropenia should be followed for kidney dysfunction.
evidence:
- reference: PMID:32325141
reference_title: Defective Sec61α1 underlies a novel cause of autosomal dominant severe congenital neutropenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Considering that clinically evident renal disease in patients with mutations in SEC61A1 occurred later in life, we propose that patients with mutations in SEC61A1 be serially monitored for renal dysfunction, regardless of the initial clinical phenotype."
explanation: Authors' recommendation for renal follow-up.
treatments:
- name: Immunoglobulin replacement therapy
description: >-
Intravenous immunoglobulin markedly reduced the number and severity of
infections in the antibody deficiency families; attempts to withdraw it
failed because immunoglobulin levels stayed low.
therapeutic_modality: PROTEIN_REPLACEMENT
treatment_term:
preferred_term: Intravenous immunoglobulin therapy
term:
id: NCIT:C121331
label: Intravenous Immunoglobulin Therapy
target_phenotypes:
- preferred_term: Recurrent respiratory infections
term:
id: HP:0002205
label: Recurrent respiratory infections
evidence:
- reference: PMID:28782633
reference_title: Plasma cell deficiency in human subjects with heterozygous mutations in Sec61 translocon alpha 1 subunit (SEC61A1).
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "They have successfully maintained a marked decrease in the number and severity of infections since initiating immunoglobulin replacement therapy with intravenous immunoglobulins (IVIG) (detailed case reports in Supplemental Information)."
explanation: Clinical benefit of immunoglobulin replacement.
- name: Granulocyte colony-stimulating factor
description: >-
The neutropenia index patient responded to G-CSF with higher neutrophil
counts, although circulating neutrophils remained immature; neutropenia
in one kidney-presentation patient did not respond.
therapeutic_modality: PROTEIN_REPLACEMENT
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: filgrastim
term:
id: CHEBI:749461
label: filgrastim
target_phenotypes:
- preferred_term: Neutropenia
term:
id: HP:0001875
label: Decreased total neutrophil count
evidence:
- reference: PMID:32325141
reference_title: Defective Sec61α1 underlies a novel cause of autosomal dominant severe congenital neutropenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Collectively, these findings indicated that although the patient was clinically G-CSF-responsive, the circulating neutrophils remained immature with hyposegmentation of the nucleus."
explanation: Clinical response to G-CSF, with persistent immaturity.
- reference: PMID:27392076
reference_title: Heterozygous Loss-of-Function SEC61A1 Mutations Cause Autosomal-Dominant Tubulo-Interstitial and Glomerulocystic Kidney Disease with Anemia.
supports: REFUTE
evidence_source: HUMAN_CLINICAL
snippet: "The affected individual had persistent granulocyte stimulating factor-unresponsive neutropenia and recurrent admissions for cutaneous abscesses."
explanation: G-CSF did not correct neutropenia in a kidney-presentation patient.
- name: Fludrocortisone
description: >-
Mineralocorticoid replacement corrected hypotension, hyperkalemia and
acidosis in a child with hypoaldosteronism, and her kidney function
improved; an adult in a founding family was also treated with
fludrocortisone.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: fludrocortisone
term:
id: CHEBI:50885
label: fludrocortisone
target_phenotypes:
- preferred_term: Hypotension
term:
id: HP:0002615
label: Hypotension
- preferred_term: Hyperkalemia
term:
id: HP:0002153
label: Hyperkalemia
evidence:
- reference: PMID:39135939
reference_title: Hypoaldosteronism due to a novel SEC61A1 variant successfully treated with fludrocortisone.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Treatment with a mineralocorticoid had a beneficial effect and corrected the electrolyte and acid-base disorder."
explanation: Benefit of fludrocortisone in one patient.
- name: Kidney transplantation
description: >-
There is no disease-specific treatment for the kidney presentation, and
management is supportive, with dialysis and kidney transplantation for
kidney failure as in other forms of ADTKD.
therapeutic_modality: SURGERY
treatment_term:
preferred_term: Kidney transplantation
term:
id: NCIT:C15265
label: Kidney Transplantation
evidence:
- reference: PMID:41850665
reference_title: "De novo SEC61A1 mutation in congenital anemia and early-onset kidney disease: Case report and review of the literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "There is no specific treatment for the SEC61A1-related ADTKD. Most reported patients survived to adulthood with supportive treatment."
explanation: Management is supportive.
- reference: PMID:27392076
reference_title: Heterozygous Loss-of-Function SEC61A1 Mutations Cause Autosomal-Dominant Tubulo-Interstitial and Glomerulocystic Kidney Disease with Anemia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: "Autosomal-dominant tubulo-interstitial kidney disease (ADTKD) encompasses a group of disorders characterized by renal tubular and interstitial abnormalities, leading to slow progressive loss of kidney function requiring dialysis and kidney transplantation."
explanation: Kidney replacement therapy as the endpoint for ADTKD in general.
animal_models:
- name: Zebrafish sec61al2 knockdown and CRISPR deletion
species: Zebrafish
genotype: sec61al2 morpholino knockdown or F0 CRISPR/Cas9 deletion
publication: PMID:27392076
modeled_mechanisms:
- target: Tubulointerstitial and Glomerulocystic Kidney Injury
relationship: PARTIALLY_RECAPITULATES
fidelity: LOW
model_scale: TISSUE
description: Loss of the ortholog disturbs convolution of the pronephric tubules.
limitations: >-
Embryonic pronephros only; fibrosis and gout cannot be modeled at this
stage, and the model is a knockdown rather than a heterozygous patient
allele.
evidence:
- reference: PMID:27392076
reference_title: Heterozygous Loss-of-Function SEC61A1 Mutations Cause Autosomal-Dominant Tubulo-Interstitial and Glomerulocystic Kidney Disease with Anemia.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Suppression or CRISPR-mediated deletions of sec61al2 in zebrafish embryos induced convolution defects of the pronephric tubules but not the pronephric ducts, consistent with the tubular atrophy observed in the affected individuals."
explanation: Tubular phenotype in the zebrafish model.
- reference: PMID:27392076
reference_title: Heterozygous Loss-of-Function SEC61A1 Mutations Cause Autosomal-Dominant Tubulo-Interstitial and Glomerulocystic Kidney Disease with Anemia.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Some of the pathologies observed in the affected individuals, such as fibrosis and gout, cannot be modeled reliably in early development."
explanation: Authors' own statement of the model's limits.
references:
- reference: PMID:27392076
title: Heterozygous Loss-of-Function SEC61A1 Mutations Cause Autosomal-Dominant Tubulo-Interstitial and Glomerulocystic Kidney Disease with Anemia.
- reference: PMID:28782633
title: Plasma cell deficiency in human subjects with heterozygous mutations in Sec61 translocon alpha 1 subunit (SEC61A1).
- reference: PMID:32325141
title: Defective Sec61α1 underlies a novel cause of autosomal dominant severe congenital neutropenia.
Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.
Create: SEC61A1_Deficiency · 2026-10-22T21:01:40Z · View source
New entry for SEC61A1 deficiency (MONDO:0100337). Lump/split decision: one Disease with three has_subtypes (ADTKD-SEC61A1 bound to MONDO:0014891, CVID15 bound to MONDO:0958013, and SEC61A1-related severe congenital neutropenia with no MONDO term), following ClinGen's Antibody Deficiencies GCEP lumping of these presentations into one autosomal dominant entity (Moderate). The polycystic liver disease family (p.Arg236Cys) is a phenotype, not a subtype. Pathograph: heterozygous variants lead to defective cotranslational translocation and increased ER calcium leak, then ER stress and terminal UPR, which branch to impaired plasma cell differentiation and granulocytic maturation arrest; translocation also feeds impaired renin biosynthesis and the tubulointerstitial and glomerulocystic kidney injury. All 29 phenotypes are causally connected. Deep research: one OpenScientist report (research/SEC61A1_Deficiency-deep-research-openscientist.md), 14/14 references resolved, one off-topic reference (PMID:21499241, a bacterial SecYEG structure) not used; just preflight-dr PASS. Literature found independently via PubMed and the ClinGen CGGV record. HP:0002850 is bound with the cached label 'Decreased circulating total IgM' because the committed HP cache predates HPO's relabel to 'Decreased circulating IgM concentration'. Validation: just validate passed (102/102 snippets), validate-terms, check-entity-refs, check-causal-targets, check-gene-validity, check-snippet-grading and the other offline gates passed.
The founding disease association was established by Bolar et al. 2016 (PMID: 27392076), who identified heterozygous missense variants c.553A>G (p.Thr185Ala) and c.200T>G (p.Val67Gly) in two families with autosomal-dominant tubulointerstitial kidney disease (ADTKD) plus congenital anemia. Both variants affect "functionally important and conserved residues in SEC61." Critically, the study provided direct tissue-level mechanistic evidence: "Both transiently expressed SEC6A1A variants are delocalized to the Golgi, a finding confirmed in a renal biopsy from an affected individual." Functional confirmation came from a zebrafish model: suppression or CRISPR deletion of the ortholog sec61al2 induced pronephric tubule convolution defects that were rescued by wild-type human mRNA but not by the patient/mutant mRNA — establishing loss of function as the disease mechanism. This finding anchors the causal gene and the two founding ADTKD-SEC61A1 variants.
Schubert et al. 2018 (PMID: 28782633) extended the phenotype to humoral immunodeficiency. They "identified novel heterozygous missense (c.254T>A, p.V85D) and nonsense (c.1325G>T, p.E381) mutations in SEC61A1, segregating with the disease phenotype" across 11 patients from two families presenting with hypogammaglobulinemia and recurrent respiratory infections. B cells from patients failed to differentiate into plasma cells in vitro. Mechanistically, "SEC61A1-V85D was deficient in cotranslational protein translocation, and it disturbed the cellular calcium homeostasis in HeLa cells,"* and triggered the terminal unfolded-protein response. This connects the translocation defect and calcium dysregulation directly to the failure of the most secretory immune lineage (the plasma cell), and defines the immune arm later catalogued as CVID15.
Sicking et al. 2022 (PMID: 35064074) dissected the biochemical consequence of the ADTKD mutations. The V67G and T185A Sec61α mutants impair translocation/transport of preprorenin into the ER lumen, offering a plausible explanation for the renal/juxtaglomerular phenotype. Importantly, "Phenylbutyrate rescues the transport defect of the Sec61α mutations V67G and T185A for renin," establishing a pharmacological rescue of the molecular lesion and a concrete therapeutic hypothesis. The study also reinforced the channel's dual role, moving both protein substrates and calcium ions across the ER membrane.
Across the ~15 reported patients (reviewed by Zhong et al. 2026, PMID: 41850665), the renal presentation comprises early-onset CKD with hyperuricemia, bland urinary sediment, absence of significant proteinuria, and renal cysts. Extrarenal features are prominent: "The extrarenal features included growth retardation, hematological abnormalities, cognitive impairment, and immunological abnormalities." Hematological abnormalities span normocytic normochromic anemia and neutropenia/agranulocytosis. Newer case reports continue to broaden the spectrum: a pediatric case from Oman (p.Thr185Ser, c.554C>G) presented with hypomagnesemia, epilepsy, and microcephaly — epilepsy being a previously unreported ADTKD-SEC61A1 feature (PMID: 42730770) — and Karpman et al. 2024 documented hypoaldosteronism with salt-wasting that was "successfully treated with fludrocortisone" (PMID: 39135939).
Population-genetic constraint data from gnomAD v2.1.1 strongly support a dosage-sensitive mechanism. For SEC61A1 (ENSG00000058262; HGNC:18276; chr3:128,051,641–128,071,683 GRCh38; 3q21.3):
| Metric | Value | Interpretation |
|---|---|---|
| pLI | 0.9998 | Near-certain intolerance to loss of function |
| LOEUF (oe_lof upper) | 0.418 | Constrained |
| observed/expected LoF | 0.272 (obs 15 / exp 55.2) | ~73% depletion of LoF alleles |
| LoF Z | 4.59 | Strong LoF constraint |
| missense Z | 5.53 (oe_mis 0.471) | Strong missense constraint |
This profile is characteristic of a haploinsufficient, dominant-acting gene, consistent with the autosomal-dominant inheritance observed clinically.
The official disease concept MONDO:0100337 ("SEC61A1 deficiency") is defined as any Mendelian disease caused by SEC61A1 mutation, "characterized by variable presentation of phenotypes... including autosomal dominant tubulointerstitial kidney disease, primary antibody deficiency, and severe congenital neutropenia." Van Nieuwenhove et al. 2020 (PMID: 32325141) established the myeloid arm: "We identified a novel de novo missense mutation in SEC61A1 (c.A275G;p.Q92R) in a patient with SCN" (designated SCN11). The shared mechanism was confirmed — "The mutation results in diminished protein expression, disturbed protein translocation, and an increase in calcium leakage from the endoplasmic reticulum" — along with UPR dysregulation. Wang et al. 2026 (PMID: 42056350) reported a second SCN variant, c.1135T>C (p.Trp379Arg), noting "This is the second reported SEC61A1 variant associated with SCN11, expanding the genetic and phenotypic spectrum of SCN." ClinVar (Oct 2025) lists 393 SEC61A1 records, including 25 pathogenic and 6 likely pathogenic, with the large majority (~360) classified as variants of uncertain significance.
Gene–disease association resolution (Monarch/OLS/MONDO) catalogues three distinct entities caused by SEC61A1:
| Arm | Disease | OMIM | MONDO | Other IDs |
|---|---|---|---|---|
| Kidney | Hyperuricemic nephropathy, familial juvenile, 4 (HNFJ4) / ADTKD-SEC61A1 | 617056 | MONDO:0014891 | DOID:0061120 |
| Immune | Immunodeficiency, common variable, 15 (CVID15) | 620670 | MONDO:0958013 | Orphanet:697417 |
| Myeloid | Neutropenia, severe congenital, 11, autosomal dominant (SCN11) | 620674 | MONDO:0958017 | — |
All three are umbrella'd by MONDO:0100337 ("SEC61A1 deficiency"). GO molecular-function annotation confirms the dual activity: GO:0008320 (transmembrane protein transporter activity) and GO:0005262 (calcium channel activity), with cellular component GO:0005784 (Sec61 translocon complex). Note: an earlier label "CVID13" was corrected to CVID15 during the investigation.
SEC61A1 is deeply conserved (HomoloGene:55537), with verified orthologs: human SEC61A1 (NCBIGene:29927), mouse Sec61a1 (NCBIGene:53421), rat Sec61a1 (NCBIGene:80843), zebrafish sec61al1 (NCBIGene:192298) and sec61al2 (NCBIGene:266796), and yeast SEC61 (NCBIGene:851095), plus orthologs across Xenopus, chicken, dog, cow, and primates. Complete loss of translocon function is expected to be lethal, consistent with the dominant, heterozygous nature of human disease. Disease-relevant modeling has succeeded in zebrafish for the renal phenotype ("Suppression or CRISPR-mediated deletions of sec61al2 in zebrafish embryos induced convolution defects of the pronephric tubules but not the pronephric ducts"; PMID: 27392076) and via CD34+ granulocytic differentiation assays for the SCN arm (PMID: 32325141).
SEC61A1 deficiency is a rare autosomal-dominant Mendelian translocopathy caused by heterozygous variants in SEC61A1, the Sec61 translocon α-subunit gene. Key identifiers: MONDO:0100337 (umbrella); constituent entities HNFJ4/ADTKD-SEC61A1 (OMIM 617056, MONDO:0014891, DOID:0061120), CVID15 (OMIM 620670, MONDO:0958013, Orphanet:697417), SCN11 (OMIM 620674, MONDO:0958017); gene OMIM 609213; HGNC:18276. Synonyms/alternative names: ADTKD-SEC61A1; familial juvenile hyperuricemic nephropathy type 4; Sec61-alphopathy/translocopathy. Information is derived from aggregated disease-level resources (OMIM, MONDO, Orphanet, ClinVar, gnomAD) combined with individual-patient reports/case series (the primary literature cited throughout).
Causal factor: monogenic — heterozygous pathogenic variants in SEC61A1. Genetic risk: the causal variant itself is sufficient; no susceptibility loci or modifier genes are established. The extreme gnomAD constraint (pLI 0.9998, missense Z 5.53) indicates strong purifying selection. Environmental risk/protective factors and gene–environment interactions: none established; this is a Mendelian disorder with no documented environmental contribution. A single founding de novo variant (p.Q92R, SCN11) indicates that disease can arise sporadically.
Representative phenotypes with suggested HPO terms:
| Phenotype | Type | HPO suggestion | Characteristics |
|---|---|---|---|
| Chronic kidney disease / tubulointerstitial nephropathy | Clinical sign | HP:0012622 / HP:0000112 | Early-onset, progressive to ESRD in adulthood |
| Hyperuricemia / gout | Lab abnormality | HP:0002149 | Juvenile onset |
| Bland urinary sediment / absent proteinuria | Lab abnormality (negative finding) | — | Characteristic for ADTKD |
| Renal cysts / glomerulocystic disease | Physical manifestation | HP:0000107 | Variable |
| Congenital/normocytic anemia | Lab abnormality | HP:0001903 | Neonatal/congenital |
| Neutropenia / agranulocytosis | Lab abnormality | HP:0001875 | SCN11 arm; severe |
| Hypogammaglobulinemia / recurrent infections | Lab abnormality / symptom | HP:0004313 / HP:0002719 | CVID15 arm; plasma-cell block |
| Growth retardation | Physical | HP:0001510 | Variable |
| Cognitive impairment | Behavioral/neuro | HP:0100543 | Reported subset |
| Hypomagnesemia | Lab abnormality | HP:0002917 | Newer feature |
| Hypoaldosteronism / salt-wasting | Lab abnormality | HP:0000846 | Fludrocortisone-responsive |
| Epilepsy, microcephaly | Clinical sign | HP:0001250 / HP:0000252 | Rare, pediatric (p.Thr185Ser) |
Onset ranges from congenital/neonatal (anemia, neutropenia) to childhood/adolescence (CKD). Severity is variable; the renal course is progressive. Quality-of-life impact is substantial owing to lifelong CKD/dialysis dependence, infection susceptibility, and transfusion/growth issues; no disease-specific QoL instruments have been applied.
Causal gene: SEC61A1 (OMIM 609213; HGNC:18276; 3q21.3). Pathogenic variants (all germline, mostly heterozygous dominant): missense p.Thr185Ala (c.553A>G), p.Val67Gly (c.200T>G), p.Thr185Ser (c.554C>G) — ADTKD; p.Val85Asp (c.254T>A) and nonsense p.Glu381 (c.1325G>T) — CVID; p.Gln92Arg (c.A275G, de novo) and p.Trp379Arg (c.1135T>C) — SCN11. Variant classes: predominantly missense, with a disease-relevant nonsense allele. ClinVar (Oct 2025): 393 records (25 pathogenic, 6 likely pathogenic, ~360 VUS). Allele frequency: pathogenic alleles are absent/ultra-rare in gnomAD; the gene is strongly LoF- and missense-constrained. Functional consequence: loss of function with likely dominant-negative contribution (mutant subunit incorporated into the heterotrimeric channel). Modifier genes/epigenetics/chromosomal abnormalities:* none established.
Not applicable — no environmental, lifestyle, or infectious contributors are known. Recurrent infections are a consequence of the immunodeficiency/neutropenia arms, not a cause.
Causal chain (initiating lesion → clinical manifestation): 1. A heterozygous SEC61A1 variant (missense or nonsense) leads to a defective or reduced Sec61α subunit incorporated into the ER translocon. 2. This results in impaired co-translational translocation of secretory/membrane precursor proteins into the ER (demonstrated for preprorenin) and, in parallel (branch), increased passive Ca²⁺ leak from the ER lumen through the defective channel (demonstrated in HeLa cells and CD34+ cells). 3. Reduced protein import leads to mislocalization of Sec61α to the Golgi (shown in patient renal biopsy) and accumulation of untranslocated/misfolded client proteins. 4. Protein-folding stress plus disturbed ER Ca²⁺ homeostasis results in activation of ER stress and the terminal (apoptotic) unfolded-protein response. 5. In the most secretory/proliferative lineages this results in cell dysfunction/death — branching into: (a) renal tubular + juxtaglomerular cells → tubulointerstitial fibrosis, impaired renin/renal function → CKD, hyperuricemia, anemia, hypoaldosteronism; (b) plasma cells → differentiation block → hypogammaglobulinemia (CVID15); (c) granulocyte precursors → maturation arrest → severe congenital neutropenia (SCN11).
Upstream: the translocation defect and Ca²⁺ dysregulation. Downstream: UPR-driven apoptosis and lineage-specific functional failure. Molecular pathways/processes: protein targeting to ER (GO:0045047), SRP-dependent co-translational translocation (GO:0006614), response to ER stress/UPR (GO:0030968), ER calcium ion homeostasis (GO:0032469), apoptotic process (GO:0006915). Cell types (CL): kidney tubule epithelial cell, juxtaglomerular cell, plasma cell (CL:0000786), neutrophil/granulocyte precursor (CL:0000775). Subcellular compartment: ER membrane / Sec61 translocon complex (GO:0005784), ER (GO:0005783). Protein dysfunction: loss of channel conductance for protein substrates + aberrant Ca²⁺ leak; mislocalization to Golgi; likely dominant-negative assembly into the heterotrimeric Sec61 complex (structural context from cryo-EM studies PMID: 33398175, PMID: 21499241).
Primary organs: kidney (UBERON:0002113) — tubulointerstitium, juxtaglomerular apparatus; bone marrow (UBERON:0002371) — myeloid compartment; secondary lymphoid organs / plasma-cell niches. Secondary involvement: systemic (anemia, growth retardation), adrenal/renin-angiotensin-aldosterone axis (hypoaldosteronism), CNS (cognitive impairment, epilepsy, microcephaly). Body systems: urinary, hematopoietic/immune, endocrine, nervous. Tissues/cells: renal epithelial cells, plasma cells (CL:0000786), neutrophils (CL:0000775). Subcellular: ER membrane (GO:0005789), Sec61 translocon (GO:0005784). Localization: bilateral kidney involvement; systemic hematologic/immune involvement.
Onset: congenital/neonatal for anemia and neutropenia; childhood-to-adolescent for CKD/hyperuricemia; insidious and chronic. Progression: renal disease is slowly progressive, advancing to end-stage kidney disease in adulthood (ESRD present at diagnosis in a substantial fraction of ADTKD cohorts). Course: chronic, lifelong, progressive; no spontaneous remission. Critical windows: early diagnosis enables renal-protective management, infection prophylaxis, and G-CSF initiation for neutropenia.
Inheritance: autosomal dominant; de novo occurrence documented (SCN11 p.Q92R). Penetrance/expressivity: appears high-penetrance but with highly variable expressivity (which organ arm predominates differs among families/variants). Epidemiology: ultra-rare; SEC61A1 accounts for a very small minority of ADTKD cases (ADTKD overall ~5% of monogenic CKD; SEC61A1 is among the rarest subtypes, with single-family yields in large cohorts such as the Japanese cohort of PMID: 39976632). No formal prevalence/incidence estimates exist. Founder effects/consanguinity: none established; gnomAD shows pathogenic alleles are essentially absent. Carrier frequency: not applicable (dominant, de novo or inherited heterozygous). Sex ratio/geographic distribution: no established skew; cases reported across multiple populations (Europe, Japan, Middle East).
Genetic testing is the diagnostic cornerstone. ADTKD is defined by identification of a pathogenic variant in one of UMOD, MUC1, REN, HNF1B, or SEC61A1. Recommended approaches: targeted single-gene/panel testing (ADTKD gene panels), whole-exome or whole-genome sequencing for unexplained CKD; long-read sequencing is especially useful to resolve MUC1 but exome/genome suffices for SEC61A1. Supportive clinical/lab findings: elevated creatinine with bland urinary sediment and minimal proteinuria, hyperuricemia/gout, normocytic anemia, neutropenia, hypogammaglobulinemia, hypomagnesemia, low aldosterone. Imaging: normal-to-small kidneys ± cysts. Biopsy: nonspecific tubulointerstitial fibrosis/tubular atrophy; immunostaining can show Sec61α Golgi mislocalization (research setting). Differential diagnosis: other ADTKD subtypes (UMOD, MUC1, REN, HNF1B), and newly described ADTKD-JAG1 (PMID: 41061854); for the immune/myeloid arms, other causes of CVID and congenital neutropenia (e.g., ELANE). Screening: cascade genetic testing of at-risk relatives.
The renal arm carries a guarded prognosis, progressing to ESRD requiring dialysis or transplantation in adulthood; transplantation is effective as the defect is intrinsic to kidney tissue but systemic. The immune arm risks recurrent/chronic infection and bronchiectasis if untreated; the myeloid arm risks severe bacterial infection and, as with other SCN, potential long-term leukemia surveillance considerations. Overall morbidity is high (lifelong CKD, infection susceptibility, growth impairment). No formal survival statistics exist given rarity. Prognostic factors: specific variant/predominant organ arm, age at CKD onset, and severity of cytopenias.
No curative, mechanism-targeted therapy is approved; management is organ-specific and supportive: - Renal: CKD management, uric-acid lowering (e.g., allopurinol), renal replacement therapy — dialysis and kidney transplantation (NCIT:C157763 kidney transplantation). - Immune (CVID15): immunoglobulin replacement therapy (IVIG/SCIG; NCIT:C29071 immunoglobulin therapy), infection prophylaxis. - Myeloid (SCN11): granulocyte colony-stimulating factor / G-CSF (filgrastim; NCIT:C1583). - Endocrine: fludrocortisone for hypoaldosteronism/salt-wasting (demonstrated effective, PMID: 39135939). - Hematologic: transfusion support for anemia; magnesium supplementation for hypomagnesemia. - Experimental / mechanism-based: the chemical chaperone 4-phenylbutyrate rescues the mutant translocon's renin-transport defect in vitro (PMID: 35064074) and is the leading candidate for molecular correction; not yet trialed clinically for this disease. Pharmacogenomics, gene/cell/RNA therapies: none established.
No primary prevention (Mendelian). Secondary prevention: early genetic diagnosis enables renal-protective care, infection prophylaxis/immunoglobulin, and timely G-CSF. Genetic counseling is central: 50% transmission risk for an affected heterozygous parent; de novo cases possible. Prenatal/preimplantation genetic testing is feasible when a familial variant is known. Cascade testing identifies at-risk relatives for surveillance.
SEC61A1 is deeply conserved across eukaryotes (HomoloGene:55537), with orthologs in mouse, rat, zebrafish, Xenopus, chicken, dog, cow, primates, and yeast (see Finding 8 for NCBI Gene IDs; NCBI Taxon IDs: human 9606, mouse 10090, rat 10116, zebrafish 7955, S. cerevisiae 559292). No naturally occurring SEC61A1 disease has been catalogued in companion animals or wildlife (no OMIA entry identified); complete translocon loss is presumed embryonic-lethal. No zoonotic relevance (non-infectious disease).
Heterozygous SEC61A1 variant (missense / nonsense)
|
defective Sec61a subunit in ER translocon
|
+----------------------+----------------------+
| |
impaired co-translational increased passive ER
protein translocation Ca2+ leak through channel
(e.g. preprorenin; (shown in HeLa, CD34+ cells)
Golgi mislocalization) |
| |
+----------------------+----------------------+
|
ER stress --> terminal (apoptotic) UPR
|
+---------------+-----------+-----------+---------------+
renal tubular/ plasma cells granulocyte CNS / endocrine
JG cells (block) precursors (variable)
| | | |
CKD, hyperuric., hypogamma- severe cognitive impair.,
anemia, cysts, globulinemia congenital epilepsy, hypo-
hypoaldosteron. (CVID15) neutropenia magnesemia
(HNFJ4/ADTKD) (SCN11)
The central insight is lineage selectivity through shared biochemistry: a single ubiquitously expressed translocon defect manifests preferentially in cells with the heaviest secretory/folding load and highest proliferative demand, where the combined protein-translocation deficit and ER-calcium dysregulation most readily tip cells into apoptotic UPR. The same molecular lesion thus produces three nosologically distinct dominant diseases that share one mechanism — a paradigm of a monogenic "translocopathy."
| PMID | Title (abbrev.) | Role | Evidence type |
|---|---|---|---|
| 27392076 | Heterozygous LoF SEC61A1 mutations cause ADTKD with anemia | Founding ADTKD variants; Golgi mislocalization in biopsy; zebrafish rescue | Human clinical + model organism |
| 28782633 | Plasma cell deficiency with heterozygous SEC61A1 mutations | CVID arm; V85D translocation + Ca²⁺ defect; terminal UPR | Human clinical + in vitro |
| 35064074 | Phenylbutyrate rescues Sec61α V67G/T185A renin transport | Druggable mechanism; preprorenin defect | In vitro / biochemical |
| 41850665 | De novo SEC61A1 in congenital anemia + early kidney disease | Multisystem phenotype review | Human clinical review |
| 39135939 | Hypoaldosteronism from novel SEC61A1 variant | Hypoaldosteronism; fludrocortisone treatment | Human clinical |
| 32325141 | Defective Sec61α1 underlies autosomal dominant SCN | SCN11 arm; Q92R; translocation + Ca²⁺ leak + UPR | Human clinical + in vitro |
| 42056350 | Novel de novo SEC61A1 variant in SCN | Second SCN11 variant (W379R) | Human clinical |
| 42730770 | Rare ADTKD in children (Oman) | p.Thr185Ser; epilepsy, microcephaly, hypomagnesemia | Human clinical |
| 33398175 | Stepwise gating of Sec61 by Sec63/Sec62 | Structural basis of channel gating | Structural/cryo-EM |
| 21499241 | Cryo-EM of ribosome–SecYE in membrane | Translocon architecture | Structural/cryo-EM |
| 34519781 | Clinical and genetic spectra of ADTKD | Places SEC61A1 among ADTKD genes | Review |
| 36531871 | ADTKD: emerging cause of genetic CKD | Gene-based ADTKD classification | Review |
| 39976632 | ADTKD phenotype/genotype in a Japanese cohort | Rarity of SEC61A1 (1 of 40 families) | Human clinical cohort |
| 41061854 | ADTKD-JAG1 | Differential diagnosis; haploinsufficiency parallel | Human clinical |
All three mechanistic studies ([27392076], [28782633], [32325141]) converge on the same molecular defect (impaired translocation + ER Ca²⁺ dysregulation + UPR), lending strong internal consistency. The constraint data (gnomAD) and conservation data (HomoloGene) are independent, non-literature lines of support for the dosage-sensitive dominant model.
Evidence source legend: human clinical, model organism (zebrafish), in vitro/biochemical, structural (cryo-EM), computational (gnomAD constraint, HomoloGene conservation).
Checked with linkml-reference-validator 0.3.0.
| Outcome | Count |
|---|---|
| References checked | 14 |
| Resolved | 14 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| References weighed for topical relevance | 14 |
| On topic | 11 |
| Off topic | 1 |
These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:
PMID:21499241 (4 mentions) - Cryo-EM structure of the ribosome-SecYE complex in the membrane environment.Weighed against this report's own most characteristic terms: sec61a1, disease, variant, renal, kidney, sec61, defect, phenotype, gene, cell, scn11, heterozygous, neutropenia, anemia, ckd, translocon, arm, congenital, dominant, missense.
All extracted references resolved successfully. Resolving is not the same as being relevant, though - see the references listed above as possibly off topic.
Checked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
|---|---|
| Terms checked | 45 |
| Resolved | 36 |
| Unresolved (possible confabulation) | 0 |
| Obsolete | 0 |
| Unverifiable | 9 |
| Terms whose name was checked | 9 |
| Terms named correctly | 0 |
| Terms named as a different term | 9 |
These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:
MONDO:0100337 (5 mentions) - the report calls it "SEC61A1 deficiency", "umbrella"; MONDO calls it SEC61A1 deficiencyHP:0002149 (1 mention) - the report calls it "Lab abnormality"; HP calls it HyperuricemiaHP:0000107 (1 mention) - the report calls it "Physical manifestation"; HP calls it Renal cystHP:0001903 (1 mention) - the report calls it "Lab abnormality"; HP calls it AnemiaHP:0001875 (1 mention) - the report calls it "Lab abnormality"; HP calls it Decreased total neutrophil countHP:0001510 (1 mention) - the report calls it "Physical"; HP calls it Growth delayHP:0100543 (1 mention) - the report calls it "Behavioral/neuro"; HP calls it Cognitive impairmentHP:0002917 (1 mention) - the report calls it "Lab abnormality"; HP calls it HypomagnesemiaHP:0000846 (1 mention) - the report calls it "Lab abnormality"; HP calls it Adrenal insufficiencyThe report gives these identifiers more than one name of its own:
MONDO:0100337 - called "SEC61A1 deficiency", "umbrella"Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: Orphanet, HomoloGene, NCBIGene.