<i>De novo</i><scp>SEC61A1</scp> mutation in autosomal dominant tubulo‐interstitial kidney disease: Phenotype expansion and review of literature

Espino-Hernández, M.; Milla, Carmen Palma; Vara-Martín, Julia; González‐Granado, Luis Ignacio

doi:10.1111/jpc.15148

Cited by 7 publications

(8 citation statements)

References 9 publications

(19 reference statements)

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“…The heterozygous SEC61A1 alleles identified in humans include four missense mutations causing the amino acid substitutions V67G (plug domain), V85D (pore ring residue, TMH 2), Q92R (TMH 2), and T185A (TMH 5) as well as one nonsense mutation introducing a premature stop at E381* (TMH 8). The rare-diseases arising from those mutations are (i) common variable immunodeficiency for V85D and E381* ( Schubert et al, 2017 ), (ii) autosomal dominant severe congenital neutropenia for V67G ( Bolar et al, 2016 ) and Q92R ( Van Nieuwenhove et al, 2020 ), and (iii) autosomal dominant tubulointerstitial kidney disease (ADTKD) for V67G and T185A ( Bolar et al, 2016 ; Espino-Hernández et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Phenylbutyrate rescues the transport defect of the Sec61α mutations V67G and T185A for renin

et al. 2022

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The human Sec61 complex is a widely distributed and abundant molecular machine. It resides in the membrane of the endoplasmic reticulum to channel two types of cargo: protein substrates and calcium ions. The SEC61A1 gene encodes for the pore-forming Sec61α subunit of the Sec61 complex. Despite their ubiquitous expression, the idiopathic SEC61A1 missense mutations p.V67G and p.T185A trigger a localized disease pattern diagnosed as autosomal dominant tubulointerstitial kidney disease (ADTKD–SEC61A1). 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. Treatment with the molecular chaperone phenylbutyrate reversed the defective protein transport of renin and the imbalanced calcium homeostasis. Signal peptide substitution experiments pointed at targeting sequences as the cause for the substrate-specific impairment of protein transport in the presence of the V67G or T185A mutations. 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.

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Section: Introductionmentioning

confidence: 99%

Phenylbutyrate rescues the transport defect of the Sec61α mutations V67G and T185A for renin

et al. 2022

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“…Mammalian cells, which are highly active in protein secretion, termed professional secretory cells, may be particularly sensitive towards problems in Sec61 channel closure and, therefore, constantly on the verge to apoptosis. This has recently been seen in human patients associated with dominant negative effects in the course of i) autosomal dominant tubulointerstitial kidney disease (ADTKD) and glomerulocystic kidney disease in kidney cells with the Sec61α 1V67G- or Sec61α 1T185A-exchanges [ 256 , 257 ], ii) hypogammaglobulinemia or primary antibody deficiency (PAD) in plasma cells with the Sec61α 1V85D exchange [ 258 ], plus iii) autosomal dominant severe congenital neutropenia (ADSCN) in neutrophils with the Sec61α 1V67G- or Sec61α 1Q92R-exchanges [ 256 , 259 ] and associated with Diabetes mellitus for the β-cells of the mouse with the homozygous Sec61α1Y344H exchange [ 260 ]. The fact that ERj6 (DNAJC3) is involved in Sec61 channel closure and that its absence in human patients, too, causes Diabetes mellitus is in perfect line with this interpretation [ 261 ].…”

Section: Sec61-channelopathiesmentioning

confidence: 99%

“…In three independent families with seven, two and one patient(s), respectively, suffering from autosomal dominant tubulointerstitial kidney disease (ADTKD) and glomerulocystic kidney disease with congenital anemia, respectively, heterozygous SEC61A1 mutations were identified. These are two missense mutations causing the amino acid substitutions V67G (in the plug helix) and T185A (near the pore ring in TMH 5), respectively [ 256 , 257 ]. The T185A mutation caused ADTKD with a more severe and complex tubular phenotype.…”

Section: Sec61-channelopathiesmentioning

confidence: 99%

Complexity and Specificity of Sec61-Channelopathies: Human Diseases Affecting Gating of the Sec61 Complex

Sicking

Lang

Bochen

et al. 2021

Cells

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The rough endoplasmic reticulum (ER) of nucleated human cells has crucial functions in protein biogenesis, calcium (Ca2+) homeostasis, and signal transduction. Among the roughly one hundred components, which are involved in protein import and protein folding or assembly, two components stand out: The Sec61 complex and BiP. The Sec61 complex in the ER membrane represents the major entry point for precursor polypeptides into the membrane or lumen of the ER and provides a conduit for Ca2+ ions from the ER lumen to the cytosol. The second component, the Hsp70-type molecular chaperone immunoglobulin heavy chain binding protein, short BiP, plays central roles in protein folding and assembly (hence its name), protein import, cellular Ca2+ homeostasis, and various intracellular signal transduction pathways. For the purpose of this review, we focus on these two components, their relevant allosteric effectors and on the question of how their respective functional cycles are linked in order to reconcile the apparently contradictory features of the ER membrane, selective permeability for precursor polypeptides, and impermeability for Ca2+. The key issues are that the Sec61 complex exists in two conformations: An open and a closed state that are in a dynamic equilibrium with each other, and that BiP contributes to its gating in both directions in cooperation with different co-chaperones. While the open Sec61 complex forms an aqueous polypeptide-conducting- and transiently Ca2+-permeable channel, the closed complex is impermeable even to Ca2+. Therefore, we discuss the human hereditary and tumor diseases that are linked to Sec61 channel gating, termed Sec61-channelopathies, as disturbances of selective polypeptide-impermeability and/or aberrant Ca2+-permeability.

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“…The total loss or reduced abundance of tissue-specific proteins could also cause or contribute to a localized disease phenotype. As is the case of the widely present Sec61α protein, the majority of analyzed Sec61α point mutations result in distinct pathological phenotypes in different organs or tissues and eventually reflect the substrate-specific requirements found in the affected body part [ 276 , 283 , 404 , 438 , 439 ].…”

Section: Disease-causing Mutations Of Targeting and Translocation Componentsmentioning

confidence: 99%

The Molecular Biodiversity of Protein Targeting and Protein Transport Related to the Endoplasmic Reticulum

Tirincsi

Sicking

Hadzibeganovic

et al. 2021

IJMS

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Looking at the variety of the thousands of different polypeptides that have been focused on in the research on the endoplasmic reticulum from the last five decades taught us one humble lesson: no one size fits all. Cells use an impressive array of components to enable the safe transport of protein cargo from the cytosolic ribosomes to the endoplasmic reticulum. Safety during the transit is warranted by the interplay of cytosolic chaperones, membrane receptors, and protein translocases that together form functional networks and serve as protein targeting and translocation routes. While two targeting routes to the endoplasmic reticulum, SRP (signal recognition particle) and GET (guided entry of tail-anchored proteins), prefer targeting determinants at the N- and C-terminus of the cargo polypeptide, respectively, the recently discovered SND (SRP-independent) route seems to preferentially cater for cargos with non-generic targeting signals that are less hydrophobic or more distant from the termini. With an emphasis on targeting routes and protein translocases, we will discuss those functional networks that drive efficient protein topogenesis and shed light on their redundant and dynamic nature in health and disease.

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De novoSEC61A1 mutation in autosomal dominant tubulo‐interstitial kidney disease: Phenotype expansion and review of literature

Cited by 7 publications

References 9 publications

Phenylbutyrate rescues the transport defect of the Sec61α mutations V67G and T185A for renin

Phenylbutyrate rescues the transport defect of the Sec61α mutations V67G and T185A for renin

Complexity and Specificity of Sec61-Channelopathies: Human Diseases Affecting Gating of the Sec61 Complex

The Molecular Biodiversity of Protein Targeting and Protein Transport Related to the Endoplasmic Reticulum

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