Dominant-negative SERPING1 variants cause intracellular retention of C1 inhibitor in hereditary angioedema

Didde Haslund, Laura Barrett Ryø, Sara Seidelin Majidi, Iben Kløvgaard Rose, Kristian Alsbjerg Skipper, Tue Fryland, Anja Bille Bohn, Claus Koch, Martin K Thomsen, Yaseelan Palarasah, Thomas J Corydon, Anette Bygum, Lene N Nejsum, Jacob Giehm Mikkelsen

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Resumé

Hereditary angioedema (HAE) is an autosomal dominant disease characterized by recurrent edema attacks associated with morbidity and mortality. HAE results from variations in the SERPING1 gene that encodes the C1 inhibitor (C1INH), a serine protease inhibitor (serpin). Reduced plasma levels of C1INH lead to enhanced activation of the contact system, triggering high levels of bradykinin and increased vascular permeability, but the cellular mechanisms leading to low C1INH levels (20%-30% of normal) in heterozygous HAE type I patients remain obscure. Here, we showed that C1INH encoded by a subset of HAE-causing SERPING1 alleles affected secretion of normal C1INH protein in a dominant-negative fashion by triggering formation of protein-protein interactions between normal and mutant C1INH, leading to the creation of larger intracellular C1INH aggregates that were trapped in the endoplasmic reticulum (ER). Notably, intracellular aggregation of C1INH and ER abnormality were observed in fibroblasts from a heterozygous carrier of a dominant-negative SERPING1 gene variant, but the condition was ameliorated by viral delivery of the SERPING1 gene. Collectively, our data link abnormal accumulation of serpins, a hallmark of serpinopathies, with dominant-negative disease mechanisms affecting C1INH plasma levels in HAE type I patients, and may pave the way for new treatments of HAE.

OriginalsprogEngelsk
ArtikelnummerCI98869
TidsskriftJournal of Clinical Investigation
Vol/bind129
Udgave nummer1
Sider (fra-til)388-405
ISSN0021-9738
DOI
StatusUdgivet - jan. 2019

Fingeraftryk

Hereditary Angioedema Types I and II
Complement C1 Inhibitor Protein
Serpins
Serine Proteinase Inhibitors
Proteins
Fibroblasts
Alleles

Citer dette

Haslund, D., Ryø, L. B., Seidelin Majidi, S., Rose, I. K., Skipper, K. A., Fryland, T., ... Mikkelsen, J. G. (2019). Dominant-negative SERPING1 variants cause intracellular retention of C1 inhibitor in hereditary angioedema. Journal of Clinical Investigation, 129(1), 388-405. [CI98869]. https://doi.org/10.1172/JCI98869
Haslund, Didde ; Ryø, Laura Barrett ; Seidelin Majidi, Sara ; Rose, Iben Kløvgaard ; Skipper, Kristian Alsbjerg ; Fryland, Tue ; Bohn, Anja Bille ; Koch, Claus ; Thomsen, Martin K ; Palarasah, Yaseelan ; Corydon, Thomas J ; Bygum, Anette ; Nejsum, Lene N ; Mikkelsen, Jacob Giehm. / Dominant-negative SERPING1 variants cause intracellular retention of C1 inhibitor in hereditary angioedema. I: Journal of Clinical Investigation. 2019 ; Bind 129, Nr. 1. s. 388-405.
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title = "Dominant-negative SERPING1 variants cause intracellular retention of C1 inhibitor in hereditary angioedema",
abstract = "Hereditary angioedema (HAE) is an autosomal dominant disease characterized by recurrent edema attacks associated with morbidity and mortality. HAE results from variations in the SERPING1 gene that encodes the C1 inhibitor (C1INH), a serine protease inhibitor (serpin). Reduced plasma levels of C1INH lead to enhanced activation of the contact system, triggering high levels of bradykinin and increased vascular permeability, but the cellular mechanisms leading to low C1INH levels (20{\%}-30{\%} of normal) in heterozygous HAE type I patients remain obscure. Here, we showed that C1INH encoded by a subset of HAE-causing SERPING1 alleles affected secretion of normal C1INH protein in a dominant-negative fashion by triggering formation of protein-protein interactions between normal and mutant C1INH, leading to the creation of larger intracellular C1INH aggregates that were trapped in the endoplasmic reticulum (ER). Notably, intracellular aggregation of C1INH and ER abnormality were observed in fibroblasts from a heterozygous carrier of a dominant-negative SERPING1 gene variant, but the condition was ameliorated by viral delivery of the SERPING1 gene. Collectively, our data link abnormal accumulation of serpins, a hallmark of serpinopathies, with dominant-negative disease mechanisms affecting C1INH plasma levels in HAE type I patients, and may pave the way for new treatments of HAE.",
author = "Didde Haslund and Ry{\o}, {Laura Barrett} and {Seidelin Majidi}, Sara and Rose, {Iben Kl{\o}vgaard} and Skipper, {Kristian Alsbjerg} and Tue Fryland and Bohn, {Anja Bille} and Claus Koch and Thomsen, {Martin K} and Yaseelan Palarasah and Corydon, {Thomas J} and Anette Bygum and Nejsum, {Lene N} and Mikkelsen, {Jacob Giehm}",
year = "2019",
month = "1",
doi = "10.1172/JCI98869",
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Haslund, D, Ryø, LB, Seidelin Majidi, S, Rose, IK, Skipper, KA, Fryland, T, Bohn, AB, Koch, C, Thomsen, MK, Palarasah, Y, Corydon, TJ, Bygum, A, Nejsum, LN & Mikkelsen, JG 2019, 'Dominant-negative SERPING1 variants cause intracellular retention of C1 inhibitor in hereditary angioedema', Journal of Clinical Investigation, bind 129, nr. 1, CI98869, s. 388-405. https://doi.org/10.1172/JCI98869

Dominant-negative SERPING1 variants cause intracellular retention of C1 inhibitor in hereditary angioedema. / Haslund, Didde; Ryø, Laura Barrett; Seidelin Majidi, Sara; Rose, Iben Kløvgaard; Skipper, Kristian Alsbjerg; Fryland, Tue; Bohn, Anja Bille; Koch, Claus; Thomsen, Martin K; Palarasah, Yaseelan; Corydon, Thomas J; Bygum, Anette; Nejsum, Lene N; Mikkelsen, Jacob Giehm.

I: Journal of Clinical Investigation, Bind 129, Nr. 1, CI98869, 01.2019, s. 388-405.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Dominant-negative SERPING1 variants cause intracellular retention of C1 inhibitor in hereditary angioedema

AU - Haslund, Didde

AU - Ryø, Laura Barrett

AU - Seidelin Majidi, Sara

AU - Rose, Iben Kløvgaard

AU - Skipper, Kristian Alsbjerg

AU - Fryland, Tue

AU - Bohn, Anja Bille

AU - Koch, Claus

AU - Thomsen, Martin K

AU - Palarasah, Yaseelan

AU - Corydon, Thomas J

AU - Bygum, Anette

AU - Nejsum, Lene N

AU - Mikkelsen, Jacob Giehm

PY - 2019/1

Y1 - 2019/1

N2 - Hereditary angioedema (HAE) is an autosomal dominant disease characterized by recurrent edema attacks associated with morbidity and mortality. HAE results from variations in the SERPING1 gene that encodes the C1 inhibitor (C1INH), a serine protease inhibitor (serpin). Reduced plasma levels of C1INH lead to enhanced activation of the contact system, triggering high levels of bradykinin and increased vascular permeability, but the cellular mechanisms leading to low C1INH levels (20%-30% of normal) in heterozygous HAE type I patients remain obscure. Here, we showed that C1INH encoded by a subset of HAE-causing SERPING1 alleles affected secretion of normal C1INH protein in a dominant-negative fashion by triggering formation of protein-protein interactions between normal and mutant C1INH, leading to the creation of larger intracellular C1INH aggregates that were trapped in the endoplasmic reticulum (ER). Notably, intracellular aggregation of C1INH and ER abnormality were observed in fibroblasts from a heterozygous carrier of a dominant-negative SERPING1 gene variant, but the condition was ameliorated by viral delivery of the SERPING1 gene. Collectively, our data link abnormal accumulation of serpins, a hallmark of serpinopathies, with dominant-negative disease mechanisms affecting C1INH plasma levels in HAE type I patients, and may pave the way for new treatments of HAE.

AB - Hereditary angioedema (HAE) is an autosomal dominant disease characterized by recurrent edema attacks associated with morbidity and mortality. HAE results from variations in the SERPING1 gene that encodes the C1 inhibitor (C1INH), a serine protease inhibitor (serpin). Reduced plasma levels of C1INH lead to enhanced activation of the contact system, triggering high levels of bradykinin and increased vascular permeability, but the cellular mechanisms leading to low C1INH levels (20%-30% of normal) in heterozygous HAE type I patients remain obscure. Here, we showed that C1INH encoded by a subset of HAE-causing SERPING1 alleles affected secretion of normal C1INH protein in a dominant-negative fashion by triggering formation of protein-protein interactions between normal and mutant C1INH, leading to the creation of larger intracellular C1INH aggregates that were trapped in the endoplasmic reticulum (ER). Notably, intracellular aggregation of C1INH and ER abnormality were observed in fibroblasts from a heterozygous carrier of a dominant-negative SERPING1 gene variant, but the condition was ameliorated by viral delivery of the SERPING1 gene. Collectively, our data link abnormal accumulation of serpins, a hallmark of serpinopathies, with dominant-negative disease mechanisms affecting C1INH plasma levels in HAE type I patients, and may pave the way for new treatments of HAE.

U2 - 10.1172/JCI98869

DO - 10.1172/JCI98869

M3 - Journal article

C2 - 30398465

VL - 129

SP - 388

EP - 405

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 1

M1 - CI98869

ER -

Haslund D, Ryø LB, Seidelin Majidi S, Rose IK, Skipper KA, Fryland T et al. Dominant-negative SERPING1 variants cause intracellular retention of C1 inhibitor in hereditary angioedema. Journal of Clinical Investigation. 2019 jan;129(1):388-405. CI98869. https://doi.org/10.1172/JCI98869