Genetic investigation of Nordic patients with complement-mediated kidney diseases

Rydberg, Viktor; Aradottir, Sigridur Sunna; Kristoffersson, Ann-Charlotte; Svitacheva, Naila; Karpman, Diana

doi:10.3389/fimmu.2023.1254759

Cited by 4 publications

(1 citation statement)

References 93 publications

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“…Our group has previously shown that monozygotic twins with a gain-of-function variant in CFB , encoding complement factor B, differed regarding the development of aHUS [ 24 ]. Moreover, the same genetic variant may be associated with aHUS in one individual and C3 glomerulopathy in another [ 28 ]. In addition to genetic composition, other factors may play a role, such as environmental exposures (i.e., vaccinations and infections.)…”

Section: Discussionmentioning

confidence: 99%

Complement dysregulation associated with a genetic variant in factor H-related protein 5 in atypical hemolytic uremic syndrome

Aradottir,

Kristoffersson,

Linnér

et al. 2023

Pediatr Nephrol

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Background Atypical hemolytic uremic syndrome (aHUS) can be associated with mutations, deletions, or hybrid genes in factor H-related (FHR) proteins. Methods A child with aHUS was investigated. Genetics was assessed by Sanger and next generation sequencing. Serum FHR5 was evaluated by immunoblotting, ELISA, and by induction of rabbit red blood cell hemolysis in the presence/absence of recombinant human rFHR5. Mutagenesis was performed in HEK cells. Results A heterozygous genetic variant in factor H-related protein 5 (CFHR5), M514R, was found in the child, who also had a homozygous deletion of CFHR3/CFHR1, and antibodies to factor H, as well as low levels of C3. Patient serum exhibited low levels of FHR5. In the presence of rabbit red blood cells, patient serum induced hemolysis which decreased when rFHR5 was added at physiological concentrations. Similar results were obtained using serum from the father, bearing the CFHR5 variant without factor H antibodies. Patient FHR5 formed normal dimers. The CFHR5 M514R variant was expressed in HEK cells and minimal secretion was detected whereas the protein level was elevated in cell lysates. Conclusions Decreased secretion of the product of the mutant allele could explain the low FHR5 levels in patient serum. Reduced hemolysis when rFHR5 was added to serum suggests a regulatory role regarding complement activation on red blood cells. As such, low levels of FHR5, as demonstrated in the patient, may contribute to complement activation. Graphical abstract

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Section: Discussionmentioning

confidence: 99%

Complement dysregulation associated with a genetic variant in factor H-related protein 5 in atypical hemolytic uremic syndrome

Aradottir,

Kristoffersson,

Linnér

et al. 2023

Pediatr Nephrol

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Extrarenal manifestations in inherited kidney diseases

Hoefele,

Eble,

Hermle

et al. 2024

Nephrology Dialysis Transplantation

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Monogenic kidney diseases result from an abundance of potential genes carrying pathogenic variants. These conditions are primarily recognized for manifesting as kidney disorders, defined as an impairment of the structure and/or function of the kidneys. However, the impact of these genetic disorders extends far beyond the kidneys, giving rise to a diverse spectrum of extrarenal manifestations. These manifestations can affect any organ system throughout the body, leading to a complex clinical presentation that demands a comprehensive understanding and interdisciplinary management of affected persons. The intricate interplay between genetic variants, molecular pathways, and systemic interactions underscores the importance of exploring the extrarenal aspects of inherited kidney diseases. This exploration not only deepens our comprehension of the diseases themselves but also opens avenues for more holistic diagnostics, treatment strategies, and improved interdisciplinary patient care. This article delves into the intricate realm of extrarenal manifestations in inherited kidney diseases, shedding light on the far-reaching impacts that these genetic conditions can exert beyond the confines of the kidney system.

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Acquired and genetic drivers of C3 and C5 convertase dysregulation in C3 glomerulopathy and immunoglobulin-associated MPGN

Roquigny,

Meuleman,

El Sissy

et al. 2024

Nephrology Dialysis Transplantation

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Dysregulation of the alternative pathway of complement plays a central role in the pathophysiology of C3 Glomerulopathy (C3G). Various autoimmune and genetic factors targeting the alternative pathway have been associated to both C3G and primary Immunoglobulin-associated Membranoproliferative Glomerulonephritis (Ig-MPGN), suggesting shared pathophysiological mechanisms. This review highlights the wide range of disease drivers identified that mainly target components or protein complexes of the alternative pathway, both in C3G and Ig-MPGN. Nephritic factors, which constitute a heterogeneous group of autoantibodies targeting the C3 or the C5 convertase, are the most common abnormalities. Monoclonal gammopathies are frequent in aging adults. They may promote complement activation and have in some cases also found to target alternative pathway regulatory proteins. Additionally, some patients with C3G and Ig-MPGN carry rare variants in genes encoding complement activating or regulating proteins of the alternative pathway. This review provides an informative overview of pathogenetic mechanisms associated with each abnormality, acting at different steps in the complement cascade. The diversity of targets involved in the C3G pathophysiology suggests the potential benefit of therapeutical approaches tailored to the underlying disease drivers, with a pivotal impact upstream or at the level of the C3 or C5 convertase activity.

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Genetic investigation of Nordic patients with complement-mediated kidney diseases

Cited by 4 publications

References 93 publications

Complement dysregulation associated with a genetic variant in factor H-related protein 5 in atypical hemolytic uremic syndrome

Complement dysregulation associated with a genetic variant in factor H-related protein 5 in atypical hemolytic uremic syndrome

Extrarenal manifestations in inherited kidney diseases

Acquired and genetic drivers of C3 and C5 convertase dysregulation in C3 glomerulopathy and immunoglobulin-associated MPGN

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