Complement dysregulation associated with a genetic variant in factor H-related protein 5 in atypical hemolytic uremic syndrome
Aradottir, Sigridur Sunna LU ; Kristoffersson, Ann-Charlotte LU ; Linnér, Erik LU and Karpman, Diana LU
(2023)
In Pediatric Nephrology
- Abstract
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... (More)
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. A higher resolution version of the Graphical abstract is available as Supplementary information.
(Less)
- author
- Aradottir, Sigridur Sunna
LU
; Kristoffersson, Ann-Charlotte
LU
; Linnér, Erik
LU
and Karpman, Diana
LU
- organization
- publishing date
- 2023-11-13
- type
- Contribution to journal
- publication status
- epub
- subject
- in
- Pediatric Nephrology
- publisher
- Springer
- external identifiers
-
- scopus:85176610491
- pmid:37955705
- ISSN
- 1432-198X
- DOI
- 10.1007/s00467-023-06184-6
- language
- English
- LU publication?
- yes
- additional info
- © 2023. The Author(s).
- id
- c5edd70e-3254-4e30-94dc-aed9dc759e24
- date added to LUP
- 2023-11-19 13:48:30
- date last changed
- 2024-04-17 08:16:46
@article{c5edd70e-3254-4e30-94dc-aed9dc759e24,
abstract = {{<p>BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) can be associated with mutations, deletions, or hybrid genes in factor H-related (FHR) proteins.</p><p>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.</p><p>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.</p><p>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. A higher resolution version of the Graphical abstract is available as Supplementary information.</p>}},
author = {{Aradottir, Sigridur Sunna and Kristoffersson, Ann-Charlotte and Linnér, Erik and Karpman, Diana}},
issn = {{1432-198X}},
language = {{eng}},
month = {{11}},
publisher = {{Springer}},
series = {{Pediatric Nephrology}},
title = {{Complement dysregulation associated with a genetic variant in factor H-related protein 5 in atypical hemolytic uremic syndrome}},
url = {{http://dx.doi.org/10.1007/s00467-023-06184-6}},
doi = {{10.1007/s00467-023-06184-6}},
year = {{2023}},
}