
PMID- 34189567
OWN - NLM
STAT- MEDLINE
DCOM- 20220103
LR  - 20220315
IS  - 1528-0020 (Electronic)
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 138
IP  - 22
DP  - 2021 Dec 2
TI  - Functional characterization of 105 factor H variants associated with aHUS: 
      lessons for variant classification.
PG  - 2185-2201
LID - 10.1182/blood.2021012037 [doi]
AB  - Atypical hemolytic uremic syndrome (aHUS) is a life-threatening thrombotic 
      microangiopathy that can progress, when untreated, to end-stage renal disease. 
      Most frequently, aHUS is caused by complement dysregulation due to pathogenic 
      variants in genes that encode complement components and regulators. Among these 
      genes, the factor H (FH) gene, CFH, presents with the highest frequency (15% to 
      20%) of variants and is associated with the poorest prognosis. Correct 
      classification of CFH variants as pathogenic or benign is essential to clinical 
      care but remains challenging owing to the dearth of functional studies. As a 
      result, significant numbers of variants are reported as variants of uncertain 
      significance. To address this knowledge gap, we expressed and functionally 
      characterized 105 aHUS-associated FH variants. All FH variants were categorized 
      as pathogenic or benign and, for each, we fully documented the nature of the 
      pathogenicity. Twenty-six previously characterized FH variants were used as 
      controls to validate and confirm the robustness of the functional assays used. Of 
      the remaining 79 uncharacterized variants, only 29 (36.7%) alter FH expression or 
      function in vitro and, therefore, are proposed to be pathogenic. We show that 
      rarity in control databases is not informative for variant classification, and we 
      identify important limitations in applying prediction algorithms to FH variants. 
      Based on structural and functional data, we suggest ways to circumvent these 
      difficulties and, thereby, improve variant classification. Our work highlights 
      the need for functional assays to interpret FH variants accurately if clinical 
      care of patients with aHUS is to be individualized and optimized.
CI  - (c) 2021 by The American Society of Hematology.
FAU - Martin Merinero, Hector
AU  - Martin Merinero H
AUID- ORCID: 0000-0002-9094-5934
AD  - Centro de Investigaciones Biologicas Margarita Salas, Consejo Superior de 
      Investigaciones Cientificas (CSIC), Madrid, Spain.
AD  - Centro de Investigacion Biomedica en Red de Enfermedades Raras, Madrid, Spain.
FAU - Zhang, Yuzhou
AU  - Zhang Y
AUID- ORCID: 0000-0002-9626-5956
AD  - Molecular Otolaryngology and Renal Research Laboratories, Carver College of 
      Medicine, University of Iowa, Iowa City, IA; and.
FAU - Arjona, Emilia
AU  - Arjona E
AD  - Centro de Investigaciones Biologicas Margarita Salas, Consejo Superior de 
      Investigaciones Cientificas (CSIC), Madrid, Spain.
AD  - Centro de Investigacion Biomedica en Red de Enfermedades Raras, Madrid, Spain.
FAU - Del Angel, Guillermo
AU  - Del Angel G
AUID- ORCID: 0000-0002-0104-1563
AD  - Alexion Pharmaceuticals, Inc, Boston, MA.
FAU - Goodfellow, Renee
AU  - Goodfellow R
AD  - Molecular Otolaryngology and Renal Research Laboratories, Carver College of 
      Medicine, University of Iowa, Iowa City, IA; and.
FAU - Gomez-Rubio, Elena
AU  - Gomez-Rubio E
AUID- ORCID: 0000-0002-8037-4007
AD  - Centro de Investigaciones Biologicas Margarita Salas, Consejo Superior de 
      Investigaciones Cientificas (CSIC), Madrid, Spain.
FAU - Ji, Rui-Ru
AU  - Ji RR
AD  - Alexion Pharmaceuticals, Inc, Boston, MA.
FAU - Michelena, Malkoa
AU  - Michelena M
AD  - Centro de Investigaciones Biologicas Margarita Salas, Consejo Superior de 
      Investigaciones Cientificas (CSIC), Madrid, Spain.
AD  - Centro de Investigacion Biomedica en Red de Enfermedades Raras, Madrid, Spain.
FAU - Smith, Richard J H
AU  - Smith RJH
AD  - Molecular Otolaryngology and Renal Research Laboratories, Carver College of 
      Medicine, University of Iowa, Iowa City, IA; and.
FAU - Rodriguez de Cordoba, Santiago
AU  - Rodriguez de Cordoba S
AUID- ORCID: 0000-0001-6401-1874
AD  - Centro de Investigaciones Biologicas Margarita Salas, Consejo Superior de 
      Investigaciones Cientificas (CSIC), Madrid, Spain.
AD  - Centro de Investigacion Biomedica en Red de Enfermedades Raras, Madrid, Spain.
LA  - eng
GR  - R01 DK110023/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Recombinant Proteins)
RN  - 80295-65-4 (Complement Factor H)
SB  - IM
MH  - Atypical Hemolytic Uremic Syndrome/*genetics/metabolism/pathology
MH  - Complement Factor H/chemistry/*genetics/metabolism
MH  - Gene Expression
MH  - Genetic Predisposition to Disease
MH  - Genetic Variation
MH  - Humans
MH  - Models, Molecular
MH  - Point Mutation
MH  - Polymorphism, Single Nucleotide
MH  - Recombinant Proteins/chemistry/genetics/metabolism
PMC - PMC8641096
EDAT- 2021/07/01 06:00
MHDA- 2022/01/04 06:00
PMCR- 2021/12/02
CRDT- 2021/06/30 06:49
PHST- 2021/04/07 00:00 [received]
PHST- 2021/06/08 00:00 [accepted]
PHST- 2021/07/01 06:00 [pubmed]
PHST- 2022/01/04 06:00 [medline]
PHST- 2021/06/30 06:49 [entrez]
PHST- 2021/12/02 00:00 [pmc-release]
AID - S0006-4971(21)01292-1 [pii]
AID - 2021/BLD2021012037 [pii]
AID - 10.1182/blood.2021012037 [doi]
PST - ppublish
SO  - Blood. 2021 Dec 2;138(22):2185-2201. doi: 10.1182/blood.2021012037.
