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Molecular characterization of two novel cases of complete complement inhibitor Factor I deficiency.

Nita, Izabela LU ; Genel, Ferah; Nilsson, Sara LU ; Smart, Joanne; Truedsson, Lennart LU ; Choo, Sharon and Blom, Anna LU (2011) In Molecular Immunology 48(8). p.1068-1072
Abstract
Factor I (FI) is the major complement inhibitor that degrades activated complement components C3b and C4b in the presence of specific cofactors. Complete FI deficiency results in secondary complement deficiency due to uncontrolled spontaneous alternative pathway activation. In this study we describe two unrelated patients with complete FI deficiency and undetectable alternative complement pathway activity. Both patients had experienced recurrent infections and arthralgia/arthritis. In one patient, analysis of genomic DNA revealed deletion of two adenine nucleotides in exon 2 of the CFI gene (c.133-134delAA), causing a frame shift and premature STOP codon/termination in the FIMAC (FI-membrane attack complex) domain (p.K45SfsX11). The other... (More)
Factor I (FI) is the major complement inhibitor that degrades activated complement components C3b and C4b in the presence of specific cofactors. Complete FI deficiency results in secondary complement deficiency due to uncontrolled spontaneous alternative pathway activation. In this study we describe two unrelated patients with complete FI deficiency and undetectable alternative complement pathway activity. Both patients had experienced recurrent infections and arthralgia/arthritis. In one patient, analysis of genomic DNA revealed deletion of two adenine nucleotides in exon 2 of the CFI gene (c.133-134delAA), causing a frame shift and premature STOP codon/termination in the FIMAC (FI-membrane attack complex) domain (p.K45SfsX11). The other patient carried an A>T substitution in exon 6 (c.866A>T) encoding the LDLr2 (low density lipoprotein receptor) domain (p.D289V), resulting in an aspartic acid to valine change. Both patients were homozygous for the mutations while their healthy parents were heterozygous carriers. The mutations were introduced into recombinant FI, causing lack of FI expression and secretion upon transient transfection. Mutation p.K45SfsX11 theoretically allows expression of a 55 amino acid fragment of FI that lacks the serine protease domain, preventing proteolytic activity. In contrast, aspartic acid D289 is crucial for folding of FI. This report describes the molecular and functional consequences of two novel mutations of FI, providing a unique insight into the pathogenesis of complete FI deficiency in these patients. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Molecular Immunology
volume
48
issue
8
pages
1068 - 1072
publisher
Pergamon
external identifiers
  • wos:000289337800011
  • pmid:21316765
  • scopus:79952446417
ISSN
1872-9142
DOI
10.1016/j.molimm.2011.01.012
language
English
LU publication?
yes
id
a7628c52-e75e-4d6b-af62-6016edbba79a (old id 1831890)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/21316765?dopt=Abstract
date added to LUP
2011-03-01 14:49:19
date last changed
2017-11-19 03:40:46
@article{a7628c52-e75e-4d6b-af62-6016edbba79a,
  abstract     = {Factor I (FI) is the major complement inhibitor that degrades activated complement components C3b and C4b in the presence of specific cofactors. Complete FI deficiency results in secondary complement deficiency due to uncontrolled spontaneous alternative pathway activation. In this study we describe two unrelated patients with complete FI deficiency and undetectable alternative complement pathway activity. Both patients had experienced recurrent infections and arthralgia/arthritis. In one patient, analysis of genomic DNA revealed deletion of two adenine nucleotides in exon 2 of the CFI gene (c.133-134delAA), causing a frame shift and premature STOP codon/termination in the FIMAC (FI-membrane attack complex) domain (p.K45SfsX11). The other patient carried an A>T substitution in exon 6 (c.866A>T) encoding the LDLr2 (low density lipoprotein receptor) domain (p.D289V), resulting in an aspartic acid to valine change. Both patients were homozygous for the mutations while their healthy parents were heterozygous carriers. The mutations were introduced into recombinant FI, causing lack of FI expression and secretion upon transient transfection. Mutation p.K45SfsX11 theoretically allows expression of a 55 amino acid fragment of FI that lacks the serine protease domain, preventing proteolytic activity. In contrast, aspartic acid D289 is crucial for folding of FI. This report describes the molecular and functional consequences of two novel mutations of FI, providing a unique insight into the pathogenesis of complete FI deficiency in these patients.},
  author       = {Nita, Izabela and Genel, Ferah and Nilsson, Sara and Smart, Joanne and Truedsson, Lennart and Choo, Sharon and Blom, Anna},
  issn         = {1872-9142},
  language     = {eng},
  number       = {8},
  pages        = {1068--1072},
  publisher    = {Pergamon},
  series       = {Molecular Immunology},
  title        = {Molecular characterization of two novel cases of complete complement inhibitor Factor I deficiency.},
  url          = {http://dx.doi.org/10.1016/j.molimm.2011.01.012},
  volume       = {48},
  year         = {2011},
}