title: Genetic, molecular and functional analyses of complement factor I deficiency.
abstract: Complete deficiency of complement inhibitor factor I (FI) results in secondary complement deficiency due to uncontrolled spontaneous alternative pathway activation leading to susceptibility to infections. Current genetic examination of two patients with near complete FI deficiency and three patients with no detectable serum FI and also close family members revealed homozygous or compound heterozygous mutations in several domains of FI. These mutations were introduced into recombinant FI and the resulting proteins were purified for functional studies, while transient transfection was used to analyze expression and secretion. The G170V mutation resulted in a protein that was not expressed, whereas the mutations Q232K, C237Y, S250L, I339M and H400L affected secretion. Furthermore, the C237Y and the S250L mutants did not degrade C4b and C3b as efficiently as the WT. The truncated Q336x mutant could be expressed, in vitro, but was not functional because it lacks the serine protease domain. Furthermore, this truncated FI was not detected in serum of the patient. Structural investigations using molecular modeling were performed to predict the potential impact the mutations have on FI structure. This is the first study that investigates, at the functional level, the consequences of molecular defects identified in patients with full FI deficiency.
authors.affiliation: Department of Laboratory Medicine, Lund University, Malmö University Hospital, Malmö, Sweden.
authors.forename: Sara C
authors.initials: SC
authors.lastname: Nilsson
authors.forename: Leendert A
authors.initials: LA
authors.lastname: Trouw
authors.forename: Nicolas
authors.initials: N
authors.lastname: Renault
authors.forename: Maria A
authors.initials: MA
authors.lastname: Miteva
authors.forename: Ferah
authors.initials: F
authors.lastname: Genel
authors.forename: Marta
authors.initials: M
authors.lastname: Zelazko
authors.forename: Hanne
authors.initials: H
authors.lastname: Marquart
authors.forename: Klaus
authors.initials: K
authors.lastname: Muller
authors.forename: Anders G
authors.initials: AG
authors.lastname: Sjöholm
authors.forename: Lennart
authors.initials: L
authors.lastname: Truedsson
authors.forename: Bruno O
authors.initials: BO
authors.lastname: Villoutreix
authors.forename: Anna M
authors.initials: AM
authors.lastname: Blom
mesh_terms: D000328:Adult; D002675:Child, Preschool; D003179:Complement C3b / Q000378:metabolism; D015935:Complement C4b / Q000378:metabolism; D017244:Complement Factor I / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics*; D005260:Female; D006801:Humans; D007223:Infant; D020125:Mutation, Missense; D011110:Polymorphism, Genetic; D011487:Protein Conformation; D017510:Protein Folding; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: D011994:Recombinant Proteins; D003179:Complement C3b; D015935:Complement C4b; D017244:Complement Factor I