scholarly journals Complement Factor I Mutation May Contribute to Development of Thrombotic Microangiopathy in Lupus Nephritis

2021 ◽  
Vol 7 ◽  
Author(s):  
Min-Hua Tseng ◽  
Wen-Lang Fan ◽  
Hsuan Liu ◽  
Chia-Yu Yang ◽  
Jhao-Jhuang Ding ◽  
...  
Keyword(s):  
Lupus Nephritis ◽  
Thrombotic Microangiopathy ◽  
Remission Rate ◽  
Normal Subjects ◽  
Factor H ◽  
Study Cohort ◽  
Complement Factor ◽  
Adamts13 Activity ◽  
Factor I ◽  
Complement Factor I

Objective: Renal thrombotic microangiopathy (TMA) is associated with complement overactivation and poor outcome in patients with lupus nephritis (LN). The role of genetic makeup of complement system in these patients remains to be elucidated.Methods: The clinical and laboratory characteristics of 100 patients with LN during 2010–2017 were retrospectively analyzed. LN patients with renal TMA and condition-matched LN patients without renal TMA were studied. Twenty normal subjects were also enrolled for comparison. Whole exome sequence followed by Sanger sequence was used in our study cohort.Results: Eight patients with renal TMA and eight condition-matched patients were enrolled from 100 LN patients with mean age 11.2 ± 2.0 years. Compared with condition-matched LN patients without renal TMA, LN patients with renal TMA exhibited statistically higher serum urea. Although most patients with renal TMA responded to plasma exchange, they had significantly higher relapse rate of nephritis, lower remission rate, and higher risk of end-stage renal disease and mortality. Compared with patients without renal TMA and normal subjects, those with renal TMA had significantly lower serum complement factor H (CFH) and plasma ADAMTS13 activity. Molecular analysis of all 100 patients with LN uncovered that three patients with renal TMA harbored mutations, two missense and non-sense, on CFI and CFHR2. The non-sense mutation, E302X, on CFI may impair its interaction C3b/CFH complex by loss of the heavy chain of complement factor I on simulation model.Conclusion: In addition to low serum CFH level and plasma ADAMTS13 activity, defects in genes responsible for complement regulatory proteins may contribute to the development of renal TMA in patients with LN.

Deficiency of Human Complement Factor I Associated with Lowered Factor H

2000 ◽  
Vol 96 (2) ◽  
pp. 162-167 ◽  
Author(s):  
G.M. Naked ◽  
M.P.C. Florido ◽  
P. Ferreira de Paula ◽  
A.M. Vinet ◽  
J.S. Inostroza ◽  
...  
Keyword(s):  
Factor H ◽  
Complement Factor ◽  
Human Complement ◽  
Factor I ◽  
Complement Factor I

scholarly journals New functional and structural insights from updated mutational databases for complement factor H, Factor I, membrane cofactor protein and C3

2014 ◽  
Vol 34 (5) ◽  
Author(s):  
Elizabeth Rodriguez ◽  
Pavithra M. Rallapalli ◽  
Amy J. Osborne ◽  
Stephen J. Perkins
Keyword(s):  
Alternative Pathway ◽  
Factor H ◽  
Complement Factor H ◽  
Complement C3 ◽  
Complement Factor ◽  
Membrane Cofactor Protein ◽  
Complement Alternative Pathway ◽  
Factor I ◽  
Mutational Hotspots ◽  
Structural Insights

A new compilation of 324 mutations in four major proteins from the complement alternative pathway reveals mutational hotspots in factor H and complement C3, and less so in factor I and membrane cofactor protein. Their associations with function are discussed.

A Family with Complement Factor I Deficiency

1986 ◽  
Vol 23 (6) ◽  
pp. 711-715 ◽  
Author(s):  
J. M. RASMUSSEN ◽  
B. TEISNER ◽  
I. BRANDSLUND ◽  
S.-E. SVEHAG
Keyword(s):  
Complement Factor ◽  
Factor I ◽  
Complement Factor I

scholarly journals Functional expression of complement factor I following AAV-mediated gene delivery in the retina of mice and human cells

Gene Therapy ◽  
2021 ◽  
Author(s):  
Anna K. Dreismann ◽  
Michelle E. McClements ◽  
Alun R. Barnard ◽  
Elise Orhan ◽  
Jane P. Hughes ◽  
...  
Keyword(s):  
Complement System ◽  
Functional Expression ◽  
Geographic Atrophy ◽  
Age Related Macular Degeneration ◽  
Complement Factor ◽  
Factor I ◽  
Complement Factor I ◽  
Age Related ◽  
The Complement System

AbstractDry age-related macular degeneration (AMD) is characterised by loss of central vision and currently has no approved medical treatment. Dysregulation of the complement system is thought to play an important role in disease pathology and supplementation of Complement Factor I (CFI), a key regulator of the complement system, has the potential to provide a treatment option for AMD. In this study, we demonstrate the generation of AAV constructs carrying the human CFI sequence and expression of CFI in cell lines and in the retina of C57BL/6 J mice. Four codon optimised constructs were compared to the most common human CFI sequence. All constructs expressed CFI protein; however, most codon optimised sequences resulted in significantly reduced CFI secretion compared to the non-optimised CFI sequence. In vivo expression analysis showed that CFI was predominantly expressed in the RPE and photoreceptors. Secreted protein in vitreous humour was demonstrated to be functionally active. The findings presented here have led to the formulation of an AAV-vectored gene therapy product currently being tested in a first-in-human clinical trial in subjects with geographic atrophy secondary to dry AMD (NCT03846193).

scholarly journals Complement factor I deficiency

2020 ◽  
Vol 7 (3) ◽  
pp. e689 ◽  
Author(s):  
Tom Altmann ◽  
Megan Torvell ◽  
Stephen Owens ◽  
Dipayan Mitra ◽  
Neil S. Sheerin ◽  
...  
Keyword(s):  
Acute Disseminated Encephalomyelitis ◽  
Complement Factor ◽  
Retrospective Diagnosis ◽  
Factor I ◽  
Complement Factor I ◽  
Whole Exome ◽  
Simple Measurement ◽  
Cerebral Inflammation ◽  
High Index Of Suspicion ◽  
Complement Pathways

ObjectiveTo raise awareness of complement factor I (CFI) deficiency as a potentially treatable cause of severe cerebral inflammation.MethodsCase report with neuroradiology, neuropathology, and functional data describing the mutation with review of literature.ResultsWe present a case of acute, fulminant, destructive cerebral edema in a previously well 11-year-old, demonstrating massive activation of complement pathways on neuropathology and compound heterozygote status for 2 pathogenic mutations in CFI which result in normal levels but completely abrogate function.ConclusionsOur case adds to a very small number of extant reports of this phenomenon associated with a spectrum of inflammatory histopathologies including hemorrhagic leukoencephalopathy and clinical presentations resembling severe acute disseminated encephalomyelitis. CFI deficiency can result in uncontrolled activation of the complement pathways in the brain resulting in devastating cerebral inflammation. The deficit is latent, but the catastrophic dysregulation of the complement system may be the result of a C3 acute phase response. Diagnoses to date have been retrospective. Diagnosis requires a high index of suspicion and clinician awareness of the limitations of first-line clinical tests of complement activity and activation. Simple measurement of circulating CFI levels, as here, may fail to diagnose functional deficiency with absent CFI activity. These diagnostic challenges may mean that the CFI deficiency is being systematically under-recognized as a cause of fulminant cerebral inflammation. Complement inhibitory therapies (such as eculizumab) offer new potential treatment, underlining the importance of prompt recognition, and real-time whole exome sequencing may play an important future role.

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