Alt. symbols: IF | FI | C3b-IKAF

Approved name: complement factor I
Alt. names: I factor (complement) | Konglutinogen-activating factor, C3b-inactivator

Location: 4q25: 109731008 - 109802150 (-)
Gene type: protein_coding, 10 transcripts.

Scores: LoFtool: 0.157000 | pLI: 0.00002238 | LOEUF: 0.761

HGNC: 5394

NCBI: 3426, RefSeq: NG_007569.1

Ensembl: ENSG00000205403.15

LRG_48 | Status: public

OMIM: 217030

Expression | ProteinAtlas

CFI encodes Complement factor I, a trypsin-like serine protease that plays an essential role in regulating the activity of all 3 complement pathways. Factor I is a plasma glycoprotein composed of 2 polypeptide chains linked by disulfide bonds. Both the light and heavy chains are encoded by CFI - the light chain contains the serine protease domain. Factor I inactivates C3b and C4b by cleaving peptide bonds within their alpha-chains (PMID: 7360115, 17320177). Complement factor H and C4BP in the fluid phase and cell surface-associated CD46 and CR1 serve as essential cofactors for these reactions include (PMID: 2141838, 9605165, 12055245). The presence of these cofactors on healthy cells allows degradation of deposited C3b by CFI in order to prevent undesired complement activation, while in apoptotic cells or microbes, the absence of such cofactors leads to C3b-mediated complement activation and subsequent opsonization (PMID: 28671664).

Nonsense, missense, frameshift and splice site mutations in CFI have been associated with a number of diverse clinical conditions. Homozygous or compound heterozygous mutations lead to autosomal recessive complement factor I deficiency [OMIM: 610984], featuring increased susceptibility to encapsulated bacterial infections due to accelerated catabolism of C3 from deficiency of the C3 inactivator. However, non-infectious presentations including rheumatological, dermatological and neurological mani festations are increasingly recognized (PMID: 31231365). Baracho et al. (2003) reported 2 Brazilian sisters born to consanguineous parents with a homozygous CFI frameshift mutation leading to complete absence of serum factor I (PMID: 12562389) - the older sister had recurrent infections and developed systemic lupus erythematosus (SLE) with glomerulonephritis and the younger sister died at age 3 years of sepsis. Shields et al. (2019) describe the identification of compound heterozygous CFI variants leading to absent Factor I levels in a 32 year old woman presenting with headache, blurred vision, slurred speech, tonic-clonic seizures and subsequent coma, and neuroimaging showing diffuse, confluent cerebral and cerebellar white matter changes, edema, and mass effect. She reportedly had suffered 3 similar episodes in the past and her sister had died of fulminant hemorrhagic leukoencephalopathy at age 16 (PMID: 31231365). More recently, Altmann et al. (2020) reported a case of fulminant CNS inflammation, radiologically resembling acute disseminated encephalomyelitis (ADEM), in association with complete CFI functional deficiency due to compound heterozygous mutations in an 11 year old Caucasian girl (PMID: 32098865). Heterozygous CFI mutations have been reported by multiple groups in association with risk for the development of atypical HUS (aHUS) [OMIM: 612923] (PMID: 15173250, 16621965), though ~5% of patients have combined mutations, usually in CFH with either CD46 or CFI (PMID: 30046676). In addition, Servais et al. (2007) described a unique form of glomerulonephritis characterized by isolated mesangial C3 deposits without dense intramembranous deposits or mesangial proliferation in individuals with complement regulatory gene mutations, including 2 patients with heterozygous CFI mutations. More recently, heterozygous CFI mutation was reported in a case of neonatal Thrombotic Microangiopathy (TMA) (PMID: 32514992) and Tseng et el. (2021) proposed that heterozygous CFI mutations may also contribute to the development of TMA in Lupus Nephritis patients (PMID: 33614676). Heterozygous CFI mutations have also been reported in association with susceptibility to the development of Age-Related Macular Degeneration (ARMD) [OMIM: 615439] (PMID: 24036952, 23685748, 25986072). Kavanagh et al. (2015) showed that individuals with advanced ARMD carrying a rare CFI variant had lower mean Factor I (FI) levels than controls carrying a variant (p<0.001), and that individuals with a CFI rare variant and low FI were more likely to have advanced ARMD (p = 5.6 x 10(-5)) (PMID: 25788521). More recently, Hallam et al. (2020) genotyped and measured FI levels in a cohort of 276 ARMD patients and 205 elderly controls (PMID: 32516404). They similarly found that median FI level was significantly lower in individuals with ARMD and a rare CFI variant compared to those with ARMD without a rare CFI variant or the control population regardless of CFI variant status. Multiple regressi [Load More]