Alt. symbols: C1NH | C1IN | C1-INH | HAE1 | HAE2 | C1INH

Approved name: serpin family G member 1
Alt. names: serine (or cysteine) proteinase inhibitor, clade G (C1 inhibitor), member 1, (angioedema, hereditary), serpin peptidase inhibitor, clade G (C1 inhibitor), member 1 | plasma protease C1 inhibitor, angioedema, hereditary, C1-inhibitor

Location: 11q12.1: 57597387 - 57619171 (+)
Gene type: protein_coding, 22 transcripts.

Scores: LoFtool: 0.005650 | pLI: 0.97283740 | LOEUF: 0.322

HGNC: 1228

NCBI: 710, RefSeq: NG_009625.1

Ensembl: ENSG00000149131.17

LRG_105 | Status: public

OMIM: 606860

Expression | ProteinAtlas

SERPING1 encodes C1-inhibitor (C1-INH), which negatively regulates activation of the C1 complex. C1-INH forms a proteolytically inactive stoichiometric complex with the C1r or C1s proteases to play crucial roles in regulating important physiological pathways including complement activation, blood coagulation, fibrinolysis and the generation of kinins such as bradykinin. It is a very efficient inhibitor of FXIIa and can also inhibit chymotrypsin and kallikrein.

Hereditary angioedema (HAE) is a rare, autosomal dominant genetic disorder of variable penetrance with estimated prevalence of 1:10,000-50,000. A bradykinin-mediated process mediates all clinical manifestations of HAE, leading to sporadic episodes of swelling potentially affecting any part of the body. This may often be clinically difficult to distinguish from other histamine-mediated causes of swelling (PMID: 32187470). The 2 classic types arise from defects in C1 inhibitor (C1-INH), which limi ts the enzymatic activity of the first complement component and other plasma serine proteases such as factor XIIa and kallikrein enzymes. Type 1 (~90% of cases involving C1-INH) is characterized by low levels of C1-INH protein, while type 2 involves normal levels of ineffective C1-INH. Both lead to excess production of bradykinin, the key molecule that acts on bradykinin 2 (BR2) receptors to increase vascular permeability and edema. SERPING1 mutations constitute >95% of all cases of HAE [OMIM: 106100], with by now over 450 mutations identified throughout the gene, ~25% de novo (PMID: 11112899). In addition to missense (30-40%), nonsense (7%), frameshift deletion or insertion (31%), or splicing (10%) defects leading to truncated or misfolded protein, deep intronic and 3' and 5' UTR variants (~1%) have also been described (PMID: 31982983, 31959500, 16617246, 19201015). These latter may not be identified through standard molecular genetic analysis. Moreover, gross alterations in SERPING1 account for ~15-20% of HAE mutations. This arises from a cluster of tandem Alu repeats on intron 7, predisposing this locus to genetic instability in the form of rearrangements and CNVs. Unequal crossovers can lead to partial deletions and duplications, but retrotransposition events have also been described (PMID: 2154751, 27158268). Additionally, heterozygosity for a Ala443Val mutation in SERPING1 was identified in a large kindred with hereditary partial C4 deficiency (serum levels < 10 mg/dl), but not associated with any defects in the C4A-C4B locus itself (PMID: 6480834, 7883978, 8144914, 3477232). At least one member was affected by SLE but no members had angioedema; metabolic turnover studies were consistent with C4 hyposynthesis rather than hypercatabolism (PMID: 3477232). Zahedi et al. (1995) found that this mutation led to a mutant C1-INH with diminished Clr binding, preserved Cls binding, and resistance to trypsin cleavage (PMID: 7883978). [Load More]