CORIN
Details of the Concept
CORIN encodes a type II transmembrane serine protease expressed predominantly on atrial cardiomyocytes (especially left atrium) and, to a lesser extent, ventricular cardiomyocytes and kidney. Its primary cardiac function is proteolytic cleavage of proANP (pro-atrial natriuretic peptide) at the N-terminal junction to generate biologically active ANP and the inactive fragment NT-proANP. This cleavage is the key activation step in the ANP arm of the cardiac natriuretic peptide system. Furin provides partial redundancy in proANP/proBNP processing, but CORIN is the dominant enzyme for ANP activation in the left atrium. Complete CORIN loss in humans causes a novel monogenic syndrome of primary isolated left atrial cardiomyopathy with fibrosis, resistant hypertension, and refractory atrial arrhythmia.
Key Facts
Gene and Protein
- Type II transmembrane serine protease; primary expression: left atrial cardiomyocytes; secondary: ventricular cardiomyocytes, kidney
- Cleaves proANP → active ANP + NT-proANP (NT-proANP used clinically as proxy for ANP production)
- Also contributes (alongside furin) to proBNP processing
- Corin⁻/⁻ mice: hypertension + cardiac hypertrophy; elevated cardiomyocyte proANP; undetectable blood ANP; no atrial fibrosis — mechanistic divergence from the human phenotype sources/corin-acmp-nejm-2023 (rating: medium)
Monogenic CORIN LOF — Human Phenotype (First Described 2023)
- Index cases: Two Filipino siblings with homozygous frameshift c.684dupG; p.Met229Aspfs*16 — ACMG pathogenic (PVS1 + PS3 + PM2 + PP1 + PP4) sources/corin-acmp-nejm-2023 (rating: medium)
- Allele frequency: 0.009204% globally; 0.1304% East Asians (gnomAD); all 26 carriers East Asian — probable enrichment in Southeast Asian populations
- Phenotype: Isolated left atrial cardiomyopathy (LA fibrosis + LA hypertrophic remodelling) + resistant hypertension + refractory AF; no ventricular or right heart involvement
- Laboratory: plasma corin undetectable; NT-proANP negligible; BNP moderately elevated (compensatory); β-ENaC upregulated; PICP elevated (fibrosis); TIMP-1 normal (favourable HF prognosis signal)
ANP Pathway Mechanism
- Loss of CORIN → no proANP → active ANP conversion → impaired cGMP-dependent downstream signalling sources/corin-acmp-nejm-2023 (rating: medium)
- Kidney: β-ENaC upregulated → impaired inhibition of epithelial sodium channel → sodium reabsorption → hypertension (mechanistically analogous to gain-of-function ENaC mutations in Liddle's syndrome)
- Left atrium: Loss of ANP anti-fibrotic effect (normally inhibits fibroblast infiltration) → LA fibrosis → electrical remodelling → refractory AF substrate
- Vasculature: Loss of ANP vasodilatory effect → contribution to hypertension
- BNP upregulation partially compensates via shared NPR-A receptor: cGMP partially preserved, explaining mild-to-moderate (not catastrophic) hypertension; β-ENaC and atrial fibrosis are not prevented
Heterozygous CORIN Variants
- Heterozygous CORIN missense variants previously associated with hypertension and arrhythmia
- Several CORIN missense variants linked to preeclampsia (a hypertensive disorder of pregnancy)
- Family of index cases: early-onset hypertension in 8 family members including heterozygous carriers; cosegregation not confirmed — heterozygous risk remains a hypothesis requiring prospective validation sources/corin-acmp-nejm-2023 (rating: medium)
Broader Natriuretic Peptide Context
- NPPA (ANP precursor gene) frameshift mutation → familial AF (NEJM 2008) — supports CORIN/ANP axis as a monogenic AF-relevant pathway
- Plasma corin levels: decreased in HF; elevated in AF — bidirectional dysregulation suggesting the amount of corin activity is tightly regulated
- Furin: provides partial redundancy in proANP/proBNP processing; total CORIN loss alone is sufficient to abolish proANP → ANP conversion
Therapeutic Implications
- Soluble corin infusion in Corin⁻/⁻ mice transiently restored proANP cleavage → elevated blood ANP + cGMP — proof-of-concept for exogenous corin as a therapeutic target sources/corin-acmp-nejm-2023 (rating: medium)
- Amiloride (ENaC blocker): targets the downstream sodium retention mechanism; current most practical option for CORIN LOF and refractory hypertension
- Modified intravenous natriuretic peptides (e.g., cenderitide): partially bypass the CORIN processing step and may be relevant in CORIN LOF
- Patient 1 underwent PVI for AF — partial initial success, AF recurred at 1 year — suggesting atrial fibrosis substrate in CORIN LOF limits ablation durability
Contradictions / Open Questions
- Mouse vs. human atrial fibrosis: Corin⁻/⁻ mice develop hypertension and hypertrophy but not atrial fibrosis. The human LA appears uniquely dependent on ANP-mediated anti-fibrotic signalling — mechanism unexplained sources/corin-acmp-nejm-2023 (rating: medium)
- BNP partial compensation: Why elevated BNP cannot prevent atrial fibrosis despite partially normalising cGMP is unresolved — ANP may signal through atrial-specific pathways not replicated by BNP
- Heterozygous carrier risk: Early-onset hypertension in family members is suggestive but cosegregation is not established; population-level MAF data for Southeast Asian subpopulations is absent from gnomAD
- PKP2 co-variant in Patient 1: A heterozygous PKP2 p.Ser571Thr variant of uncertain significance was identified; cannot exclude contribution to more severe acute presentation but ARVC phenotype absent
Connections
- Related to concepts/Atrial-Cardiomyopathy — CORIN LOF is the first identified monogenic cause of primary isolated LA cardiomyopathy
- Related to entities/Atrial-Fibrillation — LA fibrosis from CORIN LOF drives refractory AF
- Related to entities/Hypertension — ENaC-mediated sodium retention is the primary mechanism
- Related to entities/PKP2 — co-incidental heterozygous variant in Patient 1; uncertain pathogenicity