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Erythropoietic protoporphyria (EPP) is a cutaneous porphyria marked by severe photosensitivity and, in a subset of patients, progressive liver dysfunction. Pathogenic variants in FECH (ferrochelatase) reduce enzymatic insertion of iron into protoporphyrin IX, leading to its accumulation in erythrocytes and hepatocytes. Clinical expression typically follows an autosomal dominant pattern with low penetrance, requiring coinheritance of a deleterious FECH allele and a hypomorphic intronic variant. FECH mutations have been documented in over 400 probands across diverse populations, with both private and recurrent alleles identified ([PMID:9585598], [PMID:33021473]).
Genetic evidence demonstrates that EPP patients carry one loss-of-function FECH mutation in trans to the IVS3-48T>C allele (c.315-48T>C), which modulates splicing and reduces FECH mRNA levels. Variants include missense, frameshift, splice-site, deep-intronic and large deletions, with over 200 distinct mutations catalogued ([PMID:8601739], [PMID:10417624]). Segregation studies in multiple families confirm affected relatives harbor both the deleterious and hypomorphic alleles, while asymptomatic carriers lack the low-expression variant. Founder effects, such as c.314+2T>G in Northern England, and population-specific haplotypes underscore the variant spectrum and recurrence patterns ([PMID:20105171]).
Functional assays in patient cells and model systems support a haploinsufficiency mechanism. Splicing assays show increased cryptic splice usage of intron 3 in IVS3-48C carriers, yielding unstable transcripts degraded by nonsense-mediated decay. Antisense oligonucleotides targeting the cryptic splice site restore normal FECH splicing and activity in erythroid cells from symptomatic individuals ([PMID:24680888]). The Fechm1Pas mouse recapitulates EPP features, with the M98K substitution abolishing enzyme function and confirming pathogenicity ([PMID:8325637]).
Iron metabolism studies reveal that FECH deficiency alters systemic iron distribution, inducing microcytic anemia and splenic iron sequestration without classical sideroblastic features. Transferrin expression is upregulated and correlates with protoporphyrin levels, suggesting adaptive responses to mitochondrial iron overload ([PMID:17003376]). These findings inform management, indicating that iron supplementation may be harmful and that alternative strategies to reduce protoporphyrin burden are preferred.
Conflicting evidence arises from rare cases of ALAS2-associated X-linked protoporphyria, which phenocopy EPP but require different genetic testing. Moreover, homozygosity for IVS3-48C alone may produce a mild phenotype in some individuals, raising considerations for genetic counseling and variant classification ([PMID:29941360]).
In aggregate, FECH–EPP is a definitive gene–disease relationship with robust genetic and experimental concordance. Comprehensive FECH testing, including sequencing, dosage analysis and promoter assessment, is essential for accurate diagnosis and family screening. Emerging therapies targeting splicing defects hold promise for personalized intervention. Key take-home: FECH variant analysis guides risk prediction, informs management of photosensitivity and liver disease, and enables development of targeted molecular therapies.
Gene–Disease AssociationDefinitiveOver 400 probands across multiple cohorts and >50 families, extensive segregation and functional concordance (PMID:9585598, PMID:33021473, PMID:10942404) Genetic EvidenceStrong
Functional EvidenceStrongMouse Fechm1Pas model recapitulates EPP (PMID:8325637); in vitro splicing assays and antisense rescue restore normal splicing and enzyme activity (PMID:24680888, PMID:15850836) |