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Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is an autosomal dominant neurodegenerative disorder characterized by progressive cognitive decline and action myoclonus, culminating in premature death (PMID:10517635). Pathogenic variants in SERPINI1 disrupt the native folding of neuroserpin, leading to intraneuronal polymer accumulation and inclusion body formation. Clinical onset typically occurs in the second to fourth decade, with median age at death of 33 years in reported cohorts (PMID:36417830). Brain imaging often reveals cerebral and/or cerebellar atrophy, and histopathology confirms neuroserpin polymers in affected neurons.
The genetic evidence for SERPINI1 in FENIB includes 14 unrelated probands harboring heterozygous missense variants, notably c.1175G>A (p.Gly392Glu) in four cases and c.1012A>G (p.His338Arg) in one case (PMID:36417830, PMID:38166833). Two founder mutations, c.146T>C (p.Ser49Pro) and c.155C>G (p.Ser52Arg), cosegregate in multi-generation families with at least four additional affected relatives (PMID:10517635). All variants reported to date are missense substitutions within conserved regions of the shutter and breach domains, consistent with a polymerization mechanism.
Functional studies demonstrate that mutant neuroserpin undergoes aberrant polymerization within the endoplasmic reticulum (ER), impairing normal secretion. ER-associated degradation (ERAD) assays show that the lectin OS-9 recognizes glycan side chains on misfolded neuroserpin and delivers it to Hrd1/gp78-mediated ubiquitination and proteasomal clearance (PMID:24795221, PMID:21507957). Site-directed mutagenesis of N-linked glycosylation sites reveals that N157 and N321 are essential for maintaining monomeric neuroserpin, whereas aberrant glycosylation at N401 in the G392E variant facilitates degradation under proteasomal stress (PMID:26367528).
Advanced models using patient-derived induced pluripotent stem cells and base editing have corrected the c.1175G>A (p.Gly392Glu) variant, restored dendritic morphology, and reduced inclusion burden upon early intervention, highlighting therapeutic potential (PMID:39877004). Knockout zebrafish models lacking serpini1 exhibit anxiety-like behavior and altered neurodevelopmental gene expression, further supporting haploinsufficiency effects in vivo (PMID:33168193).
No credible conflicting evidence has emerged; reported bidirectional promoter polymorphisms in the shared PDCD10/SERPINI1 regulatory region appear protective rather than pathogenic in cerebral cavernous malformation cohorts (PMID:27737651).
Integration of robust segregation data, multiple unrelated probands with concordant missense variants, and consistent cellular and animal model findings supports a Strong gene–disease association. Genetic testing for SERPINI1 missense variants informs diagnosis, prognosis, and potential gene correction therapies. Key take-home: SERPINI1 pathogenic missense variants causally underlie FENIB via a toxic gain-of-function polymerization mechanism, and early genetic and functional interventions may modify disease progression.
Gene–Disease AssociationStrong14 unrelated probands with causative SERPINI1 missense variants and segregation in two families with four additional affected relatives Genetic EvidenceStrong14 pathogenic missense variants in unrelated cases, including two loci showing multi-generation segregation, fulfilling ClinGen genetic cap Functional EvidenceModerateMultiple cell and animal models demonstrate polymerization, ERAD dependence, glycosylation effects, and successful base-editing rescue |