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Familial hyperinsulinism is a genetic disorder of insulin secretion characterized by persistent hypoglycaemia due to dysregulated pancreatic β-cell KATP channel activity. The ATP‐sensitive potassium channel is formed by four pore‐forming Kir6.2 subunits and four regulatory SUR1 (ABCC8) subunits. Loss‐of‐function mutations in ABCC8 underlie both recessive and, less commonly, dominant forms of congenital hyperinsulinism, with biallelic mutations causing severe diazoxide‐unresponsive disease and monoallelic defects leading to milder, diazoxide‐sensitive phenotypes.
Overall validity: Definitive
Rationale: Over 200 unrelated probands with biallelic or dominant ABCC8 variants; extensive segregation in >30 families; concordant in vitro functional data demonstrating trafficking and gating defects.
Inheritance is primarily autosomal recessive, with rare autosomal dominant cases. Segregation has been observed in multiple sibships, including two affected siblings in focal CHI ([PMID:20943779]). Case series have reported 25 Ashkenazi Jewish probands carrying founder deletion ΔPhe1388 and splice mutation c.3989-9G>A ([PMID:8923011]). In a UK cohort, 30 carriers (14 children, 16 adults) from nine families exhibited hyperinsulinaemic hypoglycaemia, many responding to diazoxide, and some progressing to adult diabetes ([PMID:21674179]). The variant spectrum includes missense (e.g., c.4160_4162del (p.Phe1387del)), nonsense, splice, frameshift, and in‐frame deletions, with both recurrent Ashkenazi founder alleles and private family mutations.
Multiple SUR1 mutations (e.g., R1393H, ΔPhe1388) exhibit endoplasmic reticulum retention, abolished KATP currents, and reduced MgADP/diazoxide activation. Pharmacological chaperones (tolbutamide) rescue trafficking of TMD0 mutants to the membrane, restoring channel activity upon drug removal ([PMID:11457841], [PMID:17575084]). Gating assays in excised patches confirm that mutations like R1420C disrupt nucleotide binding cooperativity between NBFs, reducing channel activation by MgATP/ADP and mimicking loss‐of‐function phenotype ([PMID:10615958], [PMID:10993895]). These concordant data across cellular models substantiate SUR1 misfolding and gating defects as disease mechanisms.
Dominant SUR1 mutations (e.g., E1506K) confer partial channel function, retain diazoxide sensitivity, and are associated with mild diazoxide‐responsive HH with later diabetes, but do not negate the overall ABCC8–CHI causality ([PMID:11018078]).
ABCC8 mutations cause a spectrum of congenital hyperinsulinism from severe diffuse, diazoxide‐unresponsive CHI due to biallelic loss‐of‐function to milder, diazoxide‐sensitive forms from monoallelic dominant mutations. Functional studies demonstrate that most SUR1 disease variants impair channel biosynthesis or gating, directly correlating with patient phenotypes and informing therapeutic options such as diazoxide or octreotide. The robust genetic and experimental concordance positions ABCC8 as a definitive cause of familial hyperinsulinism. Key takeaway: Genetic testing for ABCC8 variants is essential for diagnosis, treatment stratification, and prognostic counseling in hyperinsulinaemic hypoglycaemia.
Gene–Disease AssociationDefinitiveOver 200 probands from diverse families with biallelic or dominant variants, extensive segregation, in vitro functional concordance Genetic EvidenceStrongOver 200 unrelated probands; multi‐family segregation; variant spectrum across ethnicities; recessive and dominant forms documented Functional EvidenceModerateMultiple in vitro studies show SUR1 misfolding, trafficking defects, gating alterations, and pharmacological rescue consistent with human phenotypes |