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Heterozygous activating mutations in the inwardly rectifying potassium channel gene KCNJ11 cause Transient Neonatal Diabetes Mellitus (TNDM), a disorder of insulin secretion presenting with hyperglycemia in the first six months of life followed by spontaneous remission by early childhood. Affected infants exhibit marked hyperglycemia (blood glucose >20 mmol/L) without dysmorphism or neurologic deficits, and remission typically occurs between 5 and 18 months of age. Relapse in later childhood or adulthood may occur, underscoring the biphasic nature of the disease. Functional studies show that these variants reduce ATP‐mediated channel inhibition, leading to beta‐cell membrane hyperpolarization and transient insulin deficiency ([PMID:20401705]).
Disease transmission is autosomal dominant, with heterozygous gain‐of‐function variants segregating within families. In an Indian pedigree, a novel c.158G>A (p.Gly53Asp) variant was inherited from an asymptomatic father and found in three affected siblings with remitting and relapsing diabetes ([PMID:20401705]). Two French siblings with c.679G>A (p.Glu227Lys) and a singleton with c.761C>A (p.Pro254Gln) demonstrate vertical transmission and strong segregation ([PMID:28347637]). Across 12 families in a US cohort, KCNJ11 mutations were identified in 12 probands and 26 additional relatives, 17 of whom developed neonatal or relapsing diabetes, confirming robust familial segregation ([PMID:17446535]).
Population series reinforce the prevalence of KCNJ11 variants in TNDM. Among 97 TNDM probands, KCNJ11 accounted for 12 cases (26%) of non‐6q24 TNDM, establishing its significance in disease etiology ([PMID:17446535]). Brazilian and Emirati cohorts further expanded the mutational spectrum and prevalence to nearly 30% of TNDM, identifying novel missense substitutions clustered within ATP‐binding and regulatory domains ([PMID:22749773]; [PMID:26463504]).
In vitro functional characterization across multiple studies demonstrates that TNDM‐associated KCNJ11 variants uniformly reduce ATP sensitivity, increasing KATP currents and impairing insulin release. Xenopus oocyte assays of p.Gly53Ser, p.Gly53Arg, and p.Ile182Val show rightward shifts in ATP dose–response curves (IC50 ~30 µM vs. ~7 µM for wild type) that correlate with remission rather than permanent neonatal diabetes ([PMID:15718250]). Sulfonylurea drugs restore channel inhibition in vitro, and patients rapidly convert from insulin to glibenclamide or glipizide with improved metabolic control ([PMID:15583126]).
No conflicting evidence has emerged; all reported KCNJ11 variants in TNDM are activating, and clinical phenotype consistently differs from 6q24‐mediated cases by later onset, higher birth weight, and longer time to remission ([PMID:33606663]).
Overall, abundant genetic and functional data support a Strong clinico‐genetic association between KCNJ11 and TNDM. Genetic testing in autoantibody‐negative neonatal hyperglycemia is essential, as identifying a KCNJ11 variant directs precision therapy with oral sulfonylureas, improves prognosis, and informs family counseling. Key take‐home: detection of activating KCNJ11 variants in TNDM enables targeted sulfonylurea treatment and anticipatory guidance.
Gene–Disease AssociationStrong~47 probands from 12 families with segregation and concordant functional data Genetic EvidenceStrongIdentification of heterozygous KCNJ11 variants in 26% of non-6q24 TNDM cases across multiple cohorts; significant familial segregation Functional EvidenceModerateMultiple in vitro assays show gain-of-function with reduced ATP sensitivity and rescue by sulfonylureas |