GCK – Permanent Neonatal Diabetes Mellitus

Glucokinase (GCK) encodes the key pancreatic beta-cell glucose sensor that governs insulin secretion. Bi‐allelic inactivating variants abolish enzyme activity, leading to lifelong insulin-requiring hyperglycemia presenting within the first six months of life. Inheritance is autosomal recessive, with homozygous or compound heterozygous GCK mutations causing permanent neonatal diabetes mellitus (PNDM).

Genetic evidence includes 4 probands from two families with homozygous Q98X and Gly261Arg mutations (4 probands) (PMID:21518409), 2 compound heterozygous probands in a consanguineous family (2 probands) (PMID:26587058), and 2 unrelated probands with homozygous Thr168Ala variants (2 probands) (PMID:23155716), for a total of 8 probands. Segregation of bi‐allelic alleles was observed in 3 affected siblings (PMID:21518409) and in an affected cousin (PMID:26587058).

Variant spectrum is dominated by missense and nonsense loss‐of‐function alleles distributed throughout the gene. A recurrent variant, c.781G>A (p.Gly261Arg), has been identified in PNDM patients (PMID:21518409). Compound heterozygous alleles such as c.762T>G (p.Asn254Lys) and c.1339C>G (p.Arg447Gly) also underline allelic heterogeneity.

Functional studies demonstrate that PNDM‐associated variants drastically reduce glucokinase activity (<1% residual) in vitro. A knock-in mouse bearing an I366F missense mutation mimics hyperglycemia and impaired glucose tolerance (Diabetes • 2004) (PMID:15161764). These data concord with human phenotypes and support a loss-of-function mechanism.

No contradictory reports have disputed the GCK–PNDM link. The combined genetic and experimental data provide definitive clinical validity for GCK deficiency as an autosomal recessive cause of PNDM and support its use in diagnostic testing and variant interpretation.

Key take-home: Bi-allelic inactivating GCK variants cause definitive autosomal recessive PNDM, guiding genetic diagnosis, family counseling, and personalized insulin management.

References

• Pediatric diabetes • 2011 • Four novel cases of permanent neonatal diabetes mellitus caused by homozygous mutations in the glucokinase gene. PMID:21518409
• Diabetology & metabolic syndrome • 2015 • A new compound heterozygosis for inactivating mutations in the glucokinase gene as cause of permanent neonatal diabetes mellitus (PNDM) in double-first cousins. PMID:26587058
• Journal of pediatric endocrinology & metabolism : JPEM • 2012 • Variability in the age at diagnosis of diabetes in two unrelated patients with a homozygous glucokinase gene mutation. PMID:23155716
• Diabetes • 2004 • A new mouse model of type 2 diabetes, produced by N-ethyl-nitrosourea mutagenesis, is the result of a missense mutation in the glucokinase gene. PMID:15161764

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