GK-associated hyperinsulinism

Several mutations in the human GLK gene are associated with the disease persistent hyperinsulinemic hypoglycemia of infancy (PHHI) or congenital hyprinsulinism (CHI). The stimulatory mutations represent surreptitious genetic determinants of PHHI.

Pathology

Rare GK activating mutations have been observedd in autosomal dominant congenital hyperinsulinism (MIM.602485) (V455M, A456V)

Activating glucokinase (GCK) mutations are a rarely reported cause of congenital hyperinsulinism (CHI), but the prevalence of GCK mutations is not known.

In the largest study performed to date on GCK in children with CHI, GCK mutations were found only in medically responsive children who were negative for ABCC8 and KCNJ11 mutations. The estimated prevalence (approximately 7%) suggests that screening for activating GCK mutations is warranted in those patients.

Some mutations arise de novo, others are dominantly inherited.

In the combined Danish and Norwegian cohort, the prevalence of GCK-CHI was estimated to be 1.2% (2/167, 95% confidence interval (CI) 0-2.8%) of all the CHI patients.

In the three centre combined cohort of 72 medically responsive children without K(ATP)-channel mutations, the prevalence estimate was 6.9% (5/72, 95% CI 1.1-12.8%).

All activating GCK mutations mapped to the allosteric activator site. All identified substitutions colocalize to a region of the glucokinase polypeptide where a synthetic allosteric activator binds.

GK mutations in congenital hyperinsulinism (CHI)

 V455M (9435328)
 A456V (14687251)
 S64Y (18450771)

• The novel S64Y mutation resulted in an increased affinity for the substrate glucose (S(0.5) 1.49+/-0.08 and 7.39+/-0.05 mmol/l in mutant and wild-type proteins respectively), extrapolating to a relative activity index of approximately 22 compared with the wild type.

 T65I (18450771)
 W99R (18450771)
 A456V (18450771)
 I211F (19146401)

• I211F is the most active variant identified to date, with a k(cat)/K(0.5,glucose) value (6.6 x 10(4) M(-1) s(-1)) that is 12-fold higher than that of wild-type glucokinase. (19146401)

References

 Activating glucokinase (GCK) mutations as a cause of medically responsive congenital hyperinsulinism: prevalence in children and characterisation of a novel GCK mutation. Christesen HB, Tribble ND, Molven A, Siddiqui J, Sandal T, Brusgaard K, Ellard S, Njølstad PR, Alm J, Brock Jacobsen B, Hussain K, Gloyn AL. Eur J Endocrinol. 2008 Jul;159(1):27-34. PMID: 18450771