Heterogeneity in disease severity in a family with a novel G68V <i>GCK</i> activating mutation causing persistent hyperinsulinaemic hypoglycaemia of infancy

Wabitsch, Martin; Lahr, Georgia; Bunt, Martijn van de; Marchant, Colin D.; Lindner, Martin; Puttkamer, Jesco von; Fenneberg, A.; Debatin, Klaus‐Michael; Klein, Robert; Ellard, Sian; Clark, Anne; Gloyn, Anna L.

doi:10.1111/j.1464-5491.2007.02285.x

Cited by 59 publications

(52 citation statements)

References 23 publications

(51 reference statements)

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“…Normal histologic findings in four previous cases of glucokinase-related hypoglycemia have been reported, but none of these patients underwent detailed quantitative morphometric analysis. [2][3][4] In a previously reported case that included quantitative histologic analysis, a similar increase in the mean islet profile was confirmed (it was 2.5 times larger than that of control subjects and 8.0 to 10.0 times larger than that of patients with a K ATP -channel deficiency). 5 In both that patient and our patient, the routine pathology report did not indicate any abnormality in islet size; this emphasizes the importance of quantitative morphometric analysis to determine islet size.…”

supporting

confidence: 63%

Large Islets, Beta-Cell Proliferation, and a Glucokinase Mutation

Kassem¹,

Bhandari²,

Rodriguez-Bada³

et al. 2010

N Engl J Med

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supporting

confidence: 63%

Large Islets, Beta-Cell Proliferation, and a Glucokinase Mutation

Kassem¹,

Bhandari²,

Rodriguez-Bada³

et al. 2010

N Engl J Med

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“…Other genes involved include the inward cell rectifying potassium channel (Kir6.2, KCNJ11) (5), Glutamate dehydrogenase (GLUD1) (6), short chain 3-hydroxy-acyl-CoA dehydrogenase (SCHAD, HADHSC) (7) and Glucokinase (GCK) (8). The latter appears to be a very rare cause of HI, with only seven cases described to date in the world literature (8)(9)(10)(11)(12). HI is an extremely heterogeneous disorder in all aspects, including clinical presentation, morphology and genetics.…”

Section: Introductionmentioning

confidence: 99%

“…The structural integrity of GK is crucial for the maintenance of normal glucose homeostasis. Activating mutations in glucokinase gene (GCK) result in HI (GCK-HI), both mild and severe forms (8)(9)(10)(11)(12)14).…”

Section: Introductionmentioning

confidence: 99%

Diagnostic Difficulties in Glucokinase Hyperinsulinism

Meißner¹,

Marquard²,

Cobo-Vuilleumier³

et al. 2008

Horm Metab Res

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“…A large set (>600) of inactivating mutations in gck lead to either maturity onset diabetes of the young (heterozygous) or the more severe permanent neonatal diabetes mellitus (homozygous) (29,30). In contrast, activating gck mutations lead to persistent hyperinsulinemic hypoglycemia of infancy (PHHI), the severity of which scales with the level of GCK activation (31). PHHI-associated activating mutations are of particular interest in understanding the basis of cooperativity, because the disease state appears to result from a reduction in the enzyme's cooperativity and a decrease in the glucose K 0.5 value (32-34).…”

mentioning

confidence: 99%

Dual allosteric activation mechanisms in monomeric human glucokinase

Whittington

Larion

Bowler

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Cooperativity in human glucokinase (GCK), the body's primary glucose sensor and a major determinant of glucose homeostatic diseases, is fundamentally different from textbook models of allostery because GCK is monomeric and contains only one glucosebinding site. Prior work has demonstrated that millisecond timescale order-disorder transitions within the enzyme's small domain govern cooperativity. Here, using limited proteolysis, we map the site of disorder in unliganded GCK to a 30-residue active-site loop that closes upon glucose binding. Positional randomization of the loop, coupled with genetic selection in a glucokinase-deficient bacterium, uncovers a hyperactive GCK variant with substantially reduced cooperativity. Biochemical and structural analysis of this loop variant and GCK variants associated with hyperinsulinemic hypoglycemia reveal two distinct mechanisms of enzyme activation. In α-type activation, glucose affinity is increased, the proteolytic susceptibility of the active site loop is suppressed and the 1 H-13 C heteronuclear multiple quantum coherence (HMQC) spectrum of 13 C-Ile-labeled enzyme resembles the glucose-bound state. In β-type activation, glucose affinity is largely unchanged, proteolytic susceptibility of the loop is enhanced, and the 1 H-13 C HMQC spectrum reveals no perturbation in ensemble structure. Leveraging both activation mechanisms, we engineer a fully noncooperative GCK variant, whose functional properties are indistinguishable from other hexokinase isozymes, and which displays a 100-fold increase in catalytic efficiency over wild-type GCK. This work elucidates specific structural features responsible for generating allostery in a monomeric enzyme and suggests a general strategy for engineering cooperativity into proteins that lack the structural framework typical of traditional allosteric systems.lucidating the molecular origins of allosteric regulation of protein function remains a primary goal of biochemistry, despite nearly a half-century of intense investigation (1). Early classical theories, such as the Monod-Wyman-Changeux (2) and Koshland-Nemethy-Filmer (3) models, have found utility in describing allosteric transitions (4, 5), but they are phenomenological in nature and lack a quantitative, predictive description of the underlying mechanism (6). Traditional models tend to describe allostery in terms of structural transitions between two discrete end states that are often viewed through the lens of static crystal structures. Recent focus on the role of dynamics (7,8) and intrinsic disorder in protein structures (9-11) demonstrates that classic models are far from general (12)(13)(14)(15)(16)(17)(18)(19). The ensemble allosteric model (6, 20) and the allosteric two-state model (21) reflect attempts to account for the role of dynamics and disorder in allosteric regulation. Identifying the full suite of structural and dynamic contributors to cooperativity promises to facilitate the discovery and understanding of new allosteric mechanisms that have precluded explanation to...

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Heterogeneity in disease severity in a family with a novel G68V GCK activating mutation causing persistent hyperinsulinaemic hypoglycaemia of infancy

Abstract: The novel activating GCK mutation G68V is associated with variable phenotypic severity, supporting modification of GSIR by genetic and/or environmental factors.

Cited by 59 publications

References 23 publications

Large Islets, Beta-Cell Proliferation, and a Glucokinase Mutation

Large Islets, Beta-Cell Proliferation, and a Glucokinase Mutation

Diagnostic Difficulties in Glucokinase Hyperinsulinism

Dual allosteric activation mechanisms in monomeric human glucokinase

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