Defining the Phenotype and Assessing Severity in Phosphoglucomutase-1 Deficiency

Wong, Sunnie; Beamer, Lesa J.; Gadomski, Therese; Honzík, Tomáš; Mohamed, Miski; Wortmann, Saskia B.; Holmefjord, Katja S. Brocke; Mork, Marit; Bowling, Francis; Sykut-Cegielska, Jolanta; Koch, Dominik; Ackermann, Amanda M.; Stanley, Charles A.; Rymen, Daisy; Zeharia, Avraham; Al-Sayed, Moeen; Marquardt, Thomas P.; Jaeken, Jaak; Lefeber, Dirk; Conrad, Donald F.; Kozicz, Tamás; Morava, Éva

doi:10.1016/j.jpeds.2016.04.021

Cited by 45 publications

(109 citation statements)

References 34 publications

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“…2A) imply that mutations in these regions could be disproportionately disruptive to enzyme function. Moreover, in addition to the 13 originally characterized [11], several new missense mutants of PGM1 associated with disease have recently been identified [6]. These include G230E, T337M, P336R, R422W, R503Q, and R515L (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In addition to G121R and G291R, these interdomain mutations include many previously categorized as deleterious to catalysis (D62H, T115A, G121R, G230E, D263G/Y, G291R, T337M, and R503Q) [6,11]. However, several also appear to cause folding problems (P336R, E377K, E388K, and R422W) [6,11].…”

Section: Resultsmentioning

confidence: 99%

“…However, several also appear to cause folding problems (P336R, E377K, E388K, and R422W) [6,11]. This suggests that a gradation of effects can occur due to substitutions at this interdomain interface, with the functional outcome dependent on factors such as the physicochemical change of the mutation and the structural interactions of the WT residue.…”

Section: Resultsmentioning

confidence: 99%

“…5) with distinct functional roles, perhaps in protein folding. Mutants affecting residue 38 and 41 also tend to have milder clinical phenotypes than those affecting the interface residues [6], although the heterozygous backgrounds and limited number of patients prohibits a definitive analysis.…”

Section: Resultsmentioning

confidence: 99%

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Induced Structural Disorder as a Molecular Mechanism for Enzyme Dysfunction in Phosphoglucomutase 1 Deficiency

Stiers

Kain

Graham

et al. 2016

Journal of Molecular Biology

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Human phosphoglucomutase 1 (PGM1) plays a central role in cellular glucose homeostasis, mediating the switch between glycolysis and gluconeogenesis through the conversion of glucose 1-phosphate and glucose 6-phosphate. Recent clinical studies have identified mutations in this enzyme as the cause of PGM1 deficiency, an inborn error of metabolism classified as both a glycogen storage disease and a congenital disorder of glycosylation. Reported here are the first crystal structures of two disease-related missense variants of PGM1, along with the structure of the wild-type enzyme. Two independent glycine to arginine substitutions (G121R and G291R), both affecting key active site loops of PGM1, are found to induce regions of structural disorder, as evidenced by a nearly complete loss of electron density for as many as 23 amino acids. The disordered regions are not contiguous in sequence to the site of mutation, and even cross domain boundaries. Other structural rearrangements include changes in the conformations of loops and side chains, some of which occur nearly 20 Å away from the site of mutation. The induced structural disorder is correlated with increased sensitivity to proteolysis and lower resolution diffraction, particularly for the G291R variant. Examination of the multi-domain effects of these G→R mutations establishes a correlation between interdomain interfaces of the enzyme and missense variants of PGM1 associated with disease. These crystal structures provide the first insights into the structural basis of enzyme dysfunction in PGM1 deficiency, and highlight a growing role for biophysical characterization of proteins in the field of precision medicine.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 2 more Smart Citations

Induced Structural Disorder as a Molecular Mechanism for Enzyme Dysfunction in Phosphoglucomutase 1 Deficiency

Stiers

Kain

Graham

et al. 2016

Journal of Molecular Biology

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“…Hypoglycemia is a common clinical feature in patients with inactivating mutations of PGM1, as exaggerated insulin secretion after glucose challenges often results in postprandial hypoglycemia. 80,81 The clinical studies of UCP2-and PGM1-associated CHI highlight the complexity of fuel sensing and insulin secretion regulation.…”

Section: Other Forms Of Chi Alter Glucose Sensingmentioning

confidence: 99%

Nutrient sensing in pancreatic islets: lessons from congenital hyperinsulinism and monogenic diabetes

Lü

2017

Annals of the New York Academy of Sciences

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Pancreatic beta cells sense changes in nutrients during the cycles of fasting and feeding and release insulin accordingly to maintain glucose homeostasis. Abnormal beta cell nutrient sensing resulting from gene mutations leads to hypoglycemia or diabetes. Glucokinase (GCK) plays a key role in beta cell glucose sensing. As one form of congenital hyperinsulinism (CHI), activating mutations of GCK result in a decreased threshold for glucose-stimulated insulin secretion and hypoglycemia. In contrast, inactivating mutations of GCK result in diabetes, including a mild form (MODY2) and a severe form (permanent neonatal diabetes mellitus (PNDM)). Mutations of beta cell ion channels involved in insulin secretion regulation also alter glucose sensing. Activating or inactivating mutations of ATPdependent potassium (K ATP ) channel genes result in severe but completely opposite clinical phenotypes, including PNDM and CHI. Mutations of the other ion channels, including voltage-gated potassium channels (K v 7.1) and voltage-gated calcium channels, also lead to abnormal glucose sensing and CHI. Furthermore, amino acids can stimulate insulin secretion in a glucose-independent manner in some forms of CHI, including activating mutations of the glutamate dehydrogenase gene, HDAH deficiency, and inactivating mutations of K ATP channel genes. These genetic defects have provided insight into a better understanding of the complicated nature of beta cell fuel-sensing mechanisms.

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Congenital hyperinsulinism disorders: Genetic and clinical characteristics

Rosenfeld

Ganguly

León

2019

American J of Med Genetics Pt C

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Congenital hyperinsulinism (HI) is the most frequent cause of persistent hypoglycemia in infants and children. Delays in diagnosis and initiation of appropriate treatment contribute to a high risk of neurocognitive impairment. HI represents a heterogeneous group of disorders characterized by dysregulated insulin secretion by the pancreatic beta cells, which in utero, may result in somatic overgrowth. There are at least nine known monogenic forms of HI as well as several syndromic forms. Molecular diagnosis allows for prediction of responsiveness to medical treatment and likelihood of surgically‐curable focal hyperinsulinism. Timely genetic mutation analysis has thus become standard of care. However, despite significant advances in our understanding of the molecular basis of this disorder, the number of patients without an identified genetic diagnosis remains high, suggesting that there are likely additional genetic loci that have yet to be discovered.

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Defining the Phenotype and Assessing Severity in Phosphoglucomutase-1 Deficiency

Cited by 45 publications

References 34 publications

Induced Structural Disorder as a Molecular Mechanism for Enzyme Dysfunction in Phosphoglucomutase 1 Deficiency

Induced Structural Disorder as a Molecular Mechanism for Enzyme Dysfunction in Phosphoglucomutase 1 Deficiency

Nutrient sensing in pancreatic islets: lessons from congenital hyperinsulinism and monogenic diabetes

Congenital hyperinsulinism disorders: Genetic and clinical characteristics

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