A severe case of hyperinsulinism due to hemizygous activating mutation of glutamate dehydrogenase

Mary Barrosse-Antle, Chang Su, Pan Chen, Kara E. Boodhansingh, Thomas Smith, Charles A. Stanley, Diva D. De León, Changhong Li

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Activating mutations in the GLUD1 gene, which encodes glutamate dehydrogenase (GDH), result in the hyperinsulinism-hyperammonemia syndrome. GDH is an allosterically regulated enzyme responsible for amino acid-mediated insulin secretion via the oxidative deamination of glutamate to 2-oxoglutarate, leading to ATP production and insulin release. This study characterizes a novel combination of mutations in GLUD1 found in a neonate who presented on the first day of life with severe hypoglycemia, hyperammonemia, and seizures. Mutation analysis revealed a novel frameshift mutation (c.37delC) inherited from the asymptomatic mother that results in a truncated protein and a de novo activating mutation (p.S445L) close to the GTP binding site that has previously been reported. GTP inhibition of GDH enzyme activity in 293T cells expressing the p.S445L or wild-type GDH showed that the half-maximal inhibitory concentration (IC50) for GTP was approximately 800 times higher for p.S445L compared to wild type. GTP inhibition of GDH activity in lymphoblasts from the patient, from a heterozygote for the p.S445L mutation, and in wild-type lymphoblasts showed that the IC50 for GTP of the patient was approximately 200 times that of wild type and 7 times that of heterozygote. However, while the patient had a loss of GTP inhibition of GDH that was more severe than that of heterozygotes, the patient's clinical phenotype is similar to typical heterozygous mutations of GDH. This is the first time we have observed a functionally homozygous activating mutation of GDH in a human.

Original languageEnglish (US)
JournalPediatric Diabetes
DOIs
StateAccepted/In press - 2017

Fingerprint

Glutamate Dehydrogenase
Hyperinsulinism
Guanosine Triphosphate
Mutation
Heterozygote
Inhibitory Concentration 50
Insulin
Hyperammonemia
Deamination
Frameshift Mutation
HEK293 Cells
Enzymes
Hypoglycemia
Glutamic Acid
Seizures
Adenosine Triphosphate
Binding Sites
Mothers
Newborn Infant
Phenotype

Keywords

  • Glutamate dehydrogenase
  • Hyperinsulinism
  • Hypoglycemia

ASJC Scopus subject areas

  • Internal Medicine
  • Pediatrics, Perinatology, and Child Health
  • Endocrinology, Diabetes and Metabolism

Cite this

Barrosse-Antle, M., Su, C., Chen, P., Boodhansingh, K. E., Smith, T., Stanley, C. A., ... Li, C. (Accepted/In press). A severe case of hyperinsulinism due to hemizygous activating mutation of glutamate dehydrogenase. Pediatric Diabetes. https://doi.org/10.1111/pedi.12507

A severe case of hyperinsulinism due to hemizygous activating mutation of glutamate dehydrogenase. / Barrosse-Antle, Mary; Su, Chang; Chen, Pan; Boodhansingh, Kara E.; Smith, Thomas; Stanley, Charles A.; De León, Diva D.; Li, Changhong.

In: Pediatric Diabetes, 2017.

Research output: Contribution to journalArticle

Barrosse-Antle, Mary ; Su, Chang ; Chen, Pan ; Boodhansingh, Kara E. ; Smith, Thomas ; Stanley, Charles A. ; De León, Diva D. ; Li, Changhong. / A severe case of hyperinsulinism due to hemizygous activating mutation of glutamate dehydrogenase. In: Pediatric Diabetes. 2017.
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