A severe case of hyperinsulinism due to hemizygous activating mutation of glutamate dehydrogenase.
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 IC50for 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.
Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
Mary
M
Barrosse-Antle
Endocrinology Genetics and Metabolism Department, Beijing Children's Hospital, Capital Medical University, Beijing, China.
Chang
C
Su
Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
Pan
P
Chen
Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
Kara E
KE
Boodhansingh
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch at Galveston, Galveston, Texas.
Thomas J
TJ
Smith
Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.|Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
Charles A
CA
Stanley
Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.|Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
Diva D
DD
De León
Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.|Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
Changhong
http://orcid.org/0000-0003-0513-1459
C
Li
D044903:Congenital Hyperinsulinism / Q000235:genetics*; D005260:Female; D005969:Glutamate Dehydrogenase / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D007231:Infant, Newborn; D040582:Inheritance Patterns; D009154:Mutation
D005969:Glutamate Dehydrogenase; C561840:GLUD1 protein, human
glutamate dehydrogenase; hyperinsulinism; hypoglycemia