An activating mutation of AKT2 and human hypoglycemia

Area of Science:

• Genetics
• Molecular Biology
• Pediatric Endocrinology

Background:

• Pathological fasting hypoglycemia is typically caused by excess insulin or metabolic disorders affecting glucose production.
• Unexplained recurrent severe hypoglycemia and asymmetrical growth in children prompted further investigation.

Purpose of the Study:

• To investigate the genetic basis of unexplained fasting hypoglycemia in three unrelated children with asymmetrical growth.
• To elucidate the molecular mechanism underlying the observed metabolic and growth abnormalities.

Main Methods:

• Genetic analysis to identify mutations in the AKT2 gene.
• Functional studies in heterologous cells to assess the impact of the identified mutation on AKT2 signaling.
• Clinical evaluation of affected children, including assessment of hypoglycemia and growth patterns.

Main Results:

• All three children shared a de novo mutation, p.Glu17Lys, in the serine/threonine kinase AKT2 gene.
• The mutant AKT2 protein showed constitutive recruitment to the plasma membrane, leading to insulin-independent downstream signaling.
• This molecular defect explains the observed severe fasting hypoglycemia and asymmetrical growth.

Conclusions:

• Constitutive, cell-autonomous activation of signaling pathways, as seen with the AKT2 mutation, can cause systemic metabolic disease.
• The findings expand the understanding of genetic causes for pathological fasting hypoglycemia.
• This study highlights the role of AKT2 signaling in glucose homeostasis and growth regulation.