An activating mutation of AKT2 and human hypoglycemia - PubMed (original) (raw)

. 2011 Oct 28;334(6055):474.

doi: 10.1126/science.1210878. Epub 2011 Oct 6.

B Challis, N Rocha, F Payne, M Minic, A Thompson, A Daly, C Scott, J Harris, B J L Smillie, D B Savage, U Ramaswami, P De Lonlay, S O'Rahilly, I Barroso, R K Semple

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An activating mutation of AKT2 and human hypoglycemia

K Hussain et al. Science. 2011.

Abstract

Pathological fasting hypoglycemia in humans is usually explained by excessive circulating insulin or insulin-like molecules or by inborn errors of metabolism impairing liver glucose production. We studied three unrelated children with unexplained, recurrent, and severe fasting hypoglycemia and asymmetrical growth. All were found to carry the same de novo mutation, p.Glu17Lys, in the serine/threonine kinase AKT2, in two cases as heterozygotes and in one case in mosaic form. In heterologous cells, the mutant AKT2 was constitutively recruited to the plasma membrane, leading to insulin-independent activation of downstream signaling. Thus, systemic metabolic disease can result from constitutive, cell-autonomous activation of signaling pathways normally controlled by insulin.

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Figure 1

Figure 1. Identification of a de novo activating AKT2 mutation

(A) Patient 1 showing increased left leg size, increased left truncal adipose tissue, and surgical feeding tube (B) c.49G>A/p.Glu17Lys mutation in the AKT2 gene seen in either heterozygous or mosaic form. (C) Pedigrees of affected patients, showing de novo occurrence of the mutation in each case. (D) Domain structure of AKT2, showing location of Glu17 in the pleckstrin homology domain and the location of residues phosphorylated by PDK1 and mTORC2 during activation. (E) Plasma membrane recruitment of hemagglutinin-tagged AKT2 p.Glu17Lys but not wild type in serum starved HeLa cells treated with either phosphate buffered saline (PBS) or 100 nmol/l insulin. Nuclei are stained with DAPI. Scale bars = 20μm

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