title: An activating mutation of AKT2 and human hypoglycemia.
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.
authors: Clinical and Molecular Genetics Unit, Developmental Endocrinology Research Group, Institute of Child Health, University College London, London WC1N 1EH, UK.
authors: K
authors: K
authors: Hussain
authors: B
authors: B
authors: Challis
authors: N
authors: N
authors: Rocha
authors: F
authors: F
authors: Payne
authors: M
authors: M
authors: Minic
authors: A
authors: A
authors: Thompson
authors: A
authors: A
authors: Daly
authors: C
authors: C
authors: Scott
authors: J
authors: J
authors: Harris
authors: B J L
authors: BJ
authors: Smillie
authors: D B
authors: DB
authors: Savage
authors: U
authors: U
authors: Ramaswami
authors: P
authors: P
authors: De Lonlay
authors: S
authors: S
authors: O'Rahilly
authors: I
authors: I
authors: Barroso
authors: R K
authors: RK
authors: Semple
mesh_terms: D019943:Amino Acid Substitution; D002462:Cell Membrane / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002648:Child; D005260:Female; D006128:Growth; D006367:HeLa Cells; D006579:Heterozygote; D006801:Humans; D007003:Hypoglycemia / Q000235:genetics* / Q000378:metabolism*; D007328:Insulin / Q000097:blood / Q000378:metabolism; D008297:Male; D009030:Mosaicism; D009154:Mutation; D010375:Pedigree; D054730:Protein Interaction Domains and Motifs; D051057:Proto-Oncogene Proteins c-akt / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D007328:Insulin; C494921:AKT2 protein, human; D051057:Proto-Oncogene Proteins c-akt