Clinical and Molecular Genetics Unit, Developmental Endocrinology Research Group, Institute of Child Health, University College London, London WC1N 1EH, UK.
Science. 2011 Oct 28;334(6055):474. doi: 10.1126/science.1210878. Epub 2011 Oct 6.
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.
人类病理性空腹低血糖症通常由循环胰岛素或胰岛素样分子过多，或由先天代谢缺陷导致肝脏葡萄糖生成受损引起。我们研究了三个无明显原因、反复发作且严重的空腹低血糖症和非对称性生长的无关儿童。所有患者均携带丝氨酸/苏氨酸激酶 AKT2 的相同新生突变 p.Glu17Lys，两例为杂合子，一例为嵌合体。在异源细胞中，突变型 AKT2 被持续募集到质膜，导致下游信号的胰岛素非依赖性激活。因此，全身性代谢疾病可能源于通常受胰岛素调控的信号通路的组成性、细胞自主性激活。
