9.14 MODY14 Maturity onset diabetes of the young, type XIV

Two loss-of-function mutations p.Leu552* and p.Asp94Asn were found in APPL1 that were identified by means of whole-exome sequencing in two large families with a high prevalence of diabetes not due to mutations in known genes involved in maturity onset diabetes of the young (MODY). APPL1 binds to AKT2, a key molecule in the insulin signaling pathway, thereby enhancing insulin-induced AKT2 activation and downstream signaling leading to insulin action and secretion. The p.Leu552* alteration totally abolishes APPL1 protein expression in HepG2 transfected cells and the p.Asp94Asn alteration causes significant reduction in the enhancement of the insulin-stimulated AKT2 and GSK3beta phosphorylation that is observed after wild-type APPL1 transfection (PMID:26073777).

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