Loss-of-Function Mutations in APPL1 in Familial Diabetes Mellitus

Sabrina Prudente, Prapaporn Jungtrakoon, Antonella Marucci, Ornella Ludovico, Patinut Buranasupkajorn, Tommaso Mazza, Timothy Hastings, Teresa Milano, Eleonora Morini, Luana Mercuri, Diego Bailetti, Christine Mendonca, Federica Alberico, Giorgio Basile, Marta Romani, Elide Miccinilli, Antonio Pizzuti, Massimo Carella, Fabrizio Barbetti, Stefano PascarellaPiero Marchetti, Vincenzo Trischitta, Rosa Di Paola, Alessandro Doria

Research output: Contribution to journalArticlepeer-review


Diabetes mellitus is a highly heterogeneous disorder encompassing several distinct forms with different clinical manifestations including a wide spectrum of age at onset. Despite many advances, the causal genetic defect remains unknown for many subtypes of the disease, including some of those forms with an apparent Mendelian mode of inheritance. Here we report two loss-of-function mutations (c.1655T>A [p.Leu552] and c.280G>A [p.Asp94Asn]) in the gene for the Adaptor Protein, Phosphotyrosine Interaction, PH domain, and leucine zipper containing 1 (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. Both mutations cause APPL1 loss of function. 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 GSK3β phosphorylation that is observed after wild-type APPL1 transfection. These findings - linking APPL1 mutations to familial forms of diabetes - reaffirm the critical role of APPL1 in glucose homeostasis.

Original languageEnglish
Pages (from-to)177-185
Number of pages9
JournalAmerican Journal of Human Genetics
Issue number1
Publication statusPublished - 2015

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Medicine(all)


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