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

Am J Hum Genet. 2015 Jul 2;97(1):177-85. doi: 10.1016/j.ajhg.2015.05.011.

Sabrina Prudente ¹, Prapaporn Jungtrakoon ², Antonella Marucci ³, Ornella Ludovico ³, Patinut Buranasupkajorn ², Tommaso Mazza ⁴, Timothy Hastings ⁵, Teresa Milano ⁶, Eleonora Morini ³, Luana Mercuri ⁴, Diego Bailetti ⁷, Christine Mendonca ⁵, Federica Alberico ⁴, Giorgio Basile ⁷, Marta Romani ⁴, Elide Miccinilli ⁴, Antonio Pizzuti ⁷, Massimo Carella ⁸, Fabrizio Barbetti ⁹, Stefano Pascarella ⁶, Piero Marchetti ¹⁰, Vincenzo Trischitta ¹¹, Rosa Di Paola ³, Alessandro Doria ¹²

Affiliations

1 Mendel Laboratory, IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy. Electronic address: s.prudente@css-mendel.it.
2 Research Division, Joslin Diabetes Center, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
3 Research Unit of Diabetes and Endocrine Diseases, IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy.
4 Mendel Laboratory, IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy.
5 Research Division, Joslin Diabetes Center, Boston, MA 02215, USA.
6 Department of Biochemical Sciences, Sapienza University, 00185 Rome, Italy.
7 Mendel Laboratory, IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy; Department of Experimental Medicine, Sapienza University, 00161 Rome, Italy.
8 Unit of Medical Genetics, IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy.
9 Laboratory of Mendelian Diabetes, Bambino Gesù Childrens' Hospital, 00165 Rome, Italy; Department of Experimental Medicine and Surgery, University of Tor Vergata, 00133 Rome, Italy.
10 Department of Clinical and Experimental Medicine, University of Pisa, 56127 Pisa, Italy.
11 Mendel Laboratory, IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy; Research Unit of Diabetes and Endocrine Diseases, IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy; Department of Experimental Medicine, Sapienza University, 00161 Rome, Italy.
12 Research Division, Joslin Diabetes Center, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. Electronic address: alessandro.doria@joslin.harvard.edu.

PMID: 26073777 DOI: 10.1016/j.ajhg.2015.05.011

Abstract

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.

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