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 Pascarella & 4 others Piero Marchetti, Vincenzo Trischitta, Rosa Di Paola, Alessandro Doria

Research output: Contribution to journalArticle

46 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)177-185
Number of pages9
JournalAmerican Journal of Human Genetics
Volume97
Issue number1
DOIs
Publication statusPublished - 2015

Fingerprint

Diabetes Mellitus
Insulin
Mutation
Exome
Leucine Zippers
Phosphotyrosine
Hep G2 Cells
Age of Onset
Transfection
Proteins
Homeostasis
Phosphorylation
Glucose
Genes

ASJC Scopus subject areas

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

Cite this

Loss-of-Function Mutations in APPL1 in Familial Diabetes Mellitus. / Prudente, Sabrina; Jungtrakoon, Prapaporn; Marucci, Antonella; Ludovico, Ornella; Buranasupkajorn, Patinut; Mazza, Tommaso; Hastings, Timothy; Milano, Teresa; Morini, Eleonora; Mercuri, Luana; Bailetti, Diego; Mendonca, Christine; Alberico, Federica; Basile, Giorgio; Romani, Marta; Miccinilli, Elide; Pizzuti, Antonio; Carella, Massimo; Barbetti, Fabrizio; Pascarella, Stefano; Marchetti, Piero; Trischitta, Vincenzo; Di Paola, Rosa; Doria, Alessandro.

In: American Journal of Human Genetics, Vol. 97, No. 1, 2015, p. 177-185.

Research output: Contribution to journalArticle

Prudente, S, Jungtrakoon, P, Marucci, A, Ludovico, O, Buranasupkajorn, P, Mazza, T, Hastings, T, Milano, T, Morini, E, Mercuri, L, Bailetti, D, Mendonca, C, Alberico, F, Basile, G, Romani, M, Miccinilli, E, Pizzuti, A, Carella, M, Barbetti, F, Pascarella, S, Marchetti, P, Trischitta, V, Di Paola, R & Doria, A 2015, 'Loss-of-Function Mutations in APPL1 in Familial Diabetes Mellitus', American Journal of Human Genetics, vol. 97, no. 1, pp. 177-185. https://doi.org/10.1016/j.ajhg.2015.05.011
Prudente, Sabrina ; Jungtrakoon, Prapaporn ; Marucci, Antonella ; Ludovico, Ornella ; Buranasupkajorn, Patinut ; Mazza, Tommaso ; Hastings, Timothy ; Milano, Teresa ; Morini, Eleonora ; Mercuri, Luana ; Bailetti, Diego ; Mendonca, Christine ; Alberico, Federica ; Basile, Giorgio ; Romani, Marta ; Miccinilli, Elide ; Pizzuti, Antonio ; Carella, Massimo ; Barbetti, Fabrizio ; Pascarella, Stefano ; Marchetti, Piero ; Trischitta, Vincenzo ; Di Paola, Rosa ; Doria, Alessandro. / Loss-of-Function Mutations in APPL1 in Familial Diabetes Mellitus. In: American Journal of Human Genetics. 2015 ; Vol. 97, No. 1. pp. 177-185.
@article{0adc0f401714413ab986b8162c60bc1b,
title = "Loss-of-Function Mutations in APPL1 in Familial Diabetes Mellitus",
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.",
author = "Sabrina Prudente and Prapaporn Jungtrakoon and Antonella Marucci and Ornella Ludovico and Patinut Buranasupkajorn and Tommaso Mazza and Timothy Hastings and Teresa Milano and Eleonora Morini and Luana Mercuri and Diego Bailetti and Christine Mendonca and Federica Alberico and Giorgio Basile and Marta Romani and Elide Miccinilli and Antonio Pizzuti and Massimo Carella and Fabrizio Barbetti and Stefano Pascarella and Piero Marchetti and Vincenzo Trischitta and {Di Paola}, Rosa and Alessandro Doria",
year = "2015",
doi = "10.1016/j.ajhg.2015.05.011",
language = "English",
volume = "97",
pages = "177--185",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "1",

}

TY - JOUR

T1 - Loss-of-Function Mutations in APPL1 in Familial Diabetes Mellitus

AU - Prudente, Sabrina

AU - Jungtrakoon, Prapaporn

AU - Marucci, Antonella

AU - Ludovico, Ornella

AU - Buranasupkajorn, Patinut

AU - Mazza, Tommaso

AU - Hastings, Timothy

AU - Milano, Teresa

AU - Morini, Eleonora

AU - Mercuri, Luana

AU - Bailetti, Diego

AU - Mendonca, Christine

AU - Alberico, Federica

AU - Basile, Giorgio

AU - Romani, Marta

AU - Miccinilli, Elide

AU - Pizzuti, Antonio

AU - Carella, Massimo

AU - Barbetti, Fabrizio

AU - Pascarella, Stefano

AU - Marchetti, Piero

AU - Trischitta, Vincenzo

AU - Di Paola, Rosa

AU - Doria, Alessandro

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84937522764&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84937522764&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2015.05.011

DO - 10.1016/j.ajhg.2015.05.011

M3 - Article

VL - 97

SP - 177

EP - 185

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 1

ER -