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.

Insulin Signaling Regulates the FoxM1/PLK1/CENP-A Pathway to Promote Adaptive Pancreatic β Cell Proliferation

“…These observations are consistent with the notion that reduced CENP-A expression is associated with lower β-cell mass when IRS-2 or PI3K protein expression are attenuated in islets from patients with type 2 diabetes (Folli et al, 2011; Gunton et al, 2005). A potential link to human diabetes was the identification of a missense variant of the PLK1 gene (c.A1216T, p.I406F, rs565735478) in one of 52 Joslin families with autosomal dominant diabetes that underwent whole-exome sequencing (a description of this study is provided in (Prudente et al, 2015)). This variant, having an allele frequency of 0.1% among Europeans in the 1000 Genome database, is conserved among species (GREP score=5.2, Figure S3C) and is predicted to be “disease causing” by MutationTester (with 0.99 probability) as well as other prediction softwares.…”

Incremental cost-effectiveness of algorithm-driven genetic testing versus no testing for Maturity Onset Diabetes of the Young (MODY) in Singapore

“…The 14th MODY gene APPL1 was not included in this panel as it was discovered only after this panel and study was designed 18. Those who tested negative for all 16 genes were classified as having T2D and continued their pre-existing medications in the same ratio as per usual treatment.…”

Unexpected finding of a whole HNF1B gene deletion during the screening of rare MODY types in a series of Brazilian patients negative for GCK and HNF1A mutations

“…More common forms such as GCK, HNF1A, and HNF4A comprise the majority of MODY cases [1][2][3][4][5][6][7][8][9]. Genetic testing for MODY has become a challenge, especially for rarer subtypes and for the completeness of mutation screening using traditional methods, either Sanger sequencing or multiplex ligation-dependent probe amplification (MLPA) [10].…”