Published online Feb 15, 2024. doi: 10.4239/wjd.v15.i2.275
Peer-review started: October 2, 2023
First decision: November 9, 2023
Revised: November 22, 2023
Accepted: January 9, 2024
Article in press: January 9, 2024
Published online: February 15, 2024
Processing time: 124 Days and 19.2 Hours
Mutations in the adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1 (APPL1) gene have been associated with the development of maturity-onset diabetes of the young type 14 (MODY14), a rare form of monogenic diabetes. So far, only two mutations [c.1655T>A (p.Leu552*) and c.281G>A p.(Asp94Asn)] have been found to be related to this disease. Due to the limited knowledge of MODY14, it is necessary to identify more cases and conduct a comprehensive study of MODY14 and APPL1 mutations. In this study, we discovered five new APPL1 gene mutations by whole exome sequencing (WES) and bioinformatics analysis, of which two were confirmed to be pathogenic mutations by in vitro functional assays. These mutations were all located in the phosphotyrosine binding (PTB) domain of APPL1, which has a significant impact on insulin sensitivity.
This study aimed to identify the pathogenicity and functional role of APPL1 gene mutations in diabetes. It mainly identified and evaluated the pathogenicity of APPL1 gene mutations and explored the effects of these mutations on APPL1 protein expression and insulin signaling pathway. This will provide potential targets for the diagnosis and treatment of MODY14 and will provide new clues for the interaction mechanism of the APPL1 protein and insulin receptor.
The main objective of this study was to evaluate the pathogenicity of APPL1 gene mutations in diabetic patient and to characterize the functional role of APPL1 domains. By WES and bioinformatics analysis, five novel APPL1 gene mutations were identified, among which c.1894G>T (at Asp632Tyr) and c.1595G>A (at Arg532Gln) were confirmed as pathogenic mutations by in vitro functional experiments.
This study used WES to sequence all the exons in the genome that encode proteins, thus discovering variants associated with diseases. Then, bioinformatics analysis was used to align and predict the sequencing results, thus evaluating the pathogenicity and conservation of the variants. The pathogenicity was further verified by in vitro functional experiments.
Our study identified five novel APPL1 gene mutations, among which c.1894G>T (at Asp632Tyr) and c.1595G>A (at Arg532Gln) were confirmed as pathogenic mutations by in vitro functional experiments. Both mutations are located in the PTB domain of APPL1, which has an important impact on insulin sensitivity. The results showed that the mutations can reduce the expression level of APPL1 protein, thus affecting the activation of the insulin signaling pathway and the regulation of glucose metabolism.
APPL1 gene mutations c.1894G>T (at Asp632Tyr) and c.1595G>A (at Arg532Gln) are pathogenic in diabetes, and these mutations are located in the PTB domain of APPL1, which has an important impact on insulin sensitivity.
In the future, the structure and function of APPL1 protein can be further studied, especially the mechanism of action of the PTB domain and the binding mode and regulatory effect of APPL1 protein with the insulin receptor. In addition, the effect of APPL1 gene mutations on the clinical manifestations and treatment response of diabetic patients can be verified. More effective methods and criteria for the diagnosis and treatment of MODY14 can be provided.