PIK3R1 mutations in individuals with insulin resistance or growth retardation: Case series and in silico functional analysis
ABSTRACT Aims/Introduction Phosphatidylinositol 3‐kinase (PI3K) plays a key role in insulin signaling, and mutations in PIK3R1, which encodes a regulatory subunit (p85α) of this enzyme, are responsible for SHORT syndrome, which is associated with insulin‐resistant diabetes. We here describe four Jap...
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Wiley
2025-08-01
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| Series: | Journal of Diabetes Investigation |
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| Online Access: | https://doi.org/10.1111/jdi.70062 |
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| author | Tomofumi Takayoshi Yushi Hirota Aki Sugano Kenji Sugawara Takehito Takeuchi Mika Ohta Kai Yoshimura Seiji Nishikage Akane Yamamoto Yu Mimura Shinji Higuchi Jun Mori Rie Kawakita Tohru Yorifuji Yutaka Takaoka Wataru Ogawa |
| author_facet | Tomofumi Takayoshi Yushi Hirota Aki Sugano Kenji Sugawara Takehito Takeuchi Mika Ohta Kai Yoshimura Seiji Nishikage Akane Yamamoto Yu Mimura Shinji Higuchi Jun Mori Rie Kawakita Tohru Yorifuji Yutaka Takaoka Wataru Ogawa |
| author_sort | Tomofumi Takayoshi |
| collection | DOAJ |
| description | ABSTRACT Aims/Introduction Phosphatidylinositol 3‐kinase (PI3K) plays a key role in insulin signaling, and mutations in PIK3R1, which encodes a regulatory subunit (p85α) of this enzyme, are responsible for SHORT syndrome, which is associated with insulin‐resistant diabetes. We here describe four Japanese individuals from three families with SHORT syndrome who harbor either a common or a previously unknown mutation in PIK3R1 as well as provide an in silico functional analysis of the mutant proteins. Materials and Methods Gene sequencing was performed to identify PIK3R1 mutations. 3D structural analysis of wild‐type and mutant p85α proteins was performed by homology modeling, and structural optimization and molecular dynamics simulations confirmed stable trajectories. Docking simulations of p85α with a phosphopeptide were also conducted. Results We identified two families with a common mutation (c.1945C>T, p.R649W) and one family with a previously unidentified mutation (c.1957A>T, p.K653*) of PIK3R1. In silico modeling revealed that both mutations impaired binding of p85α to phosphopeptide, with K653* resulting in the loss of amino acids that contribute to such binding. Docking simulations showed a significant loss of docking energy for the R649W mutant compared with the wild‐type protein (P = 0.00329). Conclusions The four cases of SHORT syndrome were associated with early‐onset diabetes and intrauterine growth retardation, with the identified mutations likely disrupting the binding of p85α to phosphopeptide and thereby impairing insulin signaling. One case uniquely manifested diabetes without insulin resistance, emphasizing the need for further study of the clinical variability of SHORT syndrome, especially with regard to its associated diabetes. |
| format | Article |
| id | doaj-art-aae865ec24f541d197cda3de80c69f5f |
| institution | Matheson Library |
| issn | 2040-1116 2040-1124 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Diabetes Investigation |
| spelling | doaj-art-aae865ec24f541d197cda3de80c69f5f2025-08-01T12:51:37ZengWileyJournal of Diabetes Investigation2040-11162040-11242025-08-011681526153410.1111/jdi.70062PIK3R1 mutations in individuals with insulin resistance or growth retardation: Case series and in silico functional analysisTomofumi Takayoshi0Yushi Hirota1Aki Sugano2Kenji Sugawara3Takehito Takeuchi4Mika Ohta5Kai Yoshimura6Seiji Nishikage7Akane Yamamoto8Yu Mimura9Shinji Higuchi10Jun Mori11Rie Kawakita12Tohru Yorifuji13Yutaka Takaoka14Wataru Ogawa15Division of Diabetes and Endocrinology, Department of Internal Medicine Kobe University Graduate School of Medicine Kobe JapanDivision of Diabetes and Endocrinology, Department of Internal Medicine Kobe University Graduate School of Medicine Kobe JapanLaboratory of Pharma‐Medical Informatics and AI, Graduate School of Medicine and Pharmaceutical Sciences University of Toyama Toyama JapanDivision of Diabetes and Endocrinology, Department of Internal Medicine Kobe University Graduate School of Medicine Kobe JapanDivision of Diabetes and Endocrinology, Department of Internal Medicine Kobe University Graduate School of Medicine Kobe JapanDepartment of Medical Systems Kobe University Graduate School of Medicine Kobe JapanDivision of Diabetes and Endocrinology, Department of Internal Medicine Kobe University Graduate School of Medicine Kobe JapanDivision of Diabetes and Endocrinology, Department of Internal Medicine Kobe University Graduate School of Medicine Kobe JapanDivision of Diabetes and Endocrinology, Department of Internal Medicine Kobe University Graduate School of Medicine Kobe JapanDivision of Pediatrics Toyosato Hospital Toyosato Shiga JapanDivision of Pediatric Endocrinology, Metabolism and Nephrology, Children's Medical Center Osaka City General Hospital Osaka JapanDivision of Pediatric Endocrinology, Metabolism and Nephrology, Children's Medical Center Osaka City General Hospital Osaka JapanDivision of Pediatric Endocrinology, Metabolism and Nephrology, Children's Medical Center Osaka City General Hospital Osaka JapanDivision of Pediatric Endocrinology, Metabolism and Nephrology, Children's Medical Center Osaka City General Hospital Osaka JapanDivision of Bioinformatics, Center for Advanced Antibody Drug Development University of Toyama Toyama JapanDivision of Diabetes and Endocrinology, Department of Internal Medicine Kobe University Graduate School of Medicine Kobe JapanABSTRACT Aims/Introduction Phosphatidylinositol 3‐kinase (PI3K) plays a key role in insulin signaling, and mutations in PIK3R1, which encodes a regulatory subunit (p85α) of this enzyme, are responsible for SHORT syndrome, which is associated with insulin‐resistant diabetes. We here describe four Japanese individuals from three families with SHORT syndrome who harbor either a common or a previously unknown mutation in PIK3R1 as well as provide an in silico functional analysis of the mutant proteins. Materials and Methods Gene sequencing was performed to identify PIK3R1 mutations. 3D structural analysis of wild‐type and mutant p85α proteins was performed by homology modeling, and structural optimization and molecular dynamics simulations confirmed stable trajectories. Docking simulations of p85α with a phosphopeptide were also conducted. Results We identified two families with a common mutation (c.1945C>T, p.R649W) and one family with a previously unidentified mutation (c.1957A>T, p.K653*) of PIK3R1. In silico modeling revealed that both mutations impaired binding of p85α to phosphopeptide, with K653* resulting in the loss of amino acids that contribute to such binding. Docking simulations showed a significant loss of docking energy for the R649W mutant compared with the wild‐type protein (P = 0.00329). Conclusions The four cases of SHORT syndrome were associated with early‐onset diabetes and intrauterine growth retardation, with the identified mutations likely disrupting the binding of p85α to phosphopeptide and thereby impairing insulin signaling. One case uniquely manifested diabetes without insulin resistance, emphasizing the need for further study of the clinical variability of SHORT syndrome, especially with regard to its associated diabetes.https://doi.org/10.1111/jdi.70062In silico analysisInsulin resistance syndromePIK3R1 mutation |
| spellingShingle | Tomofumi Takayoshi Yushi Hirota Aki Sugano Kenji Sugawara Takehito Takeuchi Mika Ohta Kai Yoshimura Seiji Nishikage Akane Yamamoto Yu Mimura Shinji Higuchi Jun Mori Rie Kawakita Tohru Yorifuji Yutaka Takaoka Wataru Ogawa PIK3R1 mutations in individuals with insulin resistance or growth retardation: Case series and in silico functional analysis Journal of Diabetes Investigation In silico analysis Insulin resistance syndrome PIK3R1 mutation |
| title | PIK3R1 mutations in individuals with insulin resistance or growth retardation: Case series and in silico functional analysis |
| title_full | PIK3R1 mutations in individuals with insulin resistance or growth retardation: Case series and in silico functional analysis |
| title_fullStr | PIK3R1 mutations in individuals with insulin resistance or growth retardation: Case series and in silico functional analysis |
| title_full_unstemmed | PIK3R1 mutations in individuals with insulin resistance or growth retardation: Case series and in silico functional analysis |
| title_short | PIK3R1 mutations in individuals with insulin resistance or growth retardation: Case series and in silico functional analysis |
| title_sort | pik3r1 mutations in individuals with insulin resistance or growth retardation case series and in silico functional analysis |
| topic | In silico analysis Insulin resistance syndrome PIK3R1 mutation |
| url | https://doi.org/10.1111/jdi.70062 |
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