{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T12:27:51Z","timestamp":1766492871070,"version":"3.41.2"},"reference-count":47,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T00:00:00Z","timestamp":1748304000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Diabetes Invest"],"published-print":{"date-parts":[[2025,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Aims\/Introduction<\/jats:title><jats:p>Phosphatidylinositol 3\u2010kinase (PI3K) plays a key role in insulin signaling, and mutations in <jats:italic>PIK3R1<\/jats:italic>, which encodes a regulatory subunit (p85\u03b1) of this enzyme, are responsible for SHORT syndrome, which is associated with insulin\u2010resistant diabetes. We here describe four Japanese individuals from three families with SHORT syndrome who harbor either a common or a previously unknown mutation in <jats:italic>PIK3R1<\/jats:italic> as well as provide an <jats:italic>in silico<\/jats:italic> functional analysis of the mutant proteins.<\/jats:p><\/jats:sec><jats:sec><jats:title>Materials and Methods<\/jats:title><jats:p>Gene sequencing was performed to identify <jats:italic>PIK3R1<\/jats:italic> mutations. 3D structural analysis of wild\u2010type and mutant p85\u03b1 proteins was performed by homology modeling, and structural optimization and molecular dynamics simulations confirmed stable trajectories. Docking simulations of p85\u03b1 with a phosphopeptide were also conducted.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified two families with a common mutation (c.1945C&gt;T, p.R649W) and one family with a previously unidentified mutation (c.1957A&gt;T, p.K653*) of <jats:italic>PIK3R1<\/jats:italic>. <jats:italic>In silico<\/jats:italic> modeling revealed that both mutations impaired binding of p85\u03b1 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\u2010type protein (<jats:italic>P<\/jats:italic>\u2009=\u20090.00329).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The four cases of SHORT syndrome were associated with early\u2010onset diabetes and intrauterine growth retardation, with the identified mutations likely disrupting the binding of p85\u03b1 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.<\/jats:p><\/jats:sec>","DOI":"10.1111\/jdi.70062","type":"journal-article","created":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T03:21:44Z","timestamp":1748316104000},"page":"1526-1534","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["<i>PIK3R1<\/i> mutations in individuals with insulin resistance or growth retardation: Case series and <i>in silico<\/i> functional analysis"],"prefix":"10.1111","volume":"16","author":[{"given":"Tomofumi","family":"Takayoshi","sequence":"first","affiliation":[{"name":"Division of Diabetes and Endocrinology, Department of Internal Medicine Kobe University Graduate School of Medicine  Kobe Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3035-4155","authenticated-orcid":false,"given":"Yushi","family":"Hirota","sequence":"additional","affiliation":[{"name":"Division of Diabetes and Endocrinology, Department of Internal Medicine Kobe University Graduate School of Medicine  Kobe Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aki","family":"Sugano","sequence":"additional","affiliation":[{"name":"Laboratory of Pharma\u2010Medical Informatics and AI, Graduate School of Medicine and Pharmaceutical Sciences University of Toyama  Toyama Japan"},{"name":"Division of Bioinformatics, Center for Advanced Antibody Drug Development University of Toyama  Toyama Japan"},{"name":"Department of Medical Systems Kobe University Graduate School of Medicine  Kobe Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6549-7885","authenticated-orcid":false,"given":"Kenji","family":"Sugawara","sequence":"additional","affiliation":[{"name":"Division of Diabetes and Endocrinology, Department of Internal Medicine Kobe University Graduate School of Medicine  Kobe Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takehito","family":"Takeuchi","sequence":"additional","affiliation":[{"name":"Division of Diabetes and Endocrinology, Department of Internal Medicine Kobe University Graduate School of Medicine  Kobe Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mika","family":"Ohta","sequence":"additional","affiliation":[{"name":"Department of Medical Systems Kobe University Graduate School of Medicine  Kobe Japan"},{"name":"Department of Computational Drug Design and Mathematical Medicine, Graduate School of Medicine and Pharmaceutical Sciences University of Toyama  Toyama Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-6144-1320","authenticated-orcid":false,"given":"Kai","family":"Yoshimura","sequence":"additional","affiliation":[{"name":"Division of Diabetes and Endocrinology, Department of Internal Medicine Kobe University Graduate School of Medicine  Kobe Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seiji","family":"Nishikage","sequence":"additional","affiliation":[{"name":"Division of Diabetes and Endocrinology, Department of Internal Medicine Kobe University Graduate School of Medicine  Kobe Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akane","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Division of Diabetes and Endocrinology, Department of Internal Medicine Kobe University Graduate School of Medicine  Kobe Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu","family":"Mimura","sequence":"additional","affiliation":[{"name":"Division of Pediatrics Toyosato Hospital  Toyosato Shiga Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shinji","family":"Higuchi","sequence":"additional","affiliation":[{"name":"Division of Pediatric Endocrinology, Metabolism and Nephrology, Children's Medical Center Osaka City General Hospital  Osaka Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"Mori","sequence":"additional","affiliation":[{"name":"Division of Pediatric Endocrinology, Metabolism and Nephrology, Children's Medical Center Osaka City General Hospital  Osaka Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rie","family":"Kawakita","sequence":"additional","affiliation":[{"name":"Division of Pediatric Endocrinology, Metabolism and Nephrology, Children's Medical Center Osaka City General Hospital  Osaka Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8945-4775","authenticated-orcid":false,"given":"Tohru","family":"Yorifuji","sequence":"additional","affiliation":[{"name":"Division of Pediatric Endocrinology, Metabolism and Nephrology, Children's Medical Center Osaka City General Hospital  Osaka Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yutaka","family":"Takaoka","sequence":"additional","affiliation":[{"name":"Division of Bioinformatics, Center for Advanced Antibody Drug Development University of Toyama  Toyama Japan"},{"name":"Department of Medical Systems Kobe University Graduate School of Medicine  Kobe Japan"},{"name":"Department of Computational Drug Design and Mathematical Medicine, Graduate School of Medicine and Pharmaceutical Sciences University of Toyama  Toyama Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0432-4366","authenticated-orcid":false,"given":"Wataru","family":"Ogawa","sequence":"additional","affiliation":[{"name":"Division of Diabetes and Endocrinology, Department of Internal Medicine Kobe University Graduate School of Medicine  Kobe Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,5,27]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM197604012941401"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.md.0000133625.73570.54"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1096706"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0900909106"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00063.2017"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2013.05.019"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2013.05.023"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2013.06.005"},{"key":"e_1_2_8_10_1","first-page":"46","article-title":"A selected miscellany","volume":"11","author":"Gorlin RJ","year":"1975","journal-title":"Birth Defects Res"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11892-022-01495-8"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13340-022-00570-5"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.12263"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2350-15-51"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.12688"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.88766"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-016-0281-6"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13052-017-0362-z"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clim.2017.03.004"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1111\/jdi.12825"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/jdi.13171"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1507\/endocrj.EJ20-0291"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12881-020-01146-3"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/mgg3.1385"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-020-00843-1"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1111\/jdi.13549"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.3389\/fped.2021.650920"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.62660"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07487-w"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0188407"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1107\/S0021889892009944"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1186\/1756-0500-7-446"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M116.755173"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0225244"},{"volume-title":"R: A Language and Environment for Statistical Computing","year":"2015","author":"R Core Team","key":"e_1_2_8_35_1"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3290"},{"key":"e_1_2_8_37_1","doi-asserted-by":"crossref","unstructured":"AljedaniSS AldehaimanA SandholuA et\u00a0al.Functional selection in SH3\u2010mediated activation of the PI3 kinase.bioRxiv2024https:\/\/doi.org\/10.1101\/2024.04.30.591319.","DOI":"10.1101\/2024.04.30.591319"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.278.5346.2075"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13148-020-00865-x"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1629"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI84005"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13340-020-00455-5"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2013.00037"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1463-1326.2007.00783.x"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaip.2021.07.044"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2018.08.005"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13300-023-01526-x"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1111\/jdi.14226"}],"container-title":["Journal of Diabetes Investigation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jdi.70062","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,1]],"date-time":"2025-08-01T12:50:58Z","timestamp":1754052658000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/jdi.70062"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,27]]},"references-count":47,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2025,8]]}},"alternative-id":["10.1111\/jdi.70062"],"URL":"https:\/\/doi.org\/10.1111\/jdi.70062","archive":["Portico"],"relation":{},"ISSN":["2040-1116","2040-1124"],"issn-type":[{"type":"print","value":"2040-1116"},{"type":"electronic","value":"2040-1124"}],"subject":[],"published":{"date-parts":[[2025,5,27]]},"assertion":[{"value":"2025-01-08","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-04-22","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-05-27","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}