{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T22:43:51Z","timestamp":1776984231007,"version":"3.51.4"},"reference-count":30,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2017,3,27]],"date-time":"2017-03-27T00:00:00Z","timestamp":1490572800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100003451","name":"Euskal Herriko Unibertsitatea","doi-asserted-by":"publisher","award":["IT795\u201013"],"award-info":[{"award-number":["IT795\u201013"]}],"id":[{"id":"10.13039\/501100003451","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003451","name":"Euskal Herriko Unibertsitatea","doi-asserted-by":"publisher","award":["IF\/UPV12\/135"],"award-info":[{"award-number":["IF\/UPV12\/135"]}],"id":[{"id":"10.13039\/501100003451","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["PI10\/00424"],"award-info":[{"award-number":["PI10\/00424"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical Endocrinology"],"published-print":{"date-parts":[[2017,6]]},"abstract":"<jats:title>Summary<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Mutations in the <jats:italic><jats:styled-content style=\"fixed-case\">GCK<\/jats:styled-content><\/jats:italic> gene lead to different forms of glucokinase (<jats:styled-content style=\"fixed-case\">GCK<\/jats:styled-content>)\u2010disease, activating mutations cause hyperinsulinaemic hypoglycaemia while inactivating mutations cause monogenic diabetes. Hyperinsulinism (<jats:styled-content style=\"fixed-case\">HI<\/jats:styled-content>) is a heterogeneous condition with a significant genetic component. The major causes are channelopathies, the other forms are rare and being caused by mutations in genes such as <jats:italic><jats:styled-content style=\"fixed-case\">GCK<\/jats:styled-content><\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>To describe the clinical and genetic presentation of four families with activating <jats:italic><jats:styled-content style=\"fixed-case\">GCK<\/jats:styled-content><\/jats:italic> mutations, and to explore the pathogenicity of the novel mutation identified through functional studies.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Four cases of <jats:styled-content style=\"fixed-case\">HI<\/jats:styled-content> with mutations in <jats:italic><jats:styled-content style=\"fixed-case\">GCK<\/jats:styled-content><\/jats:italic> were identified. These include one <jats:italic>novel<\/jats:italic> mutation (p.Trp99Cys). Functional analysis of the purified mutant fusion protein glutathione\u2010S\u2010transferase (<jats:styled-content style=\"fixed-case\">GST<\/jats:styled-content>)\u2010<jats:styled-content style=\"fixed-case\">GCK<\/jats:styled-content>\u2010p.Trp99Cys demonstrated that p.Trp99Cys is an activating mutation as it induces a higher affinity for glucose and increases the relative activity index more than 11 times. Moreover, the thermal stability of the mutant protein was similar to that of its wild type. All patients were responsive to diazoxide treatment. One of the mutations arose <jats:italic>de novo<\/jats:italic>, and two were dominantly inherited, although only one of them from an <jats:styled-content style=\"fixed-case\">HI<\/jats:styled-content> affected parent. The age of presentation in our cases varied widely from the neonatal period to adulthood.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The clinical phenotype of the <jats:italic><jats:styled-content style=\"fixed-case\">GCK<\/jats:styled-content><\/jats:italic> activating mutation carriers was heterogeneous, the severity of symptoms and age at presentation varied markedly between affected individuals, even within the same family. The novel activating <jats:italic><jats:styled-content style=\"fixed-case\">GCK<\/jats:styled-content><\/jats:italic> mutation (p.Trp99Cys) has a strong activating effect <jats:italic>in vitro<\/jats:italic> although it has been identified in one case of a milder and late\u2010onset form of <jats:styled-content style=\"fixed-case\">HI<\/jats:styled-content>.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cen.13318","type":"journal-article","created":{"date-parts":[[2017,3,1]],"date-time":"2017-03-01T07:13:00Z","timestamp":1488352380000},"page":"778-783","source":"Crossref","is-referenced-by-count":16,"title":["Heterogeneity in phenotype of hyperinsulinism caused by activating glucokinase mutations: a novel mutation and its functional characterization"],"prefix":"10.1111","volume":"86","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3800-531X","authenticated-orcid":false,"given":"Rosa","family":"Mart\u00ednez","sequence":"first","affiliation":[{"name":"Endocrinology and Diabetes Research Group BioCruces Health Research Institute UPV\u2010EHU, CIBERDEM, CIBERER Cruces University Hospital Barakaldo Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"\u00c1ngel","family":"Gutierrez\u2010Nogu\u00e9s","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology III Faculty of Medicine CIBERDEM and Hospital Cl\u00ednico San Carlos Health Research Institute Complutense University of Madrid Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Concepci\u00f3n","family":"Fern\u00e1ndez\u2010Ramos","sequence":"additional","affiliation":[{"name":"Pediatric Endocrinology Section BioCruces Health Research Institute UPV\/EHU Basurto University Hospital Bilbao Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Teresa","family":"Velayos","sequence":"additional","affiliation":[{"name":"Endocrinology and Diabetes Research Group BioCruces Health Research Institute UPV\u2010EHU, CIBERDEM, CIBERER Cruces University Hospital Barakaldo Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amaia","family":"Vela","sequence":"additional","affiliation":[{"name":"Pediatric Endocrinology Section BioCruces Health Research Institute UPV\/EHU Cruces University Hospital CIBERDEM, CIBERER Barakaldo Bizkaia Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"Spanish Congenital Hyperinsulinism Group","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar\u00eda\u2010\u00c1ngeles","family":"Navas","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology III Faculty of Medicine CIBERDEM and Hospital Cl\u00ednico San Carlos Health Research Institute Complutense University of Madrid Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luis","family":"Casta\u00f1o","sequence":"additional","affiliation":[{"name":"Endocrinology and Diabetes Research Group BioCruces Health Research Institute UPV\u2010EHU, CIBERDEM, CIBERER Cruces University Hospital Barakaldo Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2017,3,27]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11154-010-9147-z"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.21110"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi702516y"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M607987200"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0028-1102922"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1210\/me.2009-0094"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMc0909845"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.223362"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1159\/000334521"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.2337\/db08-1792"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199801223380404"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.51.4.1240"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.52.9.2433"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.53.8.2164"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-16-0027"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1172-6-63"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20051137"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20110440"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi802142q"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20071718"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2012.07.005"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddu360"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20131363"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1464-5491.2007.02285.x"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-08-0203"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1111\/cen.12517"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2015-2763"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1159\/000350827"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2012-2169"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-12-0673"}],"container-title":["Clinical Endocrinology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fcen.13318","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cen.13318","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,23]],"date-time":"2023-09-23T17:30:50Z","timestamp":1695490250000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cen.13318"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,3,27]]},"references-count":30,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2017,6]]}},"alternative-id":["10.1111\/cen.13318"],"URL":"https:\/\/doi.org\/10.1111\/cen.13318","archive":["Portico"],"relation":{},"ISSN":["0300-0664","1365-2265"],"issn-type":[{"value":"0300-0664","type":"print"},{"value":"1365-2265","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,3,27]]}}}