{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T07:16:44Z","timestamp":1781248604260,"version":"3.54.1"},"reference-count":12,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2019,6,14]],"date-time":"2019-06-14T00:00:00Z","timestamp":1560470400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["Ricerca Corrente 2018 - 2019 and RF-2013-02356459"],"award-info":[{"award-number":["Ricerca Corrente 2018 - 2019 and RF-2013-02356459"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp; Gen Med"],"published-print":{"date-parts":[[2019,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Homozygous inactivating <jats:italic>GCK<\/jats:italic> mutations have been repeatedly reported to cause severe hyperglycemia, presenting as permanent neonatal diabetes mellitus (PNDM). Conversely, only two cases of <jats:italic>GCK<\/jats:italic> homozygous mutations causing mild hyperglycemia have been so far described. We here report a novel <jats:italic>GCK<\/jats:italic> mutation (c.1116G&gt;C, p.E372D), in a family with one homozygous member showing mild hyperglycemia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p><jats:italic>GCK<\/jats:italic> mutational screening was carried out by Sanger sequencing. Computational analyses to investigate pathogenicity and molecular dynamics (MD) were performed for GCK\u2010E372D and for previously described homozygous mutations associated with mild (<jats:italic>n<\/jats:italic>\u00a0=\u00a02) or severe (<jats:italic>n<\/jats:italic>\u00a0=\u00a01) hyperglycemia, used as references.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Of four mildly hyperglycemic family\u2010members, three were heterozygous and one, diagnosed in the adulthood, was homozygous for GCK\u2010E372D. Two nondiabetic family members carried no mutations. Fasting glucose (<jats:italic>p<\/jats:italic>\u00a0=\u00a00.016) and HbA1c (<jats:italic>p<\/jats:italic>\u00a0=\u00a00.035) correlated with the number of mutated alleles (0\u20132).<\/jats:p><jats:p>In\u2010silico predicted pathogenicity was not correlated with the four mutations\u2019 severity. At MD, GCK\u2010E372D conferred protein structure flexibility intermediate between mild and severe <jats:italic>GCK<\/jats:italic> mutations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>We present the third case of homozygous <jats:italic>GCK<\/jats:italic> mutations associated with mild hyperglycemia, rather than PNDM. Our in\u2010silico analyses support previous evidences suggesting that protein stability plays a role in determining clinical severity of <jats:italic>GCK<\/jats:italic> mutations.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.728","type":"journal-article","created":{"date-parts":[[2019,6,14]],"date-time":"2019-06-14T07:42:05Z","timestamp":1560498125000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Association of a homozygous <i>GCK<\/i> missense mutation with mild diabetes"],"prefix":"10.1002","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8131-8317","authenticated-orcid":false,"given":"Antonella","family":"Marucci","sequence":"first","affiliation":[{"name":"Research Unit of Diabetes and Endocrine Diseases Fondazione IRCCS Casa Sollievo della Sofferenza San Giovanni Rotondo (FG) Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tommaso","family":"Biagini","sequence":"additional","affiliation":[{"name":"Unit of Bioinformatics Fondazione IRCCS Casa Sollievo della Sofferenza San Giovanni Rotondo (FG) Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosa","family":"Di Paola","sequence":"additional","affiliation":[{"name":"Research Unit of Diabetes and Endocrine Diseases Fondazione IRCCS Casa Sollievo della Sofferenza San Giovanni Rotondo (FG) Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Menzaghi","sequence":"additional","affiliation":[{"name":"Research Unit of Diabetes and Endocrine Diseases Fondazione IRCCS Casa Sollievo della Sofferenza San Giovanni Rotondo (FG) Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grazia","family":"Fini","sequence":"additional","affiliation":[{"name":"Research Unit of Diabetes and Endocrine Diseases Fondazione IRCCS Casa Sollievo della Sofferenza San Giovanni Rotondo (FG) Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Castellana","sequence":"additional","affiliation":[{"name":"Unit of Bioinformatics Fondazione IRCCS Casa Sollievo della Sofferenza San Giovanni Rotondo (FG) Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuliana Marcella","family":"Cardinale","sequence":"additional","affiliation":[{"name":"Pediatric Division Hospital F. 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