{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T22:44:26Z","timestamp":1793400266801,"version":"4.5.0"},"reference-count":46,"publisher":"American Diabetes Association","issue":"6","content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2008,6,1]]},"abstract":"<jats:p>OBJECTIVE\u2014Mutations in the alternatively spliced HNF4A gene cause maturity-onset diabetes of the young (MODY). We characterized the spatial and developmental expression patterns of HNF4A transcripts in human tissues and investigated their role as potential moderators of the MODY phenotype.<\/jats:p>\n               <jats:p>RESEARCH DESIGN AND METHODS\u2014We measured the expression of HNF4A isoforms in human adult tissues and gestationally staged fetal pancreas by isoform-specific real-time PCR. The correlation between mutation position and age of diagnosis or age-related penetrance was assessed in a cohort of 190 patients with HNF4A mutations.<\/jats:p>\n               <jats:p>RESULTS\u2014HNF4A was expressed exclusively from the P2 promoter in adult pancreas, but from 9 weeks until at least 26 weeks after conception, up to 23% of expression in fetal pancreas was of P1 origin. HNF4A4\u20136 transcripts were not detected in any tissue. In whole pancreas, HNF4A9 expression was greater than in islets isolated from the endocrine pancreas (relative level 22 vs. 7%). Patients with mutations in exons 9 and 10 (absent from HNF4A3, HNF4A6, and HNF4A9 isoforms) developed diabetes later than those with mutations in exons 2\u20138, where all isoforms were affected (40 vs. 24 years; P = 0.029). Exon 9\/10 mutations were also associated with a reduced age-related penetrance (53 vs. 10% without diabetes at age 55 years; P &amp;lt; 0.00001).<\/jats:p>\n               <jats:p>CONCLUSIONS\u2014We conclude that isoforms derived from the HNF4A P1 promoter are expressed in human fetal, but not adult, pancreas, and that their presence during pancreatic development may moderate the diabetic phenotype in individuals with mutations in the HNF4A gene.<\/jats:p>","DOI":"10.2337\/db07-1742","type":"journal-article","created":{"date-parts":[[2008,3,21]],"date-time":"2008-03-21T01:37:25Z","timestamp":1206063445000},"page":"1745-1752","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":60,"title":["The Diabetic Phenotype in <i>HNF4A<\/i> Mutation Carriers Is Moderated By the Expression of <i>HNF4A<\/i> Isoforms From the P1 Promoter During Fetal Development"],"prefix":"10.2337","volume":"57","author":[{"given":"Lorna W.","family":"Harries","sequence":"first","affiliation":[{"name":"Institute of Biomedical and Clinical Sciences, Peninsula Medical School, Exeter, U.K"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan M.","family":"Locke","sequence":"additional","affiliation":[{"name":"Institute of Biomedical and Clinical Sciences, Peninsula Medical School, Exeter, U.K"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beverley","family":"Shields","sequence":"additional","affiliation":[{"name":"Institute of Biomedical and Clinical Sciences, Peninsula Medical School, Exeter, U.K"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil A.","family":"Hanley","sequence":"additional","affiliation":[{"name":"Centre for Human Development, Stem Cells & Regeneration, Human Genetics Division, University of Southampton, Southampton, U.K"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen Piper","family":"Hanley","sequence":"additional","affiliation":[{"name":"Centre for Human Development, Stem Cells & Regeneration, Human Genetics Division, University of Southampton, Southampton, U.K"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Steele","sequence":"additional","affiliation":[{"name":"Institute of Biomedical and Clinical Sciences, Peninsula Medical School, Exeter, U.K"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pa\u030al R.","family":"Nj\u00f8lstad","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine, University of Bergen, Bergen, Norway"},{"name":"Department of Paediatrics, Haukeland University Hospital, Bergen, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sian","family":"Ellard","sequence":"additional","affiliation":[{"name":"Institute of Biomedical and Clinical Sciences, Peninsula Medical School, Exeter, U.K"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew T.","family":"Hattersley","sequence":"additional","affiliation":[{"name":"Institute of Biomedical and Clinical Sciences, Peninsula Medical School, Exeter, U.K"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","reference":[{"key":"2022031303150143400_R1","doi-asserted-by":"crossref","unstructured":"Ryffel GU: Mutations in the human genes encoding the transcription factors of the hepatocyte nuclear factor (HNF)1 and HNF4 families: functional and pathological consequences. 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