{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2022,4,4]],"date-time":"2022-04-04T15:29:49Z","timestamp":1649086189083},"reference-count":18,"publisher":"The Endocrine Society","issue":"9","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2012,9,1]]},"abstract":"<jats:sec>\n                  <jats:title>Context:<\/jats:title>\n                  <jats:p>Mutations within the PROP1 gene represent one of the main causes of familial combined pituitary hormone deficiency (CPHD). However, most of the cases are sporadic with an unknown genetic cause.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Objective:<\/jats:title>\n                  <jats:p>The aim of this study was the search for low penetrance variations within and around a conserved regulatory element in the intron 1 of PROP1, contributing to a multifactorial form of the disease in sporadic patients.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and Patients:<\/jats:title>\n                  <jats:p>A fragment of 570 bp encompassing the conserved region was sequenced in 107 CPHD patients and 294 controls, and an association study was performed with the four identified variants, namely c.109+435G&amp;gt;A (rs73346254), c.109+463C&amp;gt;T (rs4498267), c.109+768C&amp;gt;G (rs4431364), and c.109+915_917ins\/delTAG (rs148607624). The functional role of the associated polymorphisms was evaluated by luciferase reporter gene expression analyses and EMSA.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results:<\/jats:title>\n                  <jats:p>A statistically significant increased frequency was observed in the patients for rs73346254A (P = 5 \u00d7 10\u22124) and rs148607624delTAG (P = 0.01) alleles. Among all the possible allele combinations, only the haplotype bearing both risk alleles showed a significantly higher frequency in the patients vs. controls (P = 4.7 \u00d7 10\u22124) and conferred a carrier risk of 4.19 (P = 1.2 \u00d7 10\u22124). This haplotype determined a significant decrease of the luciferase activity in comparison with a basal promoter and the other allelic combinations in GH4C and MCF7 cells (P = 4.6 \u00d7 10\u22126; P = 5.5 \u00d7 10\u22124, respectively). The EMSA showed a differential affinity for nuclear proteins for the alternative alleles of the two associated variations.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions:<\/jats:title>\n                  <jats:p>Variations with a functional significance conferring susceptibility to CPHD have been identified in the PROP1 gene, indicating a multifactorial origin of this disorder in sporadic cases.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1210\/jc.2012-1527","type":"journal-article","created":{"date-parts":[[2012,6,29]],"date-time":"2012-06-29T05:50:29Z","timestamp":1340949029000},"page":"E1791-E1797","source":"Crossref","is-referenced-by-count":3,"title":["Functional SNPs within the Intron 1 of the PROP1 Gene Contribute to Combined Growth Hormone Deficiency (CPHD)"],"prefix":"10.1210","volume":"97","author":[{"given":"Michela","family":"Godi","sequence":"first","affiliation":[{"name":"Laboratory of Human Genetics (M.Go., S.M., L.T., R.M., P.M.-R., M.Gi.), 80138 Napoli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simona","family":"Mellone","sequence":"additional","affiliation":[{"name":"Laboratory of Human Genetics (M.Go., S.M., L.T., R.M., P.M.-R., M.Gi.), 80138 Napoli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luigi","family":"Tiradani","sequence":"additional","affiliation":[{"name":"Laboratory of Human Genetics (M.Go., S.M., L.T., R.M., P.M.-R., M.Gi.), 80138 Napoli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rita","family":"Marabese","sequence":"additional","affiliation":[{"name":"Laboratory of Human Genetics (M.Go., S.M., L.T., R.M., P.M.-R., M.Gi.), 80138 Napoli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudio","family":"Bardelli","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, Eastern Piedmont University and Interdisciplinary Research Centre on Autoimmune Diseases, Laboratory of Pharmacology (C.B.), 80138 Napoli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mariacarolina","family":"Salerno","sequence":"additional","affiliation":[{"name":"Eastern Piedmont University, 28100 Novara, Italy; and Department of Pediatrics (M.S.), University of Naples \u201cFederico II,\u201d 80138 Napoli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Flavia","family":"Prodam","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, and Unit of Pediatrics, Department of Health Sciences (F.P., S.B., A.P., G.B.), 80138 Napoli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simonetta","family":"Bellone","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, and Unit of Pediatrics, Department of Health Sciences (F.P., S.B., A.P., G.B.), 80138 Napoli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonella","family":"Petri","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, and Unit of Pediatrics, Department of Health Sciences (F.P., S.B., A.P., G.B.), 80138 Napoli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patricia","family":"Momigliano-Richiardi","sequence":"additional","affiliation":[{"name":"Laboratory of Human Genetics (M.Go., S.M., L.T., R.M., P.M.-R., M.Gi.), 80138 Napoli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gianni","family":"Bona","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, and Unit of Pediatrics, Department of Health Sciences (F.P., S.B., A.P., G.B.), 80138 Napoli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mara","family":"Giordano","sequence":"additional","affiliation":[{"name":"Laboratory of Human Genetics (M.Go., S.M., L.T., R.M., P.M.-R., M.Gi.), 80138 Napoli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"80","reference":[{"key":"2020071613275213100_B1","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1152\/physrev.00006.2006","article-title":"Molecular physiology of pituitary development: signaling and transcriptional networks.","volume":"87","author":"Zhu","year":"2007","journal-title":"Physiol Rev"},{"key":"2020071613275213100_B2","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1038\/384327a0","article-title":"Pituitary lineage determination by the Prophet of Pit-1 homeodomain factor defective in Ames dwarfism.","volume":"384","author":"Sornson","year":"1996","journal-title":"Nature"},{"key":"2020071613275213100_B3","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.beem.2010.10.014","article-title":"Pituitary transcription factors in the aetiology of combined pituitary hormone deficiency.","volume":"25","author":"Pf\u00e4ffle","year":"2011","journal-title":"Best Pract Res Clin Endocrinol Metab"},{"key":"2020071613275213100_B4","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.mce.2010.03.023","article-title":"W194XProp1 and S156insTProp1, both of which have intact DNA-binding domain, show a different DNA-binding activity to the Prop1-binding element in human Pit-1 gene.","volume":"323","author":"Shibahara","year":"2010","journal-title":"Mol Cell Endocrinol"},{"key":"2020071613275213100_B5","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1046\/j.1365-2265.2003.01781.x","article-title":"Combined pituitary hormone deficiency in Australian children: clinical and genetic correlates.","volume":"58","author":"McLennan","year":"2003","journal-title":"Clin Endocrinol (Oxf)"},{"key":"2020071613275213100_B6","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1111\/j.1365-2265.2004.02189.x","article-title":"Mutation analysis of POUF-1, PROP-1 and HESX-1 show low frequency of mutations in children with sporadic forms of combined pituitary hormone deficiency and septo-optic dysplasia.","volume":"62","author":"Rainbow","year":"2005","journal-title":"Clin Endocrinol (Oxf)"},{"key":"2020071613275213100_B7","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1111\/j.1365-2265.2005.02291.x","article-title":"Mutations within the transcription factor PROP1 are rare in a cohort of patients with sporadic combined pituitary hormone deficiency (CPHD).","volume":"63","author":"Turton","year":"2005","journal-title":"Clin Endocrinol (Oxf)"},{"key":"2020071613275213100_B8","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1007\/s00335-007-9008-6","article-title":"Comparative genomics reveals functional transcriptional control sequences in the Prop1 gene.","volume":"18","author":"Ward","year":"2007","journal-title":"Mamm Genome"},{"key":"2020071613275213100_B9","volume-title":"Assessment of skeletal maturity and prediction of adult height (TW2 method)","author":"Tanner","year":"1988"},{"key":"2020071613275213100_B10","first-page":"3323","article-title":"Reliability of provocative tests to asses growth hormone secretory status. 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