{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T20:26:13Z","timestamp":1790972773382,"version":"4.1.0"},"reference-count":57,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"12","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Hypertension"],"published-print":{"date-parts":[[2024,12]]},"abstract":"<jats:p>Hypertension requires increased systemic vascular resistance. Thus far, Mendelian hypertension\u2013related genes are related to salt retention, an indirect regulatory effect. With the identification of mutated, overactive, PDE3A (phosphodiesterase 3A), we have uncovered a more direct vasoconstrictive mechanism. The autosomal-dominant syndrome features another specific phenotype, brachydactyly type E. Hypertension and the bony phenotype invariably occur together. We distinguished between these phenotypes by examining individual pedigrees. We implicated the gene encoding the parathyroid hormone-related peptide in the brachydactyly. We identified the hypertensive mechanisms as involving regulatory-region, gain-of-function, exon 4 rare pathogenic variants, in the cAMP-cGMP\u2013catabolizing enzyme, PDE3A. We generated rodent models that recapitulate all human phenotypes. Comparisons not only allowed pathogenic insights into the human condition but also provided intervention models. Moreover, we identified rare pathogenic variants in exon 13 encoding the enzymatic pocket. These patients had identical phenotypes, also corroborated in a rodent model, which produced the same human phenotypes. These data could allow the differentiation between a target organ and blood pressure phenotype. The research allows visualization of enzymatic processes at the intracellular nanodomain level. The scope of this project has elucidated genetic mechanisms important to cartilage development, possibly cancer metastases, and findings relevant to cardiovascular regulation via systemic vascular resistance. For our team, the project was an educational\/scientific adventure over a professional lifetime.<\/jats:p>","DOI":"10.1161\/hypertensionaha.124.21714","type":"journal-article","created":{"date-parts":[[2024,10,2]],"date-time":"2024-10-02T09:01:22Z","timestamp":1727859682000},"page":"2395-2406","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":2,"title":["Personal Genetic-Hypertension Odyssey From Phenotypes to Genotypes and Targets"],"prefix":"10.1161","volume":"81","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8635-1199","authenticated-orcid":true,"given":"Friedrich C.","family":"Luft","sequence":"first","affiliation":[{"name":"Experimental and Clinical Research Center, a cooperation between the Max-Delbr\u00fcck Center for Molecular Medicine and the Charit\u00e9 Medical Faculty, Berlin, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/scientificamerican0412-10"},{"key":"e_1_3_3_3_2","first-page":"1535","article-title":"\u2018Treasure your exceptions\u2019: what we can learn from autosomal-dominant inherited forms of hypertension.","volume":"13","author":"Luft FC","year":"1995","unstructured":"Luft FC, Schuster H, Bilginturan N, Wienker T. \u2018Treasure your exceptions\u2019: what we can learn from autosomal-dominant inherited forms of hypertension. J Hypertens. 1995;13:1535\u20131538.","journal-title":"J Hypertens"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.10.3.253"},{"key":"e_1_3_3_5_2","first-page":"67","article-title":"Dermatoglyphics in patients with a syndrome of brachydactyly, short stature and hypertension.","volume":"15","author":"Taysi K","year":"1973","unstructured":"Taysi K, Atasu M, Say B, Bilginturan N. Dermatoglyphics in patients with a syndrome of brachydactyly, short stature and hypertension. Turk J Pediatr. 1973;15:67\u201381.","journal-title":"Turk J Pediatr"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng0596-98"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1097\/00005344-198800120-00008"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.hyp.28.6.1085"},{"key":"e_1_3_3_9_2","first-page":"732","article-title":"Deletion at 12p in a Japanese child with brachydactyly overlaps the assigned locus of brachydactyly with hypertension in a Turkish family.","volume":"60","author":"Bahring S","year":"1997","unstructured":"Bahring S, Nagai T, Toka HR, Nitz I, Toka O, Aydin A, Muhl A, Wienker TF, Schuster H, Luft FC. Deletion at 12p in a Japanese child with brachydactyly overlaps the assigned locus of brachydactyly with hypertension in a Turkish family. Am J Hum Genet. 1997;60:732\u2013735.","journal-title":"Am J Hum Genet"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-129-3-199808010-00008"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2016.03.037"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1523-1755.1998.00732.x"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.jhh.1001271"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.3174\/ajnr.A4683"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(94)90289-5"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.str.28.9.1749"},{"key":"e_1_3_3_17_2","first-page":"3","article-title":"Changes in vascular morphology in essential hypertension.","volume":"5","author":"Heagerty AM","year":"1991","unstructured":"Heagerty AM. Changes in vascular morphology in essential hypertension. J Hum Hypertens. 1991;5:3\u20138.","journal-title":"J Hum Hypertens"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.cir.102.21.2611"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.3390\/jcdd5010014"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.HYP.0000111808.08715.ec"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.5551\/jat1994.4.65"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.214155"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1097\/00004872-200204000-00028"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0921-8734(96)90010-7"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.107.101774"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.127.3.543"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.128.22.4523"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.165619"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1177\/00220345231208175"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.20652"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddp553"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2010.01.023"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI65508"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.15252\/embj.201696257"},{"key":"e_1_3_3_35_2","first-page":"255","article-title":"Brachydactyly type E: a report of a family.","volume":"58","author":"Cartwright JD","year":"1980","unstructured":"Cartwright JD, Rosin M, Robertson C. Brachydactyly type E: a report of a family. S Afr Med J. 1980;58:255\u2013257.","journal-title":"S Afr Med J"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.26508\/lsa.202302400"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.3390\/cancers15102670"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3302"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20051970"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12881-020-01077-z"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1093\/ajh\/hpz151"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41440-018-0094-5"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.119.043061"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1150609"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M202753200"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/bs.apha.2022.01.001"},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.120.15856"},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.1136\/bjo.82.12.1363"},{"key":"e_1_3_3_49_2","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.115.06000"},{"key":"e_1_3_3_50_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-642-17969-3_1"},{"key":"e_1_3_3_51_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.122.060210"},{"key":"e_1_3_3_52_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.108.179754"},{"key":"e_1_3_3_53_2","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.122.19433"},{"key":"e_1_3_3_54_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.04.043"},{"key":"e_1_3_3_55_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2022.02.011"},{"key":"e_1_3_3_56_2","doi-asserted-by":"publisher","DOI":"10.3390\/jcdd9010004"},{"key":"e_1_3_3_57_2","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.113.02444"},{"key":"e_1_3_3_58_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pharmtox-010716-104756"}],"container-title":["Hypertension"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/HYPERTENSIONAHA.124.21714","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,29]],"date-time":"2025-05-29T19:29:57Z","timestamp":1748546997000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/HYPERTENSIONAHA.124.21714"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12]]},"references-count":57,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2024,12]]}},"alternative-id":["10.1161\/HYPERTENSIONAHA.124.21714"],"URL":"https:\/\/doi.org\/10.1161\/hypertensionaha.124.21714","relation":{},"ISSN":["0194-911X","1524-4563"],"issn-type":[{"value":"0194-911X","type":"print"},{"value":"1524-4563","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12]]},"assertion":[{"value":"2024-10-02","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}