{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T00:00:42Z","timestamp":1793923242393,"version":"4.8.0"},"reference-count":20,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2018,3,16]]},"abstract":"<jats:sec>\n                    <jats:title>\n                      <jats:underline>Rationale:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>Orthostatic hypotension is a common clinical problem, but the underlying mechanisms have not been fully delineated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>\n                      <jats:underline>Objective:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>We describe 2 families, with 4 patients in total, experiencing severe life-threatening orthostatic hypotension because of a novel cause.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>\n                      <jats:underline>Methods and Results:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>\n                      As in dopamine \u03b2-hydroxylase deficiency, concentrations of norepinephrine and epinephrine in the patients were low. Plasma dopamine \u03b2-hydroxylase activity, however, was normal, and the\n                      <jats:italic>DBH<\/jats:italic>\n                      gene had no mutations. Molecular genetic analysis was performed to determine the underlying genetic cause. Homozygosity mapping and exome and Sanger sequencing revealed pathogenic homozygous mutations in the gene encoding cytochrome b561 (\n                      <jats:italic>CYB561<\/jats:italic>\n                      ); a missense variant c.262G&gt;A, p.Gly88Arg in exon 3 in the Dutch family and a nonsense mutation (c.131G&gt;A, p.Trp44*) in exon 2 in the American family. Expression of\n                      <jats:italic>CYB561<\/jats:italic>\n                      was investigated using RNA from different human adult and fetal tissues, transcription of RNA into cDNA, and real-time quantitative polymerase chain reaction. The\n                      <jats:italic>CYB561<\/jats:italic>\n                      gene was found to be expressed in many human tissues, in particular the brain. The CYB561 protein defect leads to a shortage of ascorbate inside the catecholamine secretory vesicles leading to a functional dopamine \u03b2-hydroxylase deficiency. The concentration of the catecholamines and downstream metabolites was measured in brain and adrenal tissue of 6\n                      <jats:italic>CYB561<\/jats:italic>\n                      knockout mice (reporter-tagged deletion allele [post-Cre], genetic background C57BL\/6NTac). The concentration of norepinephrine and normetanephrine was decreased in whole-brain homogenates of the\n                      <jats:italic>CYB561<\/jats:italic>\n                      <jats:sup>(\u2212<\/jats:sup>\n                      <jats:sup>\/\u2212<\/jats:sup>\n                      <jats:sup>)<\/jats:sup>\n                      mice compared with wild-type mice (\n                      <jats:italic>P<\/jats:italic>\n                      &lt;0.01), and the concentration of normetanephrine and metanephrine was decreased in adrenal glands (\n                      <jats:italic>P<\/jats:italic>\n                      &lt;0.01), recapitulating the clinical phenotype. The patients responded favorably to treatment with\n                      <jats:sc>l<\/jats:sc>\n                      -dihydroxyphenylserine, which can be converted directly to norepinephrine.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>\n                      <jats:underline>Conclusions:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>\n                      This study is the first to implicate cytochrome b561 in disease by showing that pathogenic mutations in\n                      <jats:italic>CYB561<\/jats:italic>\n                      cause an as yet unknown disease in neurotransmitter metabolism causing orthostatic hypotension.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.117.311949","type":"journal-article","created":{"date-parts":[[2018,1,17]],"date-time":"2018-01-17T05:15:28Z","timestamp":1516166128000},"page":"846-854","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":29,"title":["Mutations in\n                    <i>CYB561<\/i>\n                    Causing a Novel Orthostatic Hypotension Syndrome"],"prefix":"10.1161","volume":"122","author":[{"given":"Maarten P.","family":"van den Berg","sequence":"first","affiliation":[{"name":"From the Department of Cardiology (M.P.v.d.B., P.v.d.H., H.H.W.S., I.M.L.), Laboratory Medicine (M.v.F., I.P.K.), Department of Nephrology (G.N.), Department of Neurology (G.J.L.), and Department of Genetics (P.A.v.d.Z., J.D.H.J.), University Medical Center Groningen, University of Groningen, The Netherlands; Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, Jordan University of Science and Technology, Irbid (R.A.); Division of Clinical Pharmacology, Vanderbilt..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rowida","family":"Almomani","sequence":"additional","affiliation":[{"name":"From the Department of Cardiology (M.P.v.d.B., P.v.d.H., H.H.W.S., I.M.L.), Laboratory Medicine (M.v.F., I.P.K.), Department of Nephrology (G.N.), Department of Neurology (G.J.L.), and Department of Genetics (P.A.v.d.Z., J.D.H.J.), University Medical Center Groningen, University of Groningen, The Netherlands; Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, Jordan University of Science and Technology, Irbid (R.A.); Division of Clinical Pharmacology, Vanderbilt..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Italo","family":"Biaggioni","sequence":"additional","affiliation":[{"name":"From the Department of Cardiology (M.P.v.d.B., P.v.d.H., H.H.W.S., I.M.L.), Laboratory Medicine (M.v.F., I.P.K.), Department of Nephrology (G.N.), Department of Neurology (G.J.L.), and Department of Genetics (P.A.v.d.Z., J.D.H.J.), University Medical Center Groningen, University of Groningen, The Netherlands; Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, Jordan University of Science and Technology, Irbid (R.A.); Division of Clinical Pharmacology, Vanderbilt..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martijn","family":"van Faassen","sequence":"additional","affiliation":[{"name":"From the Department of Cardiology (M.P.v.d.B., P.v.d.H., H.H.W.S., I.M.L.), Laboratory Medicine (M.v.F., I.P.K.), Department of Nephrology (G.N.), Department of Neurology (G.J.L.), and Department of Genetics (P.A.v.d.Z., J.D.H.J.), University Medical Center Groningen, University of Groningen, The Netherlands; Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, Jordan University of Science and Technology, Irbid (R.A.); Division of Clinical Pharmacology, Vanderbilt..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pim","family":"van der Harst","sequence":"additional","affiliation":[{"name":"From the Department of Cardiology (M.P.v.d.B., P.v.d.H., H.H.W.S., I.M.L.), Laboratory Medicine (M.v.F., I.P.K.), Department of Nephrology (G.N.), Department of Neurology (G.J.L.), and Department of Genetics (P.A.v.d.Z., J.D.H.J.), University Medical Center Groningen, University of Groningen, The Netherlands; Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, Jordan University of Science and Technology, Irbid (R.A.); Division of Clinical Pharmacology, Vanderbilt..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Herman H.W.","family":"Sillj\u00e9","sequence":"additional","affiliation":[{"name":"From the Department of Cardiology (M.P.v.d.B., P.v.d.H., H.H.W.S., I.M.L.), Laboratory Medicine (M.v.F., I.P.K.), Department of Nephrology (G.N.), Department of Neurology (G.J.L.), and Department of Genetics (P.A.v.d.Z., J.D.H.J.), University Medical Center Groningen, University of Groningen, The Netherlands; Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, Jordan University of Science and Technology, Irbid (R.A.); Division of Clinical Pharmacology, Vanderbilt..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Mateo Leach","sequence":"additional","affiliation":[{"name":"From the Department of Cardiology (M.P.v.d.B., P.v.d.H., H.H.W.S., I.M.L.), Laboratory Medicine (M.v.F., I.P.K.), Department of Nephrology (G.N.), Department of Neurology (G.J.L.), and Department of Genetics (P.A.v.d.Z., J.D.H.J.), University Medical Center Groningen, University of Groningen, The Netherlands; Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, Jordan University of Science and Technology, Irbid (R.A.); Division of Clinical Pharmacology, Vanderbilt..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc H.","family":"Hemmelder","sequence":"additional","affiliation":[{"name":"From the Department of Cardiology (M.P.v.d.B., P.v.d.H., H.H.W.S., I.M.L.), Laboratory Medicine (M.v.F., I.P.K.), Department of Nephrology (G.N.), Department of Neurology (G.J.L.), and Department of Genetics (P.A.v.d.Z., J.D.H.J.), University Medical Center Groningen, University of Groningen, The Netherlands; Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, Jordan University of Science and Technology, Irbid (R.A.); Division of Clinical Pharmacology, Vanderbilt..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerjan","family":"Navis","sequence":"additional","affiliation":[{"name":"From the Department of Cardiology (M.P.v.d.B., P.v.d.H., H.H.W.S., I.M.L.), Laboratory Medicine (M.v.F., I.P.K.), Department of Nephrology (G.N.), Department of Neurology (G.J.L.), and Department of Genetics (P.A.v.d.Z., J.D.H.J.), University Medical Center Groningen, University of Groningen, The Netherlands; Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, Jordan University of Science and Technology, Irbid (R.A.); Division of Clinical Pharmacology, Vanderbilt..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gert Jan","family":"Luijckx","sequence":"additional","affiliation":[{"name":"From the Department of Cardiology (M.P.v.d.B., P.v.d.H., H.H.W.S., I.M.L.), Laboratory Medicine (M.v.F., I.P.K.), Department of Nephrology (G.N.), Department of Neurology (G.J.L.), and Department of Genetics (P.A.v.d.Z., J.D.H.J.), University Medical Center Groningen, University of Groningen, The Netherlands; Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, Jordan University of Science and Technology, Irbid (R.A.); Division of Clinical Pharmacology, Vanderbilt..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arjan P.M.","family":"de Brouwer","sequence":"additional","affiliation":[{"name":"From the Department of Cardiology (M.P.v.d.B., P.v.d.H., H.H.W.S., I.M.L.), Laboratory Medicine (M.v.F., I.P.K.), Department of Nephrology (G.N.), Department of Neurology (G.J.L.), and Department of Genetics (P.A.v.d.Z., J.D.H.J.), University Medical Center Groningen, University of Groningen, The Netherlands; Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, Jordan University of Science and Technology, Irbid (R.A.); Division of Clinical Pharmacology, Vanderbilt..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanka","family":"Venselaar","sequence":"additional","affiliation":[{"name":"From the Department of Cardiology (M.P.v.d.B., P.v.d.H., H.H.W.S., I.M.L.), Laboratory Medicine (M.v.F., I.P.K.), Department of Nephrology (G.N.), Department of Neurology (G.J.L.), and Department of Genetics (P.A.v.d.Z., J.D.H.J.), University Medical Center Groningen, University of Groningen, The Netherlands; Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, Jordan University of Science and Technology, Irbid (R.A.); Division of Clinical Pharmacology, Vanderbilt..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcel M.","family":"Verbeek","sequence":"additional","affiliation":[{"name":"From the Department of Cardiology (M.P.v.d.B., P.v.d.H., H.H.W.S., I.M.L.), Laboratory Medicine (M.v.F., I.P.K.), Department of Nephrology (G.N.), Department of Neurology (G.J.L.), and Department of Genetics (P.A.v.d.Z., J.D.H.J.), University Medical Center Groningen, University of Groningen, The Netherlands; Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, Jordan University of Science and Technology, Irbid (R.A.); Division of Clinical Pharmacology, Vanderbilt..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul A.","family":"van der Zwaag","sequence":"additional","affiliation":[{"name":"From the Department of Cardiology (M.P.v.d.B., P.v.d.H., H.H.W.S., I.M.L.), Laboratory Medicine (M.v.F., I.P.K.), Department of Nephrology (G.N.), Department of Neurology (G.J.L.), and Department of Genetics (P.A.v.d.Z., J.D.H.J.), University Medical Center Groningen, University of Groningen, The Netherlands; Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, Jordan University of Science and Technology, Irbid (R.A.); Division of Clinical Pharmacology, Vanderbilt..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan D.H.","family":"Jongbloed","sequence":"additional","affiliation":[{"name":"From the Department of Cardiology (M.P.v.d.B., P.v.d.H., H.H.W.S., I.M.L.), Laboratory Medicine (M.v.F., I.P.K.), Department of Nephrology (G.N.), Department of Neurology (G.J.L.), and Department of Genetics (P.A.v.d.Z., J.D.H.J.), University Medical Center Groningen, University of Groningen, The Netherlands; Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, Jordan University of Science and Technology, Irbid (R.A.); Division of Clinical Pharmacology, Vanderbilt..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. Peter","family":"van Tintelen","sequence":"additional","affiliation":[{"name":"From the Department of Cardiology (M.P.v.d.B., P.v.d.H., H.H.W.S., I.M.L.), Laboratory Medicine (M.v.F., I.P.K.), Department of Nephrology (G.N.), Department of Neurology (G.J.L.), and Department of Genetics (P.A.v.d.Z., J.D.H.J.), University Medical Center Groningen, University of Groningen, The Netherlands; Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, Jordan University of Science and Technology, Irbid (R.A.); Division of Clinical Pharmacology, Vanderbilt..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ron A.","family":"Wevers","sequence":"additional","affiliation":[{"name":"From the Department of Cardiology (M.P.v.d.B., P.v.d.H., H.H.W.S., I.M.L.), Laboratory Medicine (M.v.F., I.P.K.), Department of Nephrology (G.N.), Department of Neurology (G.J.L.), and Department of Genetics (P.A.v.d.Z., J.D.H.J.), University Medical Center Groningen, University of Groningen, The Netherlands; Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, Jordan University of Science and Technology, Irbid (R.A.); Division of Clinical Pharmacology, Vanderbilt..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ido P.","family":"Kema","sequence":"additional","affiliation":[{"name":"From the Department of Cardiology (M.P.v.d.B., P.v.d.H., H.H.W.S., I.M.L.), Laboratory Medicine (M.v.F., I.P.K.), Department of Nephrology (G.N.), Department of Neurology (G.J.L.), and Department of Genetics (P.A.v.d.Z., J.D.H.J.), University Medical Center Groningen, University of Groningen, The Netherlands; Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, Jordan University of Science and Technology, Irbid (R.A.); Division of Clinical Pharmacology, Vanderbilt..."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrneurol.2015.172"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198606053142307"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(87)90002-X"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2012.5065"},{"key":"e_1_3_5_6_2","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2003.009282"},{"key":"e_1_3_5_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/0006-2944(84)90019-X"},{"key":"e_1_3_5_8_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkt977"},{"key":"e_1_3_5_9_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0143833"},{"key":"e_1_3_5_10_2","doi-asserted-by":"publisher","DOI":"10.1373\/clinchem.2007.087114"},{"key":"e_1_3_5_11_2","doi-asserted-by":"publisher","DOI":"10.4155\/bio.11.170"},{"key":"e_1_3_5_12_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1323931111"},{"key":"e_1_3_5_13_2","doi-asserted-by":"publisher","DOI":"10.1097\/FPC.0b013e328350a274"},{"key":"e_1_3_5_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2013.09.025"},{"key":"e_1_3_5_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/0306-4522(87)90205-3"},{"key":"e_1_3_5_16_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.1987.tb27188.x"},{"key":"e_1_3_5_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/0306-4522(79)90227-6"},{"key":"e_1_3_5_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)84842-1"},{"key":"e_1_3_5_19_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0151760"},{"key":"e_1_3_5_20_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00394-013-0515-9"},{"key":"e_1_3_5_21_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.02-1167fje"}],"container-title":["Circulation Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/CIRCRESAHA.117.311949","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T01:20:33Z","timestamp":1715563233000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/CIRCRESAHA.117.311949"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,3,16]]},"references-count":20,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2018,3,16]]}},"alternative-id":["10.1161\/CIRCRESAHA.117.311949"],"URL":"https:\/\/doi.org\/10.1161\/circresaha.117.311949","relation":{},"ISSN":["0009-7330","1524-4571"],"issn-type":[{"value":"0009-7330","type":"print"},{"value":"1524-4571","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,3,16]]},"assertion":[{"value":"2017-08-25","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-01-12","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-01-17","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}