RATIONALE Orthostatic hypotension is a common clinical problem, but the underlying mechanisms have not been fully delineated. OBJECTIVE We describe 2 families, with 4 patients in total, experiencing severe life-threatening orthostatic hypotension because of a novel cause. METHODS AND RESULTS As in dopamine β-hydroxylase deficiency, concentrations of norepinephrine and epinephrine in the patients were low. Plasma dopamine β-hydroxylase activity, however, was normal, and the DBH 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 (CYB561); a missense variant c.262G>A, p.Gly88Arg in exon 3 in the Dutch family and a nonsense mutation (c.131G>A, p.Trp44*) in exon 2 in the American family. Expression of CYB561 was investigated using RNA from different human adult and fetal tissues, transcription of RNA into cDNA, and real-time quantitative polymerase chain reaction. The CYB561 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 β-hydroxylase deficiency. The concentration of the catecholamines and downstream metabolites was measured in brain and adrenal tissue of 6 CYB561 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 CYB561(-/-) mice compared with wild-type mice (P<0.01), and the concentration of normetanephrine and metanephrine was decreased in adrenal glands (P<0.01), recapitulating the clinical phenotype. The patients responded favorably to treatment with l-dihydroxyphenylserine, which can be converted directly to norepinephrine. CONCLUSIONS This study is the first to implicate cytochrome b561 in disease by showing that pathogenic mutations in CYB561 cause an as yet unknown disease in neurotransmitter metabolism causing orthostatic hypotension.

中文翻译：

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CYB561中的突变导致新型体位性低血压综合征。

理据体位性低血压是一个常见的临床问题，但其潜在机制尚未完全阐明。目的我们描述了2个家庭，总共4例患者，由于新病因而经历了严重威胁生命的直立性低血压。方法和结果与多巴胺β-羟化酶缺乏症一样，患者的去甲肾上腺素和肾上腺素浓度较低。然而，血浆多巴胺β-羟化酶活性是正常的，并且DBH基因没有突变。进行分子遗传分析以确定潜在的遗传原因。纯合性作图和外显子组和Sanger测序揭示了编码细胞色素b561（CYB561）的基因中的致病性纯合突变。荷兰家族第3外显子的一个错义变体c.262G> A，p.Gly88Arg和一个无意义的突变（c.131G> A，p。美国家庭第2外显子中的Trp44 *）。使用来自不同人类成人和胎儿组织的RNA，将RNA转录为cDNA以及实时定量聚合酶链反应，研究了CYB561的表达。发现CYB561基因在许多人体组织，特别是大脑中表达。CYB561蛋白缺陷导致儿茶酚胺分泌囊泡中抗坏血酸的缺乏，从而导致功能性多巴胺β-羟化酶缺乏。测量了6只CYB561基因敲除小鼠（报告者标签的缺失等位基因[Cre]，遗传背景C57BL / 6NTac）的脑和肾上腺组织中儿茶酚胺和下游代谢产物的浓度。与野生型小鼠相比，CYB561（-/-）小鼠全脑匀浆中去甲肾上腺素和去甲肾上腺素的浓度降低（P <0.01），肾上腺中去甲肾上腺素和去甲肾上腺素的浓度降低（P <0.01），再现了临床表型。患者对1-二羟基苯基丝氨酸的治疗反应良好，可以将其直接转化为去甲肾上腺素。结论本研究是第一个通过显示CYB561的致病性突变引起神经递质代谢引起直立性低血压的疾病，从而将细胞色素b561包含在疾病中的研究。