From the Department of Medicine (C.S., J.H.N., B.B., A.D., D.R., I.B.), Department of Ophthalmology and Visual Sciences, Biomedical Engineering (K.J.), Department of Pediatrics (J.A.P., J.C., R.H.), and Department of Biochemistry (J.M., J.C.), Vanderbilt University Medical Center, Nashville, TN; Department of Internal Medicine (J.S.), Washington University in St. Louis, MO; Department of Medical and Molecular Genetics (F.V.), Indiana University School of Medicine, Indianapolis, IN; and Baylor Genetics and Baylor College of Medicine (Y.Y.), Baylor College of Medicine, Houston, TX.
Neurology. 2021 Jul 13;97(2):e145-e155. doi: 10.1212/WNL.0000000000012143. Epub 2021 May 4.
To determine the molecular basis of a new monogenetic recessive disorder that results in familial autonomic ganglionopathy with diffuse autonomic failure.
Two adult siblings from one family (I-4 and I-5) and another participant from a second family (II-3) presented with severe neurogenic orthostatic hypotension (nOH), small nonreactive pupils, and constipation. All 3 affected members had low norepinephrine levels and diffuse panautonomic failure.
Whole exome sequencing of DNA from I-4 and I-5 showed compound heterozygosity for c.907_908delCT (p.L303Dfs115)/c.688 G>A (p.D230N) pathologic variants in the acetylcholine receptor, neuronal nicotinic, α3 subunit gene (). II-3 from the second family was homozygous for the same frameshift (fs) variant (p.L303Dfs115//p.L303Dfs*115). encodes a critical subunit of the nicotinic acetylcholine receptors (nAChRs) responsible for fast synaptic transmission in the autonomic ganglia. The fs variant is clearly pathogenic and the p.D230N variant is predicted to be damaging (SIFT)/probably damaging (PolyPhen2). The p.D230N variant lies on the interface between CHRNA3 and other nAChR subunits based on structural modeling and is predicted to destabilize the nAChR pentameric complex.
We report a novel genetic disease that affected 3 individuals from 2 unrelated families who presented with severe nOH, miosis, and constipation. These patients had rare pathologic variants in the gene that cosegregate with and are predicted to be the likely cause of their diffuse panautonomic failure.
确定一种新的单基因隐性遗传病的分子基础，该疾病导致家族性自主神经节病变伴弥漫性自主神经衰竭。
一个家庭的 2 名成年兄弟姐妹（I-4 和 I-5）和另一个来自第二个家庭的参与者（II-3）表现出严重的神经源性直立性低血压（nOH）、小而无反应的瞳孔和便秘。所有 3 名受影响的成员均存在去甲肾上腺素水平低和弥漫性全自主神经衰竭。
对 I-4 和 I-5 的 DNA 进行全外显子组测序显示，乙酰胆碱受体神经元型烟碱型α3 亚基基因（）中的 c.907_908delCT（p.L303Dfs115）/c.688 G>A（p.D230N）复合杂合病理性变异。来自第二个家庭的 II-3 是同一移码变异（p.L303Dfs115//p.L303Dfs*115）的纯合子。编码烟碱型乙酰胆碱受体（nAChRs）的关键亚基，负责自主神经节的快速突触传递。fs 变异显然是致病性的，p.D230N 变异被预测为有害（SIFT）/可能有害（PolyPhen2）。基于结构建模，p.D230N 变异位于 CHRNA3 与其他 nAChR 亚基之间的界面上，预计会使 nAChR 五聚体复合物不稳定。
我们报告了一种新的遗传性疾病，影响了来自 2 个无关家庭的 3 名个体，他们表现出严重的 nOH、瞳孔缩小和便秘。这些患者在基因中存在罕见的病理性变异，这些变异与弥漫性自主神经衰竭共分离，并预计是其弥漫性自主神经衰竭的可能原因。
