Loss of α1β1 Soluble Guanylate Cyclase, the Major Nitric Oxide Receptor, Leads to Moyamoya and Achalasia
Loss of α1β1 Soluble Guanylate Cyclase, the Major Nitric Oxide Receptor, Leads to Moyamoya and Achalasia
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DOI：
10.1016/j.ajhg.2014.01.018
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发表时间：
2014-03-06
影响因子：
9.8
通讯作者：
Tournier-Lasserve, Elisabeth
中科院分区：
文献类型：
--
作者：
Herve, Dominique;Philippi, Anne;Tournier-Lasserve, Elisabeth
Moyamoya是一种脑血管疾病，其特征是颈内动脉末端(ICAS)进行性狭窄和异常的“Moyamoya”血管代偿性发展。这种导致缺血性和出血性中风的疾病的病理生理学机制尚不清楚。它可以作为一种单独的脑血管病(所谓的烟雾病)发生，也可以与各种情况有关(烟雾病综合征)。在这里，我们描述了一种常染色体隐性遗传病，导致严重的烟雾病和早发性失弛缓症在三个没有血缘关系的家庭。这种综合征在所有三个家系中都与GUCY1A3纯合突变有关，GUCY1A3编码一氧化氮(NO)的主要受体--可溶性鸟氨酸环化酶(SGC)的α1亚单位。血小板分析显示，可溶性α1β1鸟苷环化酶完全丧失，并显示出血小板内sGC意想不到的刺激作用。NO-sGC-cGMP途径是控制血管平滑肌松弛、血管张力和血管重塑的主要途径。我们的数据表明，这一通路的改变可能导致ICA分叉等敏感血管区域的异常血管重塑过程。这些数据为受影响的个体提供了治疗选择，并强烈表明，GUCY1A3和其他NO-sGC-cGMP途径成员的研究在孤立的早发性失弛缓症和非综合征烟雾病中都是必要的。
Moyamoya is a cerebrovascular condition characterized by a progressive stenosis of the terminal part of the internal carotid arteries (ICAs) and the compensatory development of abnormal "moyamoya" vessels. The pathophysiological mechanisms of this condition, which leads to ischemic and hemorrhagic stroke, remain unknown. It can occur as an isolated cerebral angiopathy (so-called moyamoya disease) or in association with various conditions (moyamoya syndromes). Here, we describe an autosomal-recessive disease leading to severe moyamoya and early-onset achalasia in three unrelated families. This syndrome is associated in all three families with homozygous mutations in GUCY1A3, which encodes the alpha 1 subunit of soluble guanylate cyclase (sGC), the major receptor for nitric oxide (NO). Platelet analysis showed a complete loss of the soluble alpha 1 beta 1 guanylate cyclase and showed an unexpected stimulatory role of sGC within platelets. The NO-sGC-cGMP pathway is a major pathway controlling vascular smooth-muscle relaxation, vascular tone, and vascular remodeling. Our data suggest that alterations of this pathway might lead to an abnormal vascular-remodeling process in sensitive vascular areas such as ICA bifurcations. These data provide treatment options for affected individuals and strongly suggest that investigation of GUCY1A3 and other members of the NO-sGC-cGMP pathway is warranted in both isolated early-onset achalasia and non-syndromic moyamoya.