GNBS Mutations Cause an Autosomal-Recessive Multisystem Syndrome with Sinus Bradycardia and Cognitive Disability
GNBS Mutations Cause an Autosomal-Recessive Multisystem Syndrome with Sinus Bradycardia and Cognitive Disability
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DOI：
10.1016/j.ajhg.2016.06.025
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发表时间：
2016-09-01
影响因子：
9.8
通讯作者：
Merla, Giuseppe
中科院分区：
文献类型：
--
作者：
Lodder, Elisabeth M.;De Nittis, Pasquelena;Merla, Giuseppe
GNB 5编码G蛋白β亚基5，并参与抑制性G蛋白信号传导。在这里，我们报告了来自六个家庭的九名个体中GNB 5的突变，这些突变与心率障碍、眼部疾病、智力障碍、胃病、张力减退和癫痫发作有关。我们观察到变异的性质与临床严重程度之间的关联;具有功能丧失等位基因的个体具有更严重的症状，包括实质性发育迟缓、言语缺陷、严重肌张力减退、病理性胃食管反流、视网膜疾病和窦房结功能障碍，而具有错义变异的相关杂合子呈现临床上较温和的表型。斑马鱼gnb 5基因敲除概括了受影响个体的表型谱，包括心脏，神经和眼科异常，支持GNB 5在控制心率，张力减退和视力中的直接作用。
GNB5 encodes the G protein beta subunit 5 and is involved in inhibitory G protein signaling. Here, we report mutations in GNB5 that are associated with heart-rate disturbance, eye disease, intellectual disability, gastric problems, hypotonia, and seizures in nine individuals from six families. We observed an association between the nature of the variants and clinical severity; individuals with loss-of-function alleles had more severe symptoms, including substantial developmental delay, speech defects, severe hypotonia, pathological gastro-esophageal re flux, retinal disease, and sinus-node dysfunction, whereas related heterozygotes harboring missense variants presented with a clinically milder phenotype. Zebrafish gnb5 knockouts recapitulated the phenotypic spectrum of affected individuals, including cardiac, neurological, and ophthalmological abnormalities, supporting a direct role of GNB5 in the control of heart rate, hypotonia, and vision.