Biallelic ERBB3 loss-of-function variants are associated with a novel multisystem syndrome without congenital contracture
Biallelic ERBB3 loss-of-function variants are associated with a novel multisystem syndrome without congenital contracture
复制标题
双等位基因 ERBB3 功能丧失变异与一种新型多系统综合征（无先天性挛缩）相关
DOI：
10.1186/s13023-019-1241-z
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发表时间：
2019-11-21
影响因子：
3.7
通讯作者：
Wang, Jian
中科院分区：
文献类型：
--
作者：
Li, Niu;Xu, Yufei;Wang, Jian
Erb-B2受体酪氨酸激酶3(ERBB3)基因功能缺失变异通过激活磷脂酰肌醇3-激酶(PI3K)/AKT和细胞外信号调节激酶(ERK)信号转导途径参与多种人类肿瘤的发生和发展。ErbB3基因纯合子生殖系变异是近年来发现的常染色体隐性遗传性先天性宫缩综合征的致病因素。本研究旨在确定一个中国人家系的致病基因，该家系涉及多个系统，包括发育迟缓、出生后发育迟缓、一过性肢体不对称、面部畸形、房室管畸形、双眼眼球震颤和弱视、进食困难、免疫缺陷、贫血和肝脏损害，但没有先天性宫缩。结果Trio-Wes发现ERBB3基因中含有c.1253TC(p.I418T)和c.3182dupA(p.N1061Kfs*16)的复合杂合突变。功能研究表明，p.I418T能够正常表达ERBB3，并能与ERBB2相互作用。然而，该突变体抑制了ERBB3的磷酸化，从而阻止了ERBB2的磷酸化以及AKT和ERK的激活。由c.3182dupA变异导致的截短蛋白也缺乏激活下游信号通路的能力。结论我们报道了首例由ERBB3双等位基因功能丧失变异引起的无先天性肌挛缩的新的多系统综合征患者。
BackgroundGain-of-function pathogenic variants of the Erb-B2 receptor tyrosine kinase 3 (ERBB3) gene contribute to the occurrence and development of a variety of human carcinomas through activation of phosphatidylinositol 3-kinase (PI3K)/AKT and extracellular signal-regulated kinase (ERK) signaling. ERBB3 gene homozygous germline variants, whose loss of function may cause autosomal recessive congenital contractural syndrome, were recently identified. This study aims to identify the disease-causing gene in a Chinese pedigree with variable phenotypes involving multiple systems, including developmental delay, postnatal growth retardation, transient lower limb asymmetry, facial malformations, atrioventricular canal malformation, bilateral nystagmus and amblyopia, feeding difficulties, immunodeficiency, anemia, and liver damage, but without congenital contracture.MethodsTrio-whole exome sequencing (WES) was performed to identify the disease-causing gene in a 24-month-old Chinese female patient. The pathogenicity of the identified variants was evaluated using in silico tools and in vitro functional studies.ResultsTrio-WES revealed compound heterozygous variants of c.1253 T C (p.I418T) and c.3182dupA (p.N1061Kfs*16) in theERBB3gene. Functional studies showed that p.I418T resulted in normal expression of ERBB3, which was capable of interacting with ERBB2. However, the variant impaired ERBB3 phosphorylation, consequently blocking ERBB2 phosphorylation and AKT and ERK activation. The truncated protein resulting from the c.3182dupA variant also lacked the capacity to activate downstream signaling pathways.ConclusionsWe report the first patient with a novel multisystem syndrome disorder without congenital contracture resulting from biallelic loss-of-function variants ofERBB3.