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Biallelic loss of function variants in ATP1A2 cause hydrops fetalis, microcephaly, arthrogryposis and extensive cortical malformations.

ATP1A2双等位基因功能变异缺失导致胎儿水肿、小头畸形、关节囊病和广泛皮质畸形。

  • 影响因子:2.12
  • DOI:10.1016/j.ejmg.2019.01.014
  • 作者列表:"Monteiro FP","Curry CJ","Hevner R","Elliott S","Fisher JH","Turocy J","Dobyns WB","Costa LA","Freitas E","Kitajima JP","Kok F
  • 发表时间:2020-01-01
Abstract

:The Na+/K+- ATPase acts as an ion pump maintaining the essential plasma membrane potential in all mammalian cell types, and is essential for many cellular functions. There are four α isoforms (α1, α2, α3 and α4) with distinct expression patterns, kinetic properties and substrate affinity. The α2-isoform is encoded by ATP1A2 and evidence supports its utmost importance in Cl- homeostasis in neurons, and in the function of respiratory neurons at birth. Monallelic pathogenic variants in ATP1A2 are associated with familial hemiplegic migraine type 2 (FHM2) and on rare occasions with alternating hemiplegia of childhood 1 (AHC1). To date, no instances of biallelic loss of function variants have been reported in humans. However, Atp1a2 homozygous loss of function knockout mice (α2-/- mice) show severe motor deficits, with lack of spontaneous movements, and are perinatally lethal due to absent respiratory activity. In this report we describe three newborns from two unrelated families, who died neonatally, presenting in utero with an unusual form of fetal hydrops, seizures and polyhydramnios. At birth they had multiple joint contractures (e.g. arthrogryposis), microcephaly, malformations of cortical development, dysmorphic features and severe respiratory insufficiency. Biallelic loss of function variants in ATP1A2, predicted to be pathogenic were found on whole exome sequencing. We propose that this is a distinctive new syndrome caused by complete absence of Na+/K+- ATPase α2-isoform expression.

摘要

: Na +/K +-atp酶充当离子泵,在所有哺乳动物细胞类型中维持必需的质膜电位,并且对于许多细胞功能是必需的。有四种 α 亚型 (α1、 α2、 α3和 α4) 具有不同的表达模式、动力学性质和底物亲和力。Α2-亚型由ATP1A2编码,证据支持其在神经元的Cl-稳态以及出生时呼吸神经元的功能中至关重要。ATP1A2的单等位基因致病变异与家族性偏瘫性偏头痛2型 (FHM2) 和罕见的儿童交替性偏瘫1型 (AHC1) 相关。迄今为止,在人类中没有报道过双等位基因功能变体丧失的情况。然而,Atp1a2纯合功能缺失敲除小鼠 (α2-/-小鼠) 表现出严重的运动缺陷,缺乏自发运动,并且由于缺乏呼吸活动而导致围产期致死。在本报告中,我们描述了来自两个不相关家庭的三个新生儿,他们在新生儿中死亡,在子宫内表现为不寻常的胎儿水肿,癫痫发作和羊水过多。在出生时,他们有多个关节挛缩 (例如关节挛缩),小头畸形,皮质发育畸形,畸形特征和严重的呼吸衰竭。全外显子组测序发现ATP1A2的双等位基因功能缺失变异,预测为致病。我们认为这是一种由Na +/K +-atp酶 α2亚型表达完全缺失引起的独特的新综合征。

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