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De novo stop-loss variants in CLDN11 cause hypomyelinating leukodystrophy.

CLDN11的从头停止丢失变异体引起低髓鞘性脑白质营养不良。

  • 影响因子:7.52
  • DOI:10.1093/brain/awaa410
  • 作者列表:"Riedhammer KM","Stockler S","Ploski R","Wenzel M","Adis-Dutschmann B","Ahting U","Alhaddad B","Blaschek A","Haack TB","Kopajtich R","Lee J","Murcia Pienkowski V","Pollak A","Szymanska K","Tarailo-Graovac M","van der Lee R","van Karnebeek CD","Meitinger T","Krägeloh-Mann I","Vill K
  • 发表时间:2021-03-03
Abstract

:Claudin-11, a tight junction protein, is indispensable in the formation of the radial component of myelin. Here, we report de novo stop-loss variants in the gene encoding claudin-11, CLDN11, in three unrelated individuals presenting with an early-onset spastic movement disorder, expressive speech disorder and eye abnormalities including hypermetropia. Brain MRI showed a myelin deficit with a discrepancy between T1-weighted and T2-weighted images and some progress in myelination especially involving the central and peripheral white matter. Exome sequencing identified heterozygous stop-loss variants c.622T>C, p.(*208Glnext*39) in two individuals and c.622T>G, p.(*208Gluext*39) in one individual, all occurring de novo. At the RNA level, the variant c.622T>C did not lead to a loss of expression in fibroblasts, indicating this transcript is not subject to nonsense-mediated decay and most likely translated into an extended protein. Extended claudin-11 is predicted to form an alpha helix not incorporated into the cytoplasmic membrane, possibly perturbing its interaction with intracellular proteins. Our observations suggest that stop-loss variants in CLDN11 expand the genetically heterogeneous spectrum of hypomyelinating leukodystrophies.

摘要

: Claudin-11,一种紧密连接蛋白,在髓鞘的径向成分的形成中是不可或缺的。在此,我们报告了三个不相关个体的编码claudin-11 CLDN11的基因的从头停止丢失变异,这些个体表现为早发性痉挛运动障碍、表达性言语障碍和眼部异常,包括远视。脑MRI显示髓鞘缺损,在T1-weighted和T2-weighted图像之间的差异和髓鞘形成的一些进展,特别是涉及中央和外周白质。外显子组测序在两个个体中鉴定了杂合停止丢失变异c.622T>C,p.(* 208Glnext * 39),在一个个体中鉴定了c.622T>G,p.(* 208Gluext * 39),所有这些都从头发生。在RNA水平上,变体c.622T>C没有导致成纤维细胞中表达的丧失,表明该转录物不经历无义介导的衰变,并且最可能翻译成延伸蛋白。预计延长claudin-11形成未掺入细胞质膜的 α 螺旋,可能扰乱其与细胞内蛋白的相互作用。我们的观察表明,CLDN11中的止损变异扩大了低髓鞘性脑白质营养不良的遗传异质性谱。

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DOI:10.1007/s11033-021-06299-9
作者列表:["Louvrier A","Terranova L","Meyer C","Meyer F","Euvrard E","Kroemer M","Rolin G"]

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