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


  • 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

: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.


: 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。



作者列表:["Juan-Carlos PM","Perla-Lidia PP","Stephanie-Talia MM","Mónica-Griselda AM","Luz-María TE"]

METHODS::The ATP binding-cassette superfamily corresponds the mostly transmembrane transporters family found in humans. These proteins actively transport endogenous and exogenous substrates through biological membranes in body tissues, so they have an important role in the regulation of many physiological functions necessary for human homeostasis, as well as in response regulation to several pharmacological substrates. The development of multidrug resistance has become one of the main troubles in conventional chemotherapy in different illnesses including cancer, being the increased efflux of antineoplastic drugs the main reason for this multidrug resistance, with a key role of the ABC superfamily. Likely, the interindividual variability in the pharmacological response among patients is well known, and may be due to intrinsically factors of the disease, genetic and environmental ones. Thus, the understanding of this variability, especially the genetic variability associated with the efficacy and toxicity of drugs, can provide a safer and more effective pharmacological treatment, so ABC genes are considered as important regulators due to their relationship with the reduction in pharmacological response. In this review, updated information about transporters belonging to this superfamily was collected, the possible role of these transporters in cancer, the role of genetic variability in their genes, as well as some therapeutic tools that have been tried to raise against main transporters associated with chemoresistance in cancer.

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作者列表:["Sawada H","Oeda T","Kohsaka M","Tomita S","Umemura A","Park K","Yamamoto K","Kiyohara K"]

METHODS:BACKGROUND:Cholinergic neurotransmission regulates neuroinflammation in Parkinson disease (PD). RESEARCH DESIGN AND METHODS:The authors conducted a delayed-start study of donepezil for cognitive decline in non-demented PD patients. The study consisted of a 96-week randomized placebo-controlled double-blind phase 1, followed by a 24-week donepezil extension phase 2. The primary outcome measure was a change in the Mini-Mental State Examination (MMSE) at week 120. RESULTS:A total of 98 patients were randomly allocated to the early-start (donepezil-to-donepezil) and delayed-start (placebo-to-donepezil) groups. Mean (SD) of the baseline MMSE was 27.6 (2.0) and 28.0 (2.1), respectively. MMSE change at week 120 was better in the early-start group than in the delayed-start group, but the difference was not significant. The MMSE declined in apolipoprotein ε4 carriers, but not in non-carriers, and the factor interaction (intervention × ε4 genotype) was highly significant (P < 0.001). Analyzed with the interaction, the difference was significant (group difference 1.95 [0.33 to 3.57], P = 0.018). The MMSE decline slope in phase 1 was significantly better in the early-start group than in the delayed-start group (P = 0.048). CONCLUSIONS:Cognitive function deteriorated in ε4 carriers, but not in non-carriers, and early-start donepezil may postpone cognitive decline in the former.

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作者列表:["Louvrier A","Terranova L","Meyer C","Meyer F","Euvrard E","Kroemer M","Rolin G"]

METHODS::Since the discovery of dental pulp stem cells, a lot of teams have expressed an interest in dental pulp regeneration. Many approaches, experimental models and biological explorations have been developed, each including the use of stem cells and scaffolds with the final goal being clinical application in humans. In this review, the authors' objective was to compare the experimental models and strategies used for the development of biomaterials for tissue engineering of dental pulp with stem cells. Electronic queries were conducted on PubMed using the following terms: pulp regeneration, scaffold, stem cells, tissue engineering and biomaterial. The extracted data included the following information: the strategy envisaged, the type of stem cells, the experimental models, the exploration or analysis methods, the cytotoxicity or viability or proliferation cellular tests, the tests of scaffold antibacterial properties and take into account the vascularization of the regenerated dental pulp. From the 71 selected articles, 59% focused on the "cell-transplantation" strategy, 82% used in vitro experimentation, 58% in vivo animal models and only one described an in vivo in situ human clinical study. 87% used dental pulp stem cells. A majority of the studies reported histology (75%) and immunohistochemistry explorations (66%). 73% mentioned the use of cytotoxicity, proliferation or viability tests. 48% took vascularization into account but only 6% studied the antibacterial properties of the scaffolds. This article gives an overview of the methods used to regenerate dental pulp from stem cells and should help researchers create the best development strategies for research in this field.

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