一种导致中度运输缺陷的低形态FLVCR2变异可导致无脑积水综合征伴脑钙化。

IF 4.6 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Marcello Scala, Nancy C P Leong, Thanh Nha Uyen Le, Yu Zhang, Yichang Wu, Mariasavina Severino, Francesca Madia, Mohammad Sadegh Shams Nosrati, Alireza Dostmohammadi, Valeria Capra, Dario Paladini, Francesca Buffelli, Ezio Fulcheri, Serena Cappato, Ludovica Menta, Renata Bocciardi, Federico Zara, Long N Nguyen
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引用次数: 0

摘要

FLVCR2是主要促进剂超家族(MFS)中高度保守的成员,MFS是最大的溶质载体超家族,参与小分子在脂质双分子层上的运输。鼠类同源基因Mfsd7c(一种脑血管内皮转运蛋白)的缺失会导致脑血管生长缺陷和致死性。隐性FLVCR2变异可引起增殖性血管病变和无脑-脑积水综合征(PVHH),也称为福勒综合征。这种通常致命的疾病以小头畸形、骨骼畸形和严重的脑血管缺陷为特征。尽管已经报道了一些病例,但关于FLVCR2变异致病性的证据非常有限。在这项研究中,我们彻底调查了一个新的胎儿福勒综合征病例。通过外显子组测序,我们鉴定出两个复合杂合FLVCR2变异体:母体c.1124+3_1124+6del和父亲p.(Arg492Trp)。c.1124+3_1124+6del变异对FLVCR2的影响通过微基因实验进行了研究,结果显示FLVCR2外显子5剪接受损。为了描述p.(Arg492Trp)取代的影响,我们使用Rosetta和DynaMut2进行了蛋白质建模,显示出高度不稳定的影响。然后,基于胆碱是FLVCR2主要配体的最新证据,我们在HEK 293细胞中进行了放射性标记的胆碱或乙醇胺运输试验,发现p.(Arg492Trp)变体导致FLVCR2运输活性降低50-60%,导致净活性降低25-30%。我们的研究结果表明,即使在运输活性没有完全丧失的情况下,FLVCR2缺乏也可能足以导致PVHH,可能涉及这种复杂疾病的病理生理中的遗传外因素。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
A hypomorphic FLVCR2 variant resulting in moderate transport deficiency causes hydranencephaly syndrome with brain calcifications.

FLVCR2 is a highly conserved member of the major facilitator superfamily (MFS), the largest superfamily of solute carriers that are involved in the transport of small molecules across lipid bilayers. The loss of the murine ortholog Mfsd7c, an endothelial transporter in brain blood vessels, causes brain angiogenic growth deficiency and lethality. Recessive FLVCR2 variants cause proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome (PVHH), also known as Fowler syndrome. This often-lethal condition features microcephaly, skeletal deformities, and severe cerebrovascular defects. Although a number of cases have been reported, very limited evidence of the pathogenicity of FLVCR2 variants is available. In this study, we thoroughly investigated a new fetal case of Fowler syndrome. Through exome sequencing, we identified two compound heterozygous FLVCR2 variants: the maternal c.1124+3_1124+6del and the paternal p.(Arg492Trp). The effects of the c.1124+3_1124+6del variant were investigated through a minigene assay, which showed impaired splicing of the exon 5 of FLVCR2. To characterize the impact of the p.(Arg492Trp) substitution, we performed protein modeling using Rosetta and DynaMut2, that showed a highly destabilizing effect. Then, based on the very recent evidence that choline is a major FLVCR2 ligand, we performed a radiolabeled-choline or ethanolamine transport assays in HEK 293 cells and found that the p.(Arg492Trp) variant causes a 50-60% reduction of FLVCR2 transport activity, resulting in a net activity of 25-30%. Our findings suggest that FLVCR2 deficiency may be sufficient to cause PVHH even in the absence of a complete loss of transport activity, possibly involving extragenetic factors in the pathophysiology of this complex condition.

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来源期刊
European Journal of Human Genetics
European Journal of Human Genetics 生物-生化与分子生物学
CiteScore
9.90
自引率
5.80%
发文量
216
审稿时长
2 months
期刊介绍: The European Journal of Human Genetics is the official journal of the European Society of Human Genetics, publishing high-quality, original research papers, short reports and reviews in the rapidly expanding field of human genetics and genomics. It covers molecular, clinical and cytogenetics, interfacing between advanced biomedical research and the clinician, and bridging the great diversity of facilities, resources and viewpoints in the genetics community. Key areas include: -Monogenic and multifactorial disorders -Development and malformation -Hereditary cancer -Medical Genomics -Gene mapping and functional studies -Genotype-phenotype correlations -Genetic variation and genome diversity -Statistical and computational genetics -Bioinformatics -Advances in diagnostics -Therapy and prevention -Animal models -Genetic services -Community genetics
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