An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids.
An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids.
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DOI：
10.1038/s41436-020-01027-3
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发表时间：
2021-04
期刊：
影响因子：
--
通讯作者：
Vaz FM
中科院分区：
文献类型：
--
作者：
Ferdinandusse S;McWalter K;Te Brinke H;IJlst L;Mooijer PM;Ruiter JPN;van Lint AEM;Pras-Raves M;Wever E;Millan F;Guillen Sacoto MJ;Begtrup A;Tarnopolsky M;Brady L;Ladda RL;Sell SL;Nowak CB;Douglas J;Tian C;Ulm E;Perlman S;Drack AV;Chong K;Martin N;Brault J;Brokamp E;Toro C;Gahl WA;Macnamara EF;Wolfe L;Undiagnosed Diseases Network;Waisfisz Q;Zwijnenburg PJG;Ziegler A;Barth M;Smith R;Ellingwood S;Gaebler-Spira D;Bakhtiari S;Kruer MC;van Kampen AHC;Wanders RJA;Waterham HR;Cassiman D;Vaz FM
在这项研究中，我们调查了12例患者的疾病病因与新发变异FAR 1所有导致氨基酸的变化，在位置480（p.Arg480Cys/His/Leu）。在下一代测序和临床表型分析之后，使用FAR 1酶分析、FAR 1免疫印迹/免疫荧光和脂质组学在患者的成纤维细胞中进行功能表征。所有患者均患有痉挛性下肢轻瘫和双侧先天性/青少年白内障，大多数伴有言语和大运动发育迟缓和躯干肌张力减退。由双等位基因变体引起的FAR 1缺陷导致醚脂质合成缺陷和缩醛磷脂缺乏。相反，具有新生FAR 1变体的患者的成纤维细胞显示出升高的缩醛磷脂水平。在成纤维细胞中的进一步功能研究表明，这些变体引起FAR 1蛋白水平的缩醛磷脂依赖性反馈调节的破坏，导致不受控制的醚脂质产生。影响FAR 1的Arg 480残基的杂合从头变异导致常染色体显性遗传疾病，其发病机制与隐性FAR 1缺陷不同，并且具有完全相反的生化表型。我们的研究结果表明，对于痉挛性截瘫和双侧白内障患者，FAR 1应被视为候选基因，并添加到遗传性痉挛性截瘫，脑瘫和青少年白内障的基因面板。
In this study we investigate the disease etiology in 12 patients with de novo variants in FAR1 all resulting in an amino acid change at position 480 (p.Arg480Cys/His/Leu). Following next-generation sequencing and clinical phenotyping, functional characterization was performed in patients’ fibroblasts using FAR1 enzyme analysis, FAR1 immunoblotting/immunofluorescence, and lipidomics. All patients had spastic paraparesis and bilateral congenital/juvenile cataracts, in most combined with speech and gross motor developmental delay and truncal hypotonia. FAR1 deficiency caused by biallelic variants results in defective ether lipid synthesis and plasmalogen deficiency. In contrast, patients’ fibroblasts with the de novo FAR1 variants showed elevated plasmalogen levels. Further functional studies in fibroblasts showed that these variants cause a disruption of the plasmalogen-dependent feedback regulation of FAR1 protein levels leading to uncontrolled ether lipid production. Heterozygous de novo variants affecting the Arg480 residue of FAR1 lead to an autosomal dominant disorder with a different disease mechanism than that of recessive FAR1 deficiency and a diametrically opposed biochemical phenotype. Our findings show that for patients with spastic paraparesis and bilateral cataracts, FAR1 should be considered as a candidate gene and added to gene panels for hereditary spastic paraplegia, cerebral palsy, and juvenile cataracts.
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