An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids,Genetics in Medicine

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An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids
Genetics in Medicine ( IF 8.8 ) Pub Date : 2020-11-26 , DOI: 10.1038/s41436-020-01027-3
Sacha Ferdinandusse ₁ , Kirsty McWalter ₂ , Heleen Te Brinke ₁ , Lodewijk IJlst ₁ , Petra M Mooijer ₁ , Jos P N Ruiter ₁ , Alida E M van Lint ₁ , Mia Pras-Raves _{1,

3,

4} , Eric Wever _{1,

3,

4} , Francisca Millan ₂ , Maria J Guillen Sacoto ₂ , Amber Begtrup ₂ , Mark Tarnopolsky ₅ , Lauren Brady ₅ , Roger L Ladda ₆ , Susan L Sell ₆ , Catherine B Nowak ₇ , Jessica Douglas ₇ , Cuixia Tian ₈ , Elizabeth Ulm ₉ , Seth Perlman ₁₀ , Arlene V Drack ₁₁ , Karen Chong ₁₂ , Nicole Martin ₁₂ , Jennifer Brault ₁₃ , Elly Brokamp ₁₃ , Camilo Toro ₁₄ , William A Gahl ₁₄ , Ellen F Macnamara ₁₄ , Lynne Wolfe ₁₄ , , Quinten Waisfisz ₁₅ , Petra J G Zwijnenburg ₁₅ , Alban Ziegler ₁₆ , Magalie Barth ₁₆ , Rosemarie Smith ₁₇ , Sara Ellingwood ₁₇ , Deborah Gaebler-Spira ₁₈ , Somayeh Bakhtiari ₁₉ , Michael C Kruer ₁₉ , Antoine H C van Kampen _{4,

20} , Ronald J A Wanders ₁ , Hans R Waterham ₁ , David Cassiman ₂₁ , Frédéric M Vaz ₁

Affiliation

Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Department of Clinical Chemistry, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands.
GeneDx, Gaithersburg, MD, USA.
Core Facility Metabolomics, Amsterdam UMC, Amsterdam, The Netherlands.
Bioinformatics Laboratory, Department of Epidemiology and Data Science, Amsterdam Public Health Research Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
Department of Pediatrics, McMaster University Children's Hospital, Hamilton, ON, Canada.
Department of Pediatrics, Penn State Children's Hospital, Hershey, PA, USA.
The Feingold Center for Children, Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA.
Division of Neurology, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Department of Neurology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA.
Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA, USA.
Mount Sinai Hospital, Department of Obstetrics and Gynecology, Prenatal Diagnosis and Medical Genetics Program, Toronto, ON, Canada.
Vanderbilt University Medical Center, Department of Pediatrics, Nashville, TN, USA.
NIH Undiagnosed Diseases Program, Office of the Clinical Director, National Human Genome Research Institute, NIH, Bethesda, MD, USA.
Department of Clinical Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
Genetic department, University Hospital Angers, Angers, France.
Division of Genetics, Department of Pediatrics, Maine Medical Center, Portland, ME, USA.
Feinberg Northwestern University School of Medicine, Shirley Ryan Ability Lab, Chicago, IL, USA.
Barrow Neurological Institute, Phoenix Children's Hospital and University of Arizona College of Medicine, Phoenix, AZ, USA.
Biosystems Data Analysis, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands.
Department of Gastroenterology-Hepatology, Metabolic Center, University Hospitals Leuven, Leuven, Belgium.

Purpose

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).

Methods

Following next-generation sequencing and clinical phenotyping, functional characterization was performed in patients’ fibroblasts using FAR1 enzyme analysis, FAR1 immunoblotting/immunofluorescence, and lipidomics.

Results

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.

Conclusion

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.

中文翻译：

由 FAR1 中的从头变异引起的一种常染色体显性神经系统疾病，导致醚脂合成失控

目的

在这项研究中，我们调查了 12 名FAR1从头变异患者的疾病病因，所有这些患者均导致第 480 位氨基酸发生变化 (p.Arg480Cys/His/Leu)。

方法

在下一代测序和临床表型分析之后，使用 FAR1 酶分析、FAR1 免疫印迹/免疫荧光和脂质组学对患者的成纤维细胞进行功能表征。

结果

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，大多数患者伴有言语和粗大运动发育迟缓和躯干肌张力减退。由双等位基因变异引起的 FAR1 缺乏导致醚脂质合成缺陷和缩醛磷脂缺乏。相比之下，具有从头FAR1变体的患者的成纤维细胞显示出缩醛磷脂水平升高。对成纤维细胞的进一步功能研究表明，这些变体会破坏 FAR1 蛋白水平的缩醛磷脂依赖性反馈调节，从而导致不受控制的醚脂质产生。