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An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids. / Undiagnosed Diseases Network.

In: Genetics in medicine, Vol. 23, No. 4, 04.2021, p. 740-750.

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Undiagnosed Diseases Network. / An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids. In: Genetics in medicine. 2021 ; Vol. 23, No. 4. pp. 740-750.

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@article{b00d5ca41a22450cb2afe32d75b9ccb9,
title = "An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids",
abstract = "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{\textquoteright} 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{\textquoteright} 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.",
author = "Sacha Ferdinandusse and Kirsty McWalter and {te Brinke}, Heleen and Lodewijk IJlst and Mooijer, {Petra M.} and Ruiter, {Jos P. N.} and {van Lint}, {Alida E. M.} and Mia Pras-Raves and Eric Wever and Francisca Millan and {Guillen Sacoto}, {Maria J.} and Amber Begtrup and Mark Tarnopolsky and Lauren Brady and Ladda, {Roger L.} and Sell, {Susan L.} and Nowak, {Catherine B.} and Jessica Douglas and Cuixia Tian and Elizabeth Ulm and Seth Perlman and Drack, {Arlene V.} and Karen Chong and Nicole Martin and Jennifer Brault and Elly Brokamp and Camilo Toro and Gahl, {William A.} and Macnamara, {Ellen F.} and Lynne Wolfe and Alejandro, {Mercedes E.} and Azamian, {Mahshid S.} and Bacino, {Carlos A.} and Ashok Balasubramanyam and Burrage, {Lindsay C.} and Hsiao-Tuan Chao and Clark, {Gary D.} and Craigen, {William J.} and Hongzheng Dai and Dhar, {Shweta U.} and Emrick, {Lisa T.} and Goldman, {Alica M.} and Hanchard, {Neil A.} and Fariha Jamal and Lefkothea Karaviti and {Undiagnosed Diseases Network} and Zwijnenburg, {Petra J. G.} and {van Kampen}, {Antoine H. C.} and Wanders, {Ronald J. A.} and Waterham, {Hans R.} and Vaz, {Fr{\'e}d{\'e}ric M.}",
note = "Funding Information: The authors thank Elise van der Sluijs, Henny Rusch, Henk van Lenthe, and Serhii Chornyi for technical assistance and Clara van Karnebeek and Carlos Ferreira for helpful discussions. The Core Facility Metabolomics Amsterdam UMC is acknowledged for the lipidomics studies. This work was supported in part by the Common Fund, Office of the Director, National Institutes of Health (NIH) and the Intramural Research Program of the National Human Genome Research Institute, NIH (Bethesda, MD, USA). Portions of this work were supported by 1R01 NS106298. Publisher Copyright: {\textcopyright} 2020, The Author(s).",
year = "2021",
month = apr,
doi = "10.1038/s41436-020-01027-3",
language = "English",
volume = "23",
pages = "740--750",
journal = "Genetics in medicine",
issn = "1098-3600",
publisher = "Lippincott Williams and Wilkins",
number = "4",

}

RIS

TY - JOUR

T1 - An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids

AU - Ferdinandusse, Sacha

AU - McWalter, Kirsty

AU - te Brinke, Heleen

AU - IJlst, Lodewijk

AU - Mooijer, Petra M.

AU - Ruiter, Jos P. N.

AU - van Lint, Alida E. M.

AU - Pras-Raves, Mia

AU - Wever, Eric

AU - Millan, Francisca

AU - Guillen Sacoto, Maria J.

AU - Begtrup, Amber

AU - Tarnopolsky, Mark

AU - Brady, Lauren

AU - Ladda, Roger L.

AU - Sell, Susan L.

AU - Nowak, Catherine B.

AU - Douglas, Jessica

AU - Tian, Cuixia

AU - Ulm, Elizabeth

AU - Perlman, Seth

AU - Drack, Arlene V.

AU - Chong, Karen

AU - Martin, Nicole

AU - Brault, Jennifer

AU - Brokamp, Elly

AU - Toro, Camilo

AU - Gahl, William A.

AU - Macnamara, Ellen F.

AU - Wolfe, Lynne

AU - Alejandro, Mercedes E.

AU - Azamian, Mahshid S.

AU - Bacino, Carlos A.

AU - Balasubramanyam, Ashok

AU - Burrage, Lindsay C.

AU - Chao, Hsiao-Tuan

AU - Clark, Gary D.

AU - Craigen, William J.

AU - Dai, Hongzheng

AU - Dhar, Shweta U.

AU - Emrick, Lisa T.

AU - Goldman, Alica M.

AU - Hanchard, Neil A.

AU - Jamal, Fariha

AU - Karaviti, Lefkothea

AU - Undiagnosed Diseases Network

AU - Zwijnenburg, Petra J. G.

AU - van Kampen, Antoine H. C.

AU - Wanders, Ronald J. A.

AU - Waterham, Hans R.

AU - Vaz, Frédéric M.

N1 - Funding Information: The authors thank Elise van der Sluijs, Henny Rusch, Henk van Lenthe, and Serhii Chornyi for technical assistance and Clara van Karnebeek and Carlos Ferreira for helpful discussions. The Core Facility Metabolomics Amsterdam UMC is acknowledged for the lipidomics studies. This work was supported in part by the Common Fund, Office of the Director, National Institutes of Health (NIH) and the Intramural Research Program of the National Human Genome Research Institute, NIH (Bethesda, MD, USA). Portions of this work were supported by 1R01 NS106298. Publisher Copyright: © 2020, The Author(s).

PY - 2021/4

Y1 - 2021/4

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85096552716&partnerID=8YFLogxK

U2 - 10.1038/s41436-020-01027-3

DO - 10.1038/s41436-020-01027-3

M3 - Article

C2 - 33239752

VL - 23

SP - 740

EP - 750

JO - Genetics in medicine

JF - Genetics in medicine

SN - 1098-3600

IS - 4

ER -

ID: 14399144