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An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids.
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- Author(s): Ferdinandusse S;Ferdinandusse S; McWalter K; McWalter K; Te Brinke H; Te Brinke H; IJlst L; IJlst L; Mooijer PM; Mooijer PM; Ruiter JPN; Ruiter JPN; van Lint AEM; van Lint AEM; Pras-Raves M; Pras-Raves M; Pras-Raves M; Pras-Raves M; Wever E; Wever E; Wever E; Wever E; Millan F; Millan F; Guillen Sacoto MJ; Guillen Sacoto MJ; Begtrup A; Begtrup A; Tarnopolsky M; Tarnopolsky M; Brady L; Brady L; Ladda RL; Ladda RL; Sell SL; Sell SL; Nowak CB; Nowak CB; Douglas J; Douglas J; Tian C; Tian C; Ulm E; Ulm E; Perlman S; Perlman S; Drack AV; Drack AV; Chong K; Chong K; Martin N; Martin N; Brault J; Brault J; Brokamp E; Brokamp E; Toro C; Toro C; Gahl WA; Gahl WA; Macnamara EF; Macnamara EF; Wolfe L; Wolfe L; Waisfisz Q; Waisfisz Q; Zwijnenburg PJG; Zwijnenburg PJG; Ziegler A; Ziegler A; Barth M; Barth M; Smith R; Smith R; Ellingwood S; Ellingwood S; Gaebler-Spira D; Gaebler-Spira D; Bakhtiari S; Bakhtiari S; Kruer MC; Kruer MC; van Kampen AHC; van Kampen AHC; van Kampen AHC; Wanders RJA; Wanders RJA; Waterham HR; Waterham HR; Cassiman D; Cassiman D; Vaz FM; Vaz FM
- Source:Genetics in medicine : official journal of the American College of Medical Genetics [Genet Med] 2021 Apr; Vol. 23 (4), pp. 740-750. Date of Electronic Publication: 2020 Nov 26.
- Publication Type:Journal Article; Research Support, N.I.H., Extramural; Research Support, N.I.H., Intramural
- Language:English
- Additional Information
- Corporate Authors:
- Source: Publisher: Elsevier Country of Publication: United States NLM ID: 9815831 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1530-0366 (Electronic) Linking ISSN: 10983600 NLM ISO Abbreviation: Genet Med Subsets: MEDLINE
- Publication Information: Publication: 2022- : [New York] : Elsevier
Original Publication: Baltimore, MD : Lippincott, Williams & Wilkins, c1998- - Subject Terms:
- 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' 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. - Comments: Erratum in: Genet Med. 2021 Dec;23(12):2467. (PMID: 34667295)
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- Accession Number: 0 (Ethers)
0 (Lipids)
EC 1.2.- (Aldehyde Oxidoreductases)
EC 1.2.1.84 (FAR1 protein, human) - Publication Date: Date Created: 20201126 Date Completed: 20210603 Latest Revision: 20240222
- Publication Date: 20240222
- Accession Number: PMC8026396
- Accession Number: 10.1038/s41436-020-01027-3
- Accession Number: 33239752
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