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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • 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

Published Date

  • April 2021

Published In

Volume / Issue

  • 23 / 4

Start / End Page

  • 740 - 750

PubMed ID

  • 33239752

Pubmed Central ID

  • PMC8026396

Electronic International Standard Serial Number (EISSN)

  • 1530-0366

Digital Object Identifier (DOI)

  • 10.1038/s41436-020-01027-3


  • eng

Conference Location

  • United States