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.
Original language | English (US) |
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Pages (from-to) | 740-750 |
Number of pages | 11 |
Journal | Genetics in Medicine |
Volume | 23 |
Issue number | 4 |
DOIs | |
State | Published - Apr 2021 |
Funding
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.
ASJC Scopus subject areas
- Genetics(clinical)