TY - JOUR
T1 - An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids
AU - Undiagnosed Diseases Network
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 - Cole, F. Sessions
AU - Wambach, Jennifer
AU - Baldridge, Dustin
AU - Pak, Stephen
AU - Schedl, Timothy
AU - Shin, Jimann
AU - Solnica-Krezel, Lilianna
N1 - 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
AN - SCOPUS:85096552716
SN - 1098-3600
VL - 23
SP - 740
EP - 750
JO - Genetics in Medicine
JF - Genetics in Medicine
IS - 4
ER -