Journal article
An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids
Genetics in medicine, Vol.23, pp.740-750
04/2021
DOI: 10.1038/s41436-020-01027-3
PMCID: PMC8026396
PMID: 33239752
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.
Details
- Title: Subtitle
- An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids
- Creators
- Sacha Ferdinandusse - University of AmsterdamKirsty McWalterHeleen te Brinke - University of AmsterdamLodewijk IJlst - University of AmsterdamPetra M Mooijer - University of AmsterdamJos P.N Ruiter - University of AmsterdamAlida E.M van Lint - University of AmsterdamMia Pras-Raves - University of AmsterdamEric Wever - University of AmsterdamFrancisca MillanMaria J Guillen SacotoAmber BegtrupMark TarnopolskyLauren Brady - McMaster UniversityRoger L Ladda - Pennsylvania State UniversitySusan L Sell - Pennsylvania State UniversityCatherine B NowakJessica DouglasCuixia TianElizabeth Ulm - Children's Hospital & Medical CenterSeth PerlmanJoy D Cogan - Vanderbilt UniversityArlene V DrackF. Sessions ColeKaren Chong - Sinai HospitalNichole HayesNicole Martin - Sinai HospitalDana KileyJennifer Brault - Vanderbilt UniversityKathy SiscoJimann ShinElly Brokamp - Vanderbilt UniversityUndiagnosed Diseases NetworkJennifer WambachMercedes E AlejanoLilianna Solnica-KrezelDaniel WegnerMahshid S AzamianQuinten Waisfisz - Vrije Universiteit AmsterdamCamilo ToroCarlos A BacinoPetra J.G ZwijnenburgWilliam A GahlAshok BalasubramanyamAlban ZieglerDustin BalidgeLindsay C BurrageMagalie BarthEllen F Macnamara - National Institutes of HealthHsiao Tuan ChaoRosemarie Smith - Maine Medical CenterStephen PakGary D ClarkSara EllingwoodLynne A Wolfe - National Institutes of HealthDeborah Gaebler-Spira - Shirley Ryan AbilityLabWilliam J CraigenTimothy SchedlHongzheng DaiSomayeh Bakhtiari - University of ArizonaShweta U DharLisa T EmrickAlica M GoldmanNeil A HanchardFariha JamalLefkothea KaravitiSeema R LalaniBrendan H LeeRichard A LewisRonit MaromPaolo MorettiDavid R MurdockSarah K NicholasJames P OrengoJennifer E PoseyLorraine PotockiJill A RosenfeldSusan L SamsonDaryl A ScottAlyssa A TranTiphanie P VogelMichael F WanglerShinya YamamotoChristine M EngPengfei Liu - Baylor College of MedicinePatricia A WardEdward BehrensMatthew DeardorffMarni FalkKelly HasseyKathleen Sullivan - Children's Hospital of PhiladelphiaAdeline VanderverDavid B GoldsteinHeidi CopeAllyn McConkie-RosellKelly SchochVandana ShashiEdward C SmithRebecca C SpillmannJennifer A SullivanQueenie K.G TanNicole M WalleyPankaj B AgrawalAlan H BeggsGerard T BerryLauren C BriereLaurel A CobbanMatthew CogginsCynthia M CooperElizabeth L FiegFrances HighIngrid A HolmSusan KorrickJoel B KrierSharyn A LincolnJoseph LoscalzoRichard L MaasCalum A MacRaeJ. Carl PallaisDeepak A RaoLance H RodanEdwin K SilvermanJoan M StolerDavid A SweetserMelissa WalkerChris A WalshCecilia EstevesEmily G KelleyIsaac S KohaneKimberly LeBlancAlexa T McCrayAnna NagySurena DasariBrendan C LanpherIan R LanzaEva MoravaDevin OglesbeeGuney BademciDeborah BarbouthStephanie BivonaOlveen CarrasquilloTa Chen Peter ChangIrman ForghaniAlana GrajewskiRosario IsasiByron LamRoy LevittXue Zhong Liu - University of MiamiJacob McCauleyRalph SaccoMario SaportaJudy SchaechterMustafa TekinFred TelischiWilla ThorsonStephan ZuchnerHeather A ColleyJyoti G DayalDavid J EcksteinLaurie C FindleyDonna M KrasnewichLaura A MamounasTeri A ManolioJohn J MulvihillGrace L LaMoureMadison P GolichTiina K UrvArgenia L DossMaria T AcostaCarsten BonnenmannPrecilla D’SouzaDavid D perCarlos FerreiraRena A GodfreyCatherine A GrodenValerie V MaduroThomas C MarkelloAvi NathDonna NovacicBarbara N PuseyColleen E WahlEva BakerElizabeth A BurkeDavid R AdamsMay Christine V MalicdanCynthia J TifftJohn YangBradley PowerBernadette GochuicoLaryssa HurynLea LathamJoie Davis - National Institutes of HealthDeborah Mosbrook-DavisFrancis RossignolBen SolomonJohn MacDowallAuey ThurmWadih ZeinMuhammad YousefMargaret AdamLaura AmendolaMichael BamshadAnita BeckJimmy BennettBeverly Berg-RoodElizabeth BlueBrenna BoydPeter ByersSirisak ChanprasertMichael CunninghamKatrina DippleDaniel DohertyDawn EarlIan GlassKatie Golden-GrantSihoun HahnAnne Hing - University of Washington Medical CenterFuki M HisamaMartha Horike-PyneGail P JarvikJeffrey JarvikSuman JayadevChristina LamKenneth MaravillaHeather MeffordJ. Lawrence MerrittGhayda MirzaaDeborah NickersonWendy RaskindNatalie RosenwasserC. Ron ScottAngela SunVirginia SybertStephanie WallaceMark WenerTara WengerEuan A AshleyGill BejeranoJonathan A BernsteinDevon BonnerTerra R CoakleyLiliana FernandezPaul G FisherLaure FresardJason HomYong HuangJennefer N KohlerElijah KravetsMarta M MajcherskaBeth A MartinShruti MarwahaColleen E McCormackArchana N RajaChloe M ReuterMaura RuzhnikovJacinda B SampsonKevin S SmithShirley SuttonHolly K TaborBrianna M TuckerMatthew T WheelerDiane B ZastrowChunli ZhaoWilliam E ByrdAnew B CrouseMatthew MightMariko Nakano-OkunoJordan WhitlockGabrielle BrownManish J ButteEsteban C Dell’AngelicaNaghmeh DorraniEmilie D DouineBrent L FogelIrma GutierrezAlden HuangDeborah KrakowHane LeeSana K LooBryan C MakMartin G Martin - University of California, Los AngelesJulian A Martínez-AgostoElisabeth McGeeStanley F Nelson - University of California, Los AngelesShirley Nieves-RoiguezChristina G.S PalmerJeanette C PappNeil H ParkerGenecee RenteriaRebecca H SignerJanet S SinsheimerJijun WanLee kai WangKatherine Wesseling PerryJeremy D WoodsJustin AlveyAshley AnewsJim BaleJohn BohnsackLorenzo BottoJohn CareyLaura PaceNicola LongoGabor MarthAaron QuinlanMatt VelinderDave ViskochilPinar Bayrak-ToydemirRong MaoMonte WesterfieldAnna BicanLaura DuncanRizwan HamidJennifer KennedyMary KozuiraJohn H Newman - Vanderbilt UniversityJohn A PhillipsLynette RivesAmy K RobertsonEmily SolemMichael C KruerAntoine H.C van Kampen - University of AmsterdamRonald J.A Wanders - University of AmsterdamHans R Waterham - University of AmsterdamDavid CassimanFrédéric M Vaz - University of Amsterdam
- Resource Type
- Journal article
- Publication Details
- Genetics in medicine, Vol.23, pp.740-750
- DOI
- 10.1038/s41436-020-01027-3
- PMID
- 33239752
- PMCID
- PMC8026396
- ISSN
- 1098-3600
- eISSN
- 1530-0366
- Language
- English
- Electronic publication date
- 11/26/2020
- Date published
- 04/2021
- Academic Unit
- Stead Family Department of Pediatrics; Ophthalmology and Visual Sciences
- Record Identifier
- 9984181079902771
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