New HSP-associated gene FAR1

Posted - February 2021 in Research Highlights

AD form with different disease mechanism

 

FAR1 should be considered as a candidate gene for HSP according to the conclusions of this huge multinational study of autosomal dominant HSP in 12 people with sporadic mutations in the FAR1 gene.

 

Autosomal recessive mutations in this gene have a different disease mechanism with the exact opposite effect on certain lipid levels (lower versus higher in the AD form).

 

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.

SOURCE: Genet Med. 2020 Nov 26. doi: 10.1038/s41436-020-01027-3. Online ahead of print. PMID: 33239752

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

Sacha Ferdinandusse  1 Kirsty McWalter  2 Heleen Te Brinke  3 Lodewijk IJlst  3 Petra M Mooijer  3 Jos P N Ruiter  3 Alida E M van Lint  3 Mia Pras-Raves  3   4   5 Eric Wever  3   4   5 Francisca Millan  2 Maria J Guillen Sacoto  2 Amber Begtrup  2 Mark Tarnopolsky  6 Lauren Brady  6 Roger L Ladda  7 Susan L Sell  7 Catherine B Nowak  8 Jessica Douglas  8 Cuixia Tian  9 Elizabeth Ulm  10 Seth Perlman  11 Arlene V Drack  12 Karen Chong  13 Nicole Martin  13 Jennifer Brault  14 Elly Brokamp  14 Camilo Toro  15 William A Gahl  15 Ellen F Macnamara  15 Lynne Wolfe  15 Undiagnosed Diseases NetworkQuinten Waisfisz  16 Petra J G Zwijnenburg  16 Alban Ziegler  17 Magalie Barth  17 Rosemarie Smith  18 Sara Ellingwood  18 Deborah Gaebler-Spira  19 Somayeh Bakhtiari  20 Michael C Kruer  20 Antoine H C van Kampen  5   21 Ronald J A Wanders  3 Hans R Waterham  3 David Cassiman  22 Frédéric M Vaz  23

 

Undiagnosed Diseases Network: Mercedes E AlejandroMahshid S AzamianCarlos A BacinoAshok BalasubramanyamLindsay C BurrageHsiao-Tuan ChaoGary D ClarkWilliam J CraigenHongzheng DaiShweta U DharLisa T EmrickAlica M GoldmanNeil A HanchardFariha JamalLefkothea KaravitiSeema R LalaniBrendan H LeeRichard A LewisRonit MaromPaolo M 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 LiuPatricia A WardEdward BehrensMatthew DeardorffMarni FalkKelly HasseyKathleen SullivanAdeline 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 NagySurendra DasariBrendan C LanpherIan R LanzaEva MoravaDevin OglesbeeGuney BademciDeborah BarbouthStephanie BivonaOlveen CarrasquilloTa Chen Peter ChangIrman ForghaniAlana GrajewskiRosario IsasiByron LamRoy LevittXue Zhong LiuJacob 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 GoldrichTiina K UrvArgenia L DossMaria T AcostaCarsten BonnenmannPrecilla D’SouzaDavid D DraperCarlos FerreiraRena A GodfreyCatherine A GrodenEllen F MacnamaraValerie V MaduroThomas C MarkelloAvi NathDonna NovacicBarbara N PuseyCamilo ToroColleen E WahlEva BakerElizabeth A BurkeDavid R AdamsWilliam A GahlMay Christine V MalicdanCynthia J TifftLynne A WolfeJohn YangBradley PowerBernadette GochuicoLaryssa HurynLea LathamJoie DavisDeborah Mosbrook-DavisFrancis RossignolBen SolomonJohn MacDowallAudrey ThurmWadih ZeinMuhammad YousefMargaret AdamLaura AmendolaMichael BamshadAnita BeckJimmy BennettBeverly Berg-RoodElizabeth BlueBrenna BoydPeter ByersSirisak ChanprasertMichael CunninghamKatrina DippleDaniel DohertyDawn EarlIan GlassKatie Golden-GrantSihoun HahnAnne HingFuki 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 ByrdAndrew B CrouseMatthew MightMariko Nakano-OkunoJordan WhitlockGabrielle BrownManish J ButteEsteban C Dell’AngelicaNaghmeh DorraniEmilie D DouineBrent L FogelIrma GutierrezAlden HuangDeborah KrakowHane LeeSandra K LooBryan C MakMartin G MartinJulian A Martínez-AgostoElisabeth McGeeStanley F NelsonShirley Nieves-RodriguezChristina G S PalmerJeanette C PappNeil H ParkerGenecee RenteriaRebecca H SignerJanet S SinsheimerJijun WanLee-Kai WangKatherine Wesseling PerryJeremy D WoodsJustin AlveyAshley AndrewsJim BaleJohn BohnsackLorenzo BottoJohn CareyLaura PaceNicola LongoGabor MarthPaolo MorettiAaron QuinlanMatt VelinderDave ViskochilPinar Bayrak-ToydemirRong MaoMonte WesterfieldAnna BicanElly BrokampLaura DuncanRizwan HamidJennifer KennedyMary KozuiraJohn H NewmanJohn A Phillips 3rdLynette RivesAmy K RobertsonEmily SolemJoy D CoganF Sessions ColeNichole HayesDana KileyKathy SiscoJennifer WambachDaniel WegnerDustin BaldridgeStephen PakTimothy SchedlJimann ShinLilianna Solnica-Krezel

1 Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Department of Clinical Chemistry, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands.

2 GeneDx, Gaithersburg, MD, USA.

3 Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Department of Clinical Chemistry, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands.

4 Core Facility Metabolomics, Amsterdam UMC, Amsterdam, The Netherlands.

5 Bioinformatics Laboratory, Department of Epidemiology and Data Science, Amsterdam Public Health Research Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

6 Department of Pediatrics, McMaster University Children’s Hospital, Hamilton, ON, Canada.

7 Department of Pediatrics, Penn State Children’s Hospital, Hershey, PA, USA.

8 The Feingold Center for Children, Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA, USA.

9 Division of Neurology, Cincinnati Children’s Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.

10 Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA.

11 Department of Neurology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA.

12 Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA, USA.

13 Mount Sinai Hospital, Department of Obstetrics and Gynecology, Prenatal Diagnosis and Medical Genetics Program, Toronto, ON, Canada.

14 Vanderbilt University Medical Center, Department of Pediatrics, Nashville, TN, USA.

15 NIH Undiagnosed Diseases Program, Office of the Clinical Director, National Human Genome Research Institute, NIH, Bethesda, MD, USA.

16 Department of Clinical Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.

17 Genetic department, University Hospital Angers, Angers, France.

18 Division of Genetics, Department of Pediatrics, Maine Medical Center, Portland, ME, USA.

19 Feinberg Northwestern University School of Medicine, Shirley Ryan Ability Lab, Chicago, IL, USA.

20 Barrow Neurological Institute, Phoenix Children’s Hospital and University of Arizona College of Medicine, Phoenix, AZ, USA.

21 Biosystems Data Analysis, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands.

22 Department of Gastroenterology-Hepatology, Metabolic Center, University Hospitals Leuven, Leuven, Belgium.

23 Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Department of Clinical Chemistry, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands.

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