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

Sacha Ferdinandusse; Kirsty McWalter; Heleen te Brinke; Lodewijk IJlst; Petra M Mooijer; Jos P.N Ruiter; Alida E.M van Lint; Mia Pras-Raves; Eric Wever; Francisca Millan; Maria J Guillen Sacoto; Amber Begtrup; Mark Tarnopolsky; Lauren Brady; Roger L Ladda; Susan L Sell; Catherine B Nowak; Jessica Douglas; Cuixia Tian; Elizabeth Ulm; Seth Perlman; Arlene V Drack; Karen Chong; Nicole Martin; Jennifer Brault; Elly Brokamp; Camilo Toro; William A Gahl; Ellen F Macnamara; Lynne A Wolfe; Undiagnosed Diseases Network; Mercedes E Alejano; Mahshid S Azamian; Carlos A Bacino; Ashok Balasubramanyam; Lindsay C Burrage; Hsiao Tuan Chao; Gary D Clark; William J Craigen; Hongzheng Dai; Shweta U Dhar; Lisa T Emrick; Alica M Goldman; Neil A Hanchard; Fariha Jamal; Lefkothea Karaviti; Seema R Lalani; Brendan H Lee; Richard A Lewis; Ronit Marom; Paolo Moretti; David R Murdock; Sarah K Nicholas; James P Orengo; Jennifer E Posey; Lorraine Potocki; Jill A Rosenfeld; Susan L Samson; Daryl A Scott; Alyssa A Tran; Tiphanie P Vogel; Michael F Wangler; Shinya Yamamoto; Christine M Eng; Pengfei Liu; Patricia A Ward; Edward Behrens; Matthew Deardorff; Marni Falk; Kelly Hassey; Kathleen Sullivan; Adeline Vanderver; David B Goldstein; Heidi Cope; Allyn McConkie-Rosell; Kelly Schoch; Vandana Shashi; Edward C Smith; Rebecca C Spillmann; Jennifer A Sullivan; Queenie K.G Tan; Nicole M Walley; Pankaj B Agrawal; Alan H Beggs; Gerard T Berry; Lauren C Briere; Laurel A Cobban; Matthew Coggins; Cynthia M Cooper; Elizabeth L Fieg; Frances High; Ingrid A Holm; Susan Korrick; Joel B Krier; Sharyn A Lincoln; Joseph Loscalzo; Richard L Maas; Calum A MacRae; J. Carl Pallais; Deepak A Rao; Lance H Rodan; Edwin K Silverman; Joan M Stoler; David A Sweetser; Melissa Walker; Chris A Walsh; Cecilia Esteves; Emily G Kelley; Isaac S Kohane; Kimberly LeBlanc; Alexa T McCray; Anna Nagy; Surena Dasari; Brendan C Lanpher; Ian R Lanza; Eva Morava; Devin Oglesbee; Guney Bademci; Deborah Barbouth; Stephanie Bivona; Olveen Carrasquillo; Ta Chen Peter Chang; Irman Forghani; Alana Grajewski; Rosario Isasi; Byron Lam; Roy Levitt; Xue Zhong Liu; Jacob McCauley; Ralph Sacco; Mario Saporta; Judy Schaechter; Mustafa Tekin; Fred Telischi; Willa Thorson; Stephan Zuchner; Heather A Colley; Jyoti G Dayal; David J Eckstein; Laurie C Findley; Donna M Krasnewich; Laura A Mamounas; Teri A Manolio; John J Mulvihill; Grace L LaMoure; Madison P Golich; Tiina K Urv; Argenia L Doss; Maria T Acosta; Carsten Bonnenmann; Precilla D’Souza; David D per; Carlos Ferreira; Rena A Godfrey; Catherine A Groden; Valerie V Maduro; Thomas C Markello; Avi Nath; Donna Novacic; Barbara N Pusey; Colleen E Wahl; Eva Baker; Elizabeth A Burke; David R Adams; May Christine V Malicdan; Cynthia J Tifft; John Yang; Bradley Power; Bernadette Gochuico; Laryssa Huryn; Lea Latham; Joie Davis; Deborah Mosbrook-Davis; Francis Rossignol; Ben Solomon; John MacDowall; Auey Thurm; Wadih Zein; Muhammad Yousef; Margaret Adam; Laura Amendola; Michael Bamshad; Anita Beck; Jimmy Bennett; Beverly Berg-Rood; Elizabeth Blue; Brenna Boyd; Peter Byers; Sirisak Chanprasert; Michael Cunningham; Katrina Dipple; Daniel Doherty; Dawn Earl; Ian Glass; Katie Golden-Grant; Sihoun Hahn; Anne Hing; Fuki M Hisama; Martha Horike-Pyne; Gail P Jarvik; Jeffrey Jarvik; Suman Jayadev; Christina Lam; Kenneth Maravilla; Heather Mefford; J. Lawrence Merritt; Ghayda Mirzaa; Deborah Nickerson; Wendy Raskind; Natalie Rosenwasser; C. Ron Scott; Angela Sun; Virginia Sybert; Stephanie Wallace; Mark Wener; Tara Wenger; Euan A Ashley; Gill Bejerano; Jonathan A Bernstein; Devon Bonner; Terra R Coakley; Liliana Fernandez; Paul G Fisher; Laure Fresard; Jason Hom; Yong Huang; Jennefer N Kohler; Elijah Kravets; Marta M Majcherska; Beth A Martin; Shruti Marwaha; Colleen E McCormack; Archana N Raja; Chloe M Reuter; Maura Ruzhnikov; Jacinda B Sampson; Kevin S Smith; Shirley Sutton; Holly K Tabor; Brianna M Tucker; Matthew T Wheeler; Diane B Zastrow; Chunli Zhao; William E Byrd; Anew B Crouse; Matthew Might; Mariko Nakano-Okuno; Jordan Whitlock; Gabrielle Brown; Manish J Butte; Esteban C Dell’Angelica; Naghmeh Dorrani; Emilie D Douine; Brent L Fogel; Irma Gutierrez; Alden Huang; Deborah Krakow; Hane Lee; Sana K Loo; Bryan C Mak; Martin G Martin; Julian A Martínez-Agosto; Elisabeth McGee; Stanley F Nelson; Shirley Nieves-Roiguez; Christina G.S Palmer; Jeanette C Papp; Neil H Parker; Genecee Renteria; Rebecca H Signer; Janet S Sinsheimer; Jijun Wan; Lee kai Wang; Katherine Wesseling Perry; Jeremy D Woods; Justin Alvey; Ashley Anews; Jim Bale; John Bohnsack; Lorenzo Botto; John Carey; Laura Pace; Nicola Longo; Gabor Marth; Aaron Quinlan; Matt Velinder; Dave Viskochil; Pinar Bayrak-Toydemir; Rong Mao; Monte Westerfield; Anna Bican; Laura Duncan; Rizwan Hamid; Jennifer Kennedy; Mary Kozuira; John H Newman; John A Phillips; Lynette Rives; Amy K Robertson; Emily Solem; Joy D Cogan; F. Sessions Cole; Nichole Hayes; Dana Kiley; Kathy Sisco; Jennifer Wambach; Daniel Wegner; Dustin Balidge; Stephen Pak; Timothy Schedl; Jimann Shin; Lilianna Solnica-Krezel; Quinten Waisfisz; Petra J.G Zwijnenburg; Alban Ziegler; Magalie Barth; Rosemarie Smith; Sara Ellingwood; Deborah Gaebler-Spira; Somayeh Bakhtiari; Michael C Kruer; Antoine H.C van Kampen; Ronald J.A Wanders; Hans R Waterham; David Cassiman; Frédéric M Vaz

doi:10.1038/s41436-020-01027-3

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

Journal article

Peer reviewed

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

Sacha Ferdinandusse, Kirsty McWalter, Heleen te Brinke, Lodewijk IJlst, Petra M Mooijer, Jos P.N Ruiter, Alida E.M van Lint, Mia Pras-Raves, Eric Wever, Francisca Millan, …

04/2021

DOI: https://doi.org/10.1038/s41436-020-01027-3

PMID: 33239752

Abstract

Genetics(clinical)

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.

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Title: An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids
Creators: Sacha Ferdinandusse
Kirsty McWalter
Heleen te Brinke
Lodewijk IJlst
Petra M Mooijer
Jos P.N Ruiter
Alida E.M van Lint
Mia Pras-Raves
Eric Wever
Francisca Millan
Maria J Guillen Sacoto
Amber Begtrup
Mark Tarnopolsky
Lauren Brady
Roger L Ladda
Susan L Sell
Catherine B Nowak
Jessica Douglas
Cuixia Tian
Elizabeth Ulm
Seth Perlman
Arlene V Drack
Karen Chong
Nicole Martin
Jennifer Brault
Elly Brokamp
Camilo Toro
William A Gahl
Ellen F Macnamara
Lynne A Wolfe
Undiagnosed Diseases Network
Mercedes E Alejano
Mahshid S Azamian
Carlos A Bacino
Ashok Balasubramanyam
Lindsay C Burrage
Hsiao Tuan Chao
Gary D Clark
William J Craigen
Hongzheng Dai
Shweta U Dhar
Lisa T Emrick
Alica M Goldman
Neil A Hanchard
Fariha Jamal
Lefkothea Karaviti
Seema R Lalani
Brendan H Lee
Richard A Lewis
Ronit Marom
Paolo Moretti
David R Murdock
Sarah K Nicholas
James P Orengo
Jennifer E Posey
Lorraine Potocki
Jill A Rosenfeld
Susan L Samson
Daryl A Scott
Alyssa A Tran
Tiphanie P Vogel
Michael F Wangler
Shinya Yamamoto
Christine M Eng
Pengfei Liu
Patricia A Ward
Edward Behrens
Matthew Deardorff
Marni Falk
Kelly Hassey
Kathleen Sullivan
Adeline Vanderver
David B Goldstein
Heidi Cope
Allyn McConkie-Rosell
Kelly Schoch
Vandana Shashi
Edward C Smith
Rebecca C Spillmann
Jennifer A Sullivan
Queenie K.G Tan
Nicole M Walley
Pankaj B Agrawal
Alan H Beggs
Gerard T Berry
Lauren C Briere
Laurel A Cobban
Matthew Coggins
Cynthia M Cooper
Elizabeth L Fieg
Frances High
Ingrid A Holm
Susan Korrick
Joel B Krier
Sharyn A Lincoln
Joseph Loscalzo
Richard L Maas
Calum A MacRae
J. Carl Pallais
Deepak A Rao
Lance H Rodan
Edwin K Silverman
Joan M Stoler
David A Sweetser
Melissa Walker
Chris A Walsh
Cecilia Esteves
Emily G Kelley
Isaac S Kohane
Kimberly LeBlanc
Alexa T McCray
Anna Nagy
Surena Dasari
Brendan C Lanpher
Ian R Lanza
Eva Morava
Devin Oglesbee
Guney Bademci
Deborah Barbouth
Stephanie Bivona
Olveen Carrasquillo
Ta Chen Peter Chang
Irman Forghani
Alana Grajewski
Rosario Isasi
Byron Lam
Roy Levitt
Xue Zhong Liu
Jacob McCauley
Ralph Sacco
Mario Saporta
Judy Schaechter
Mustafa Tekin
Fred Telischi
Willa Thorson
Stephan Zuchner
Heather A Colley
Jyoti G Dayal
David J Eckstein
Laurie C Findley
Donna M Krasnewich
Laura A Mamounas
Teri A Manolio
John J Mulvihill
Grace L LaMoure
Madison P Golich
Tiina K Urv
Argenia L Doss
Maria T Acosta
Carsten Bonnenmann
Precilla D’Souza
David D per
Carlos Ferreira
Rena A Godfrey
Catherine A Groden
Valerie V Maduro
Thomas C Markello
Avi Nath
Donna Novacic
Barbara N Pusey
Colleen E Wahl
Eva Baker
Elizabeth A Burke
David R Adams
May Christine V Malicdan
Cynthia J Tifft
John Yang
Bradley Power
Bernadette Gochuico
Laryssa Huryn
Lea Latham
Joie Davis
Deborah Mosbrook-Davis
Francis Rossignol
Ben Solomon
John MacDowall
Auey Thurm
Wadih Zein
Muhammad Yousef
Margaret Adam
Laura Amendola
Michael Bamshad
Anita Beck
Jimmy Bennett
Beverly Berg-Rood
Elizabeth Blue
Brenna Boyd
Peter Byers
Sirisak Chanprasert
Michael Cunningham
Katrina Dipple
Daniel Doherty
Dawn Earl
Ian Glass
Katie Golden-Grant
Sihoun Hahn
Anne Hing
Fuki M Hisama
Martha Horike-Pyne
Gail P Jarvik
Jeffrey Jarvik
Suman Jayadev
Christina Lam
Kenneth Maravilla
Heather Mefford
J. Lawrence Merritt
Ghayda Mirzaa
Deborah Nickerson
Wendy Raskind
Natalie Rosenwasser
C. Ron Scott
Angela Sun
Virginia Sybert
Stephanie Wallace
Mark Wener
Tara Wenger
Euan A Ashley
Gill Bejerano
Jonathan A Bernstein
Devon Bonner
Terra R Coakley
Liliana Fernandez
Paul G Fisher
Laure Fresard
Jason Hom
Yong Huang
Jennefer N Kohler
Elijah Kravets
Marta M Majcherska
Beth A Martin
Shruti Marwaha
Colleen E McCormack
Archana N Raja
Chloe M Reuter
Maura Ruzhnikov
Jacinda B Sampson
Kevin S Smith
Shirley Sutton
Holly K Tabor
Brianna M Tucker
Matthew T Wheeler
Diane B Zastrow
Chunli Zhao
William E Byrd
Anew B Crouse
Matthew Might
Mariko Nakano-Okuno
Jordan Whitlock
Gabrielle Brown
Manish J Butte
Esteban C Dell’Angelica
Naghmeh Dorrani
Emilie D Douine
Brent L Fogel
Irma Gutierrez
Alden Huang
Deborah Krakow
Hane Lee
Sana K Loo
Bryan C Mak
Martin G Martin
Julian A Martínez-Agosto
Elisabeth McGee
Stanley F Nelson
Shirley Nieves-Roiguez
Christina G.S Palmer
Jeanette C Papp
Neil H Parker
Genecee Renteria
Rebecca H Signer
Janet S Sinsheimer
Jijun Wan
Lee kai Wang
Katherine Wesseling Perry
Jeremy D Woods
Justin Alvey
Ashley Anews
Jim Bale
John Bohnsack
Lorenzo Botto
John Carey
Laura Pace
Nicola Longo
Gabor Marth
Aaron Quinlan
Matt Velinder
Dave Viskochil
Pinar Bayrak-Toydemir
Rong Mao
Monte Westerfield
Anna Bican
Laura Duncan
Rizwan Hamid
Jennifer Kennedy
Mary Kozuira
John H Newman
John A Phillips
Lynette Rives
Amy K Robertson
Emily Solem
Joy D Cogan
F. Sessions Cole
Nichole Hayes
Dana Kiley
Kathy Sisco
Jennifer Wambach
Daniel Wegner
Dustin Balidge
Stephen Pak
Timothy Schedl
Jimann Shin
Lilianna Solnica-Krezel
Quinten Waisfisz
Petra J.G Zwijnenburg
Alban Ziegler
Magalie Barth
Rosemarie Smith
Sara Ellingwood
Deborah Gaebler-Spira
Somayeh Bakhtiari
Michael C Kruer
Antoine H.C van Kampen
Ronald J.A Wanders
Hans R Waterham
David Cassiman
Frédéric M Vaz
Publisher: Elsevier BV
Identifiers: 9924150810701921
Academic Unit: Interdepartmental Program in Genetic Counseling
Language: English
Resource Type: Journal article

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

Abstract

UN Sustainable Development Goals (SDGs)

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