A novel DPH5-related diphthamide-deficiency syndrome causing embryonic lethality or profound neurodevelopmental disorder.
Nonverbal neurodevelopment delays
Novel gene discovery
Precision animal modeling
Precision genomics
Translational genetics
Journal
Genetics in medicine : official journal of the American College of Medical Genetics
ISSN: 1530-0366
Titre abrégé: Genet Med
Pays: United States
ID NLM: 9815831
Informations de publication
Date de publication:
07 2022
07 2022
Historique:
received:
02
11
2021
revised:
16
03
2022
accepted:
16
03
2022
pubmed:
29
4
2022
medline:
14
7
2022
entrez:
28
4
2022
Statut:
ppublish
Résumé
Diphthamide is a post-translationally modified histidine essential for messenger RNA translation and ribosomal protein synthesis. We present evidence for DPH5 as a novel cause of embryonic lethality and profound neurodevelopmental delays (NDDs). Molecular testing was performed using exome or genome sequencing. A targeted Dph5 knockin mouse (C57BL/6Ncrl-Dph5 DPH5 variants p.His260Arg (homozygous), p.Asn110Ser and p.Arg207Ter (heterozygous), and p.Asn174LysfsTer10 (homozygous) were identified in 3 unrelated families with distinct overlapping craniofacial features, profound NDDs, multisystem abnormalities, and miscarriages. Dph5 p.His260Arg homozygous knockin was embryonically lethal with only 1 subviable mouse exhibiting impaired growth, craniofacial dysmorphology, and multisystem dysfunction recapitulating the human phenotype. Adenosine diphosphate-ribosylation assays showed absent to decreased function in DPH5-knockout human and yeast cells. In silico modeling of the variants showed altered DPH5 structure and disruption of its interaction with eEF2. We provide strong clinical, biochemical, and functional evidence for DPH5 as a novel cause of embryonic lethality or profound NDDs with multisystem involvement and expand diphthamide-deficiency syndromes and ribosomopathies.
Identifiants
pubmed: 35482014
pii: S1098-3600(22)00704-3
doi: 10.1016/j.gim.2022.03.014
pmc: PMC9426662
mid: NIHMS1800445
pii:
doi:
Substances chimiques
Saccharomyces cerevisiae Proteins
0
Histidine
4QD397987E
Adenosine Diphosphate
61D2G4IYVH
diphthamide
75645-22-6
Methyltransferases
EC 2.1.1.-
DPH5 protein, S cerevisiae
EC 2.1.1.98
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1567-1582Subventions
Organisme : NHGRI NIH HHS
ID : U01 HG007690
Pays : United States
Organisme : NIH HHS
ID : UM1 OD023221
Pays : United States
Organisme : NIH HHS
ID : U42 OD012210
Pays : United States
Organisme : NIH HHS
ID : K01 OD026608
Pays : United States
Organisme : NHGRI NIH HHS
ID : U41 HG006834
Pays : United States
Investigateurs
Maria T Acosta
(MT)
Margaret Adam
(M)
David R Adams
(DR)
Justin Alvey
(J)
Laura Amendola
(L)
Ashley Andrews
(A)
Euan A Ashley
(EA)
Mahshid S Azamian
(MS)
Carlos A Bacino
(CA)
Guney Bademci
(G)
Ashok Balasubramanyam
(A)
Dustin Baldridge
(D)
Jim Bale
(J)
Michael Bamshad
(M)
Deborah Barbouth
(D)
Pinar Bayrak-Toydemir
(P)
Anita Beck
(A)
Alan H Beggs
(AH)
Edward Behrens
(E)
Gill Bejerano
(G)
Jimmy Bennet
(J)
Beverly Berg-Rood
(B)
Jonathan A Bernstein
(JA)
Gerard T Berry
(GT)
Anna Bican
(A)
Stephanie Bivona
(S)
Elizabeth Blue
(E)
John Bohnsack
(J)
Devon Bonner
(D)
Lorenzo Botto
(L)
Brenna Boyd
(B)
Lauren C Briere
(LC)
Elly Brokamp
(E)
Gabrielle Brown
(G)
Elizabeth A Burke
(EA)
Lindsay C Burrage
(LC)
Manish J Butte
(MJ)
Peter Byers
(P)
William E Byrd
(WE)
John Carey
(J)
Olveen Carrasquillo
(O)
Thomas Cassini
(T)
Ta Chen Peter Chang
(TC)
Sirisak Chanprasert
(S)
Hsiao-Tuan Chao
(HT)
Gary D Clark
(GD)
Terra R Coakley
(TR)
Laurel A Cobban
(LA)
Joy D Cogan
(JD)
Matthew Coggins
(M)
F Sessions Cole
(FS)
Heather A Colley
(HA)
Cynthia M Cooper
(CM)
Heidi Cope
(H)
William J Craigen
(WJ)
Andrew B Crouse
(AB)
Michael Cunningham
(M)
Precilla D'Souza
(P)
Hongzheng Dai
(H)
Surendra Dasari
(S)
Joie Davis
(J)
Jyoti G Dayal
(JG)
Matthew Deardorff
(M)
Esteban C Dell'Angelica
(EC)
Katrina Dipple
(K)
Daniel Doherty
(D)
Naghmeh Dorrani
(N)
Argenia L Doss
(AL)
Emilie D Douine
(ED)
Laura Duncan
(L)
Dawn Earl
(D)
David J Eckstein
(DJ)
Lisa T Emrick
(LT)
Christine M Eng
(CM)
Cecilia Esteves
(C)
Marni Falk
(M)
Liliana Fernandez
(L)
Elizabeth L Fieg
(EL)
Paul G Fisher
(PG)
Brent L Fogel
(BL)
Irman Forghani
(I)
William A Gahl
(WA)
Ian Glass
(I)
Bernadette Gochuico
(B)
Rena A Godfrey
(RA)
Katie Golden-Grant
(K)
Madison P Goldrich
(MP)
Alana Grajewski
(A)
Irma Gutierrez
(I)
Don Hadley
(D)
Sihoun Hahn
(S)
Rizwan Hamid
(R)
Kelly Hassey
(K)
Nichole Hayes
(N)
Frances High
(F)
Anne Hing
(A)
Fuki M Hisama
(FM)
Ingrid A Holm
(IA)
Jason Hom
(J)
Martha Horike-Pyne
(M)
Alden Huang
(A)
Yong Huang
(Y)
Wendy Introne
(W)
Rosario Isasi
(R)
Kosuke Izumi
(K)
Fariha Jamal
(F)
Gail P Jarvik
(GP)
Jeffrey Jarvik
(J)
Suman Jayadev
(S)
Orpa Jean-Marie
(O)
Vaidehi Jobanputra
(V)
Lefkothea Karaviti
(L)
Jennifer Kennedy
(J)
Shamika Ketkar
(S)
Dana Kiley
(D)
Gonench Kilich
(G)
Shilpa N Kobren
(SN)
Isaac S Kohane
(IS)
Jennefer N Kohler
(JN)
Deborah Krakow
(D)
Donna M Krasnewich
(DM)
Elijah Kravets
(E)
Susan Korrick
(S)
Mary Koziura
(M)
Seema R Lalani
(SR)
Byron Lam
(B)
Christina Lam
(C)
Grace L LaMoure
(GL)
Brendan C Lanpher
(BC)
Ian R Lanza
(IR)
Kimberly LeBlanc
(K)
Brendan H Lee
(BH)
Roy Levitt
(R)
Richard A Lewis
(RA)
Pengfei Liu
(P)
Xue Zhong Liu
(XZ)
Nicola Longo
(N)
Sandra K Loo
(SK)
Joseph Loscalzo
(J)
Richard L Maas
(RL)
Ellen F Macnamara
(EF)
Calum A MacRae
(CA)
Valerie V Maduro
(VV)
Bryan C Mak
(BC)
May Christine V Malicdan
(MCV)
Laura A Mamounas
(LA)
Teri A Manolio
(TA)
Rong Mao
(R)
Kenneth Maravilla
(K)
Ronit Marom
(R)
Gabor Marth
(G)
Beth A Martin
(BA)
Martin G Martin
(MG)
Julian A Martínez-Agosto
(JA)
Shruti Marwaha
(S)
Jacob McCauley
(J)
Allyn McConkie-Rosell
(A)
Alexa T McCray
(AT)
Elisabeth McGee
(E)
Heather Mefford
(H)
J Lawrence Merritt
(JL)
Matthew Might
(M)
Ghayda Mirzaa
(G)
Eva Morava
(E)
Paolo M Moretti
(PM)
Mariko Nakano-Okuno
(M)
Stan F Nelson
(SF)
John H Newman
(JH)
Sarah K Nicholas
(SK)
Deborah Nickerson
(D)
Shirley Nieves-Rodriguez
(S)
Donna Novacic
(D)
Devin Oglesbee
(D)
James P Orengo
(JP)
Laura Pace
(L)
Stephen Pak
(S)
J Carl Pallais
(JC)
Christina G S Palmer
(CGS)
Jeanette C Papp
(JC)
Neil H Parker
(NH)
John A Phillips
(JA)
Jennifer E Posey
(JE)
Lorraine Potocki
(L)
Barbara N Pusey
(BN)
Aaron Quinlan
(A)
Wendy Raskind
(W)
Archana N Raja
(AN)
Deepak A Rao
(DA)
Anna Raper
(A)
Genecee Renteria
(G)
Chloe M Reuter
(CM)
Lynette Rives
(L)
Amy K Robertson
(AK)
Lance H Rodan
(LH)
Jill A Rosenfeld
(JA)
Natalie Rosenwasser
(N)
Francis Rossignol
(F)
Maura Ruzhnikov
(M)
Ralph Sacco
(R)
Jacinda B Sampson
(JB)
Mario Saporta
(M)
C Ron Scott
(CR)
Judy Schaechter
(J)
Timothy Schedl
(T)
Kelly Schoch
(K)
Daryl A Scott
(DA)
Vandana Shashi
(V)
Jimann Shin
(J)
Edwin K Silverman
(EK)
Janet S Sinsheimer
(JS)
Kathy Sisco
(K)
Edward C Smith
(EC)
Kevin S Smith
(KS)
Emily Solem
(E)
Lilianna Solnica-Krezel
(L)
Ben Solomon
(B)
Rebecca C Spillmann
(RC)
Joan M Stoler
(JM)
Jennifer A Sullivan
(JA)
Kathleen Sullivan
(K)
Angela Sun
(A)
Shirley Sutton
(S)
David A Sweetser
(DA)
Virginia Sybert
(V)
Holly K Tabor
(HK)
Amelia L M Tan
(ALM)
K-G Queenie
(KG)
Tan Mustafa Tekin
(TM)
Fred Telischi
(F)
Willa Thorson
(W)
Cynthia J Tifft
(CJ)
Camilo Toro
(C)
Alyssa A Tran
(AA)
Brianna M Tucker
(BM)
Tiina K Urv
(TK)
Adeline Vanderver
(A)
Matt Velinder
(M)
Dave Viskochil
(D)
Tiphanie P Vogel
(TP)
Colleen E Wahl
(CE)
Stephanie Wallace
(S)
Nicole M Walley
(NM)
Melissa Walker
(M)
Jennifer Wambach
(J)
Jijun Wan
(J)
Lee-Kai Wang
(LK)
Michael F Wangler
(MF)
Patricia A Ward
(PA)
Daniel Wegner
(D)
Monika Weisz-Hubshman
(M)
Mark Wener
(M)
Tara Wenger
(T)
Katherine Wesseling Perry
(KW)
Monte Westerfield
(M)
Matthew T Wheeler
(MT)
Jordan Whitlock
(J)
Lynne A Wolfe
(LA)
Kim Worley
(K)
Changrui Xiao
(C)
Shinya Yamamoto
(S)
John Yang
(J)
Diane B Zastrow
(DB)
Zhe Zhang
(Z)
Chunli Zhao
(C)
Stephan Zuchner
(S)
Hugo Bellen
(H)
Rachel Mahoney
(R)
Commentaires et corrections
Type : ErratumIn
Informations de copyright
Copyright © 2022. Published by Elsevier Inc.
Déclaration de conflit d'intérêts
Conflicts of Interest K.G.M. is an employee of GeneDx, Inc. K.M. and U.B. are members of and employed by Roche Pharma Research & Early Development. Roche is interested in targeted therapies and diagnostics. All other authors declare no conflicts of interest.
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