Bi-allelic variants in INTS11 are associated with a complex neurological disorder.
CPSF3L
Drosophila
INTS11
brain atrophy
dIntS11
delayed language development
developmental delay
impaired motor development
intellectual disability
Journal
American journal of human genetics
ISSN: 1537-6605
Titre abrégé: Am J Hum Genet
Pays: United States
ID NLM: 0370475
Informations de publication
Date de publication:
04 05 2023
04 05 2023
Historique:
received:
05
01
2023
accepted:
18
03
2023
medline:
8
5
2023
pubmed:
14
4
2023
entrez:
13
4
2023
Statut:
ppublish
Résumé
The Integrator complex is a multi-subunit protein complex that regulates the processing of nascent RNAs transcribed by RNA polymerase II (RNAPII), including small nuclear RNAs, enhancer RNAs, telomeric RNAs, viral RNAs, and protein-coding mRNAs. Integrator subunit 11 (INTS11) is the catalytic subunit that cleaves nascent RNAs, but, to date, mutations in this subunit have not been linked to human disease. Here, we describe 15 individuals from 10 unrelated families with bi-allelic variants in INTS11 who present with global developmental and language delay, intellectual disability, impaired motor development, and brain atrophy. Consistent with human observations, we find that the fly ortholog of INTS11, dIntS11, is essential and expressed in the central nervous systems in a subset of neurons and most glia in larval and adult stages. Using Drosophila as a model, we investigated the effect of seven variants. We found that two (p.Arg17Leu and p.His414Tyr) fail to rescue the lethality of null mutants, indicating that they are strong loss-of-function variants. Furthermore, we found that five variants (p.Gly55Ser, p.Leu138Phe, p.Lys396Glu, p.Val517Met, and p.Ile553Glu) rescue lethality but cause a shortened lifespan and bang sensitivity and affect locomotor activity, indicating that they are partial loss-of-function variants. Altogether, our results provide compelling evidence that integrity of the Integrator RNA endonuclease is critical for brain development.
Identifiants
pubmed: 37054711
pii: S0002-9297(23)00096-4
doi: 10.1016/j.ajhg.2023.03.012
pmc: PMC10183469
pii:
doi:
Substances chimiques
Drosophila Proteins
0
RNA, Messenger
0
Ints11 protein, Drosophila
0
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
774-789Subventions
Organisme : NHGRI NIH HHS
ID : UM1 HG008900
Pays : United States
Organisme : NICHD NIH HHS
ID : P50 HD105351
Pays : United States
Organisme : NIH HHS
ID : R24 OD031447
Pays : United States
Organisme : NHGRI NIH HHS
ID : R01 HG009141
Pays : United States
Organisme : Intramural NIH HHS
ID : Z01 OD022005
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG073260
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS035129
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM134539
Pays : United States
Organisme : NINDS NIH HHS
ID : U54 NS093793
Pays : United States
Organisme : NIH HHS
ID : R24 OD022005
Pays : United States
Organisme : Department of Health
ID : NIHR-RP-2016-07-019
Pays : United Kingdom
Organisme : NICHD NIH HHS
ID : P50 HD103555
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)
Hugo J Bellen
(HJ)
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
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Sihoun Hahn
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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)
Rachel Mahoney
(R)
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 Gs Palmer
(CG)
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)
Judy Schaechter
(J)
Timothy Schedl
(T)
Kelly Schoch
(K)
C Ron Scott
(CR)
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
(LS)
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)
Queenie K-G Tan
(QK)
Mustafa Tekin
(M)
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
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Matt Velinder
(M)
Dave Viskochil
(D)
Tiphanie P Vogel
(TP)
Colleen E Wahl
(CE)
Melissa Walker
(M)
Stephanie Wallace
(S)
Nicole M Walley
(NM)
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)
Informations de copyright
Copyright © 2023 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
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