HNRNPC haploinsufficiency affects alternative splicing of intellectual disability-associated genes and causes a neurodevelopmental disorder

Eva Niggl; Arjan Bouman; Lauren C. Briere; Remco M. Hoogenboezem; Ilse Wallaard; Joohyun Park; Jakob Admard; Martina Wilke; Emilio D.R.O. Harris-Mostert; Minetta Elgersma; Jennifer Bain; Meena Balasubramanian; Siddharth Banka; Paul J. Benke; Miriam Bertrand; Alyssa E. Blesson; Jill Clayton-Smith; Jamie M. Ellingford; Madelyn A. Gillentine; Dana H. Goodloe; Tobias B. Haack; Mahim Jain; Ian Krantz; Sharon M. Luu; Molly McPheron; Candace L. Muss; Sarah E. Raible; Nathaniel H. Robin; Michael Spiller; Susan Starling; David A. Sweetser; Isabelle Thiffault; Francesco Vetrini; Dennis Witt; Emily Woods; Dihong Zhou; J.C. Ambrose; P. Arumugam; R. Bevers; M. Bleda; F. Boardman-Pretty; C.R. Boustred; H. Brittain; M.A. Brown; M.J. Caulfield; G.C. Chan; A. Giess; J.N. Griffin; A. Hamblin; S. Henderson; T.J.P. Hubbard; R. Jackson; L.J. Jones; D. Kasperaviciute; M. Kayikci; A. Kousathanas; L. Lahnstein; A. Lakey; S.E.A. Leigh; I.U.S. Leong; F.J. Lopez; F. Maleady-Crowe; M. McEntagart; F. Minneci; J. Mitchell; L. Moutsianas; M. Mueller; N. Murugaesu; A.C. Need; P. O‘Donovan; C.A. Odhams; C. Patch; D. Perez-Gil; M.B. Pereira; J. Pullinger; T. Rahim; A. Rendon; T. Rogers; K. Savage; K. Sawant; R.H. Scott; A. Siddiq; A. Sieghart; S.C. Smith; A. Sosinsky; A. Stuckey; M. Tanguy; A.L. Taylor Tavares; E.R.A. Thomas; S.R. Thompson; A. Tucci; M.J. Welland; E. Williams; K. Witkowska; S.M. Wood; M. Zarowiecki; Maria T. Acosta; David R. Adams; Raquel L. Alvarez; Justin Alvey; Aimee Allworth; Ashley Andrews; Euan A. Ashley; Ben Afzali; Carlos A. Bacino; Guney Bademci; Ashok Balasubramanyam; Dustin Baldridge; Jim Bale; Michael Bamshad; Deborah Barbouth; Pinar Bayrak-Toydemir; Anita Beck; Alan H. Beggs; Edward Behrens; Gill Bejerano; Hugo J. Bellen; Jimmy Bennet; Jonathan A. Bernstein; Gerard T. Berry; Anna Bican; Stephanie Bivona; Elizabeth Blue; John Bohnsack; Devon Bonner; Lorenzo Botto; Gabrielle Brown; Elizabeth A. Burke; Lindsay C. Burrage; Manish J. Butte; Peter Byers; William E. Byrd; John Carey; Olveen Carrasquillo; Thomas Cassini; Ta Chen Chang; Sirisak Chanprasert; Hsiao-Tuan Chao; Ivan Chinn; Gary D. Clark; Terra R. Coakley; Laurel A. Cobban; Joy D. Cogan; Matthew Coggins; F. Sessions Cole; Heather A. Colley; Heidi Cope; Rosario Corona; William J. Craigen; Andrew B. Crouse; Michael Cunningham; Precilla D'Souza; Hongzheng Dai; Surendra Dasari; Joie Davis; Jyoti G. Dayal; Margaret Delgado; Esteban C. Dell'Angelica; Katrina Dipple; Daniel Doherty; Naghmeh Dorrani; Argenia L. Doss; Emilie D. Douine; Dawn Earl; David J. Eckstein; Lisa T. Emrick; Christine M. Eng; Marni Falk; Elizabeth L. Fieg; Paul G. Fisher; Brent L. Fogel; Irman Forghani; Jiayu Fu; William A. Gahl; Ian Glass; Page C. Goddard; Rena A. Godfrey; Alana Grajewski; Meghan C. Halley; Rizwan Hamid; Neal Hanchard; Kelly Hassey; Nichole Hayes; Frances High; Anne Hing; Fuki M. Hisama; Ingrid A. Holm; Jason Hom; Martha Horike-Pyne; Alden Huang; Yan Huang; Sarah Hutchison; Wendy Introne; Rosario Isasi; Kosuke Izumi; Gail P. Jarvik; Jeffrey Jarvik; Suman Jayadev; Orpa Jean-Marie; Vaidehi Jobanputra; Emerald Kaitryn; Shamika Ketkar; Dana Kiley; Gonench Kilich; Shilpa N. Kobren; Isaac S. Kohane; Jennefer N. Kohler; Susan Korrick; Deborah Krakow; Donna M. Krasnewich; Elijah Kravets; Seema R. Lalani; Byron Lam; Christina Lam; Brendan C. Lanpher; Ian R. Lanza; Kimberly LeBlanc; Brendan H. Lee; Roy Levitt; Richard A. Lewis; Pengfei Liu; Xue Zhong Liu; Nicola Longo; Sandra K. Loo; Joseph Loscalzo; Richard L. Maas; Ellen F. Macnamara; Calum A. MacRae; Valerie V. Maduro; AudreyStephannie Maghiro; Rachel Mahoney; May Christine Malicdan; Laura A. Mamounas; Teri A. Manolio; Rong Mao; Ronit Marom; Gabor Marth; Beth A. Martin; Martin G. Martin; Julian A. Martínez-Agosto; Shruti Marwaha; Jacob McCauley; Allyn McConkie-Rosell; Alexa T. McCray; Elisabeth McGee; Matthew Might; Danny Miller; Ghayda Mirzaa; Eva Morava; Paolo Moretti; Marie Morimoto; John J. Mulvihill; Mariko Nakano-Okuno; Stanley F. Nelson; Shirley Nieves-Rodriguez; Donna Novacic; Devin Oglesbee; James P. Orengo; Laura Pace; Stephen Pak; J. Carl Pallais; Jeanette C. Papp; Neil H. Parker; Leoyklang Petcharet; John A. Phillips; Jennifer E. Posey; Lorraine Potocki; Barbara N. Swerdzewski; Aaron Quinlan; Deepak A. Rao; Anna Raper; Wendy Raskind; Genecee Renteria; Chloe Reuter; Lynette Rives; Amy K. Robertson; Lance H. Rodan; Jill A. Rosenfeld; Elizabeth Rosenthal; Francis Rossignol; Maura Ruzhnikov; Marla Sabaii; Ralph Sacco; Jacinda B. Sampson; Mario Saporta; Judy Schaechter; Timothy Schedl; Kelly Schoch; Daryl A. Scott; Elaine Seto; Prashant Sharma; Vandana Shashi; Emily Shelkowitz; Sam Sheppeard; Jimann Shin; Edwin Silverman; Janet Sinsheimer; Kathy Sisco; Edward Smith; Kevin Smith; Lilianna Solnica-Krezel; Ben Solomon; Rebecca Spillmann; Andrew Stergachis; Joan Stoler; Kathleen Sullivan; Jennifer Sullivan; Shirley Sutton; Virginia Sybert; Holly K. Tabor; Queenie K.-G. Tan; Amelia L. Tan; Arjun Tarakad; Mustafa Tekin; Fred Telischi; Willa Thorson; Cynthia Tifft; Camilo Toro; Alyssa A. Tran; Rachel A. Ungar; Tiina K. Urv; Adeline Vanderver; Matt Velinder; Dave Viskochil; Tiphanie P. Vogel; Colleen E. Wahl; Melissa Walker; Nicole M. Walley; Jennifer Wambach; Jijun Wan; Lee-kai Wang; Michael F. Wangler; Patricia A. Ward; Daniel Wegner; Monika Weisz; Mark Wener; Tara Wenger; Monte Westerfield; Matthew T. Wheeler; Jordan Whitlock; Lynne A. Wolfe; Shinya Yamamoto; Zhe Zhang; Stephan Zuchner; Ype Elgersma; Annelot C.M. van Esbroeck; Genomics England Research Consortium

doi:10.1016/j.ajhg.2023.07.005

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HNRNPC haploinsufficiency affects alternative splicing of intellectual disability-associated genes and causes a neurodevelopmental disorder

Journal article

Peer reviewed

HNRNPC haploinsufficiency affects alternative splicing of intellectual disability-associated genes and causes a neurodevelopmental disorder

Eva Niggl, Arjan Bouman, Lauren C. Briere, Remco M. Hoogenboezem, Ilse Wallaard, Joohyun Park, Jakob Admard, Martina Wilke, Emilio D.R.O. Harris-Mostert, Minetta Elgersma, …

American journal of human genetics, Vol.110(8), pp.1414-1435

2023-08-03

DOI: https://doi.org/10.1016/j.ajhg.2023.07.005

Appears in Miller School of Medicine - Latest Publications

Abstract

alternative splicing

heterogeneous ribonucleoprotein C

HNRNP

HNRNPC

induced pluripotent stem cells

intellectual disability

iPSCs

NDD

neurodevelopmental disorder

RNA processing

Heterogeneous nuclear ribonucleoprotein C (HNRNPC) is an essential, ubiquitously abundant protein involved in mRNA processing. Genetic variants in other members of the HNRNP family have been associated with neurodevelopmental disorders. Here, we describe 13 individuals with global developmental delay, intellectual disability, behavioral abnormalities, and subtle facial dysmorphology with heterozygous HNRNPC germline variants. Five of them bear an identical in-frame deletion of nine amino acids in the extreme C terminus. To study the effect of this recurrent variant as well as HNRNPC haploinsufficiency, we used induced pluripotent stem cells (iPSCs) and fibroblasts obtained from affected individuals. While protein localization and oligomerization were unaffected by the recurrent C-terminal deletion variant, total HNRNPC levels were decreased. Previously, reduced HNRNPC levels have been associated with changes in alternative splicing. Therefore, we performed a meta-analysis on published RNA-seq datasets of three different cell lines to identify a ubiquitous HNRNPC-dependent signature of alternative spliced exons. The identified signature was not only confirmed in fibroblasts obtained from an affected individual but also showed a significant enrichment for genes associated with intellectual disability. Hence, we assessed the effect of decreased and increased levels of HNRNPC on neuronal arborization and neuronal migration and found that either condition affects neuronal function. Taken together, our data indicate that HNRNPC haploinsufficiency affects alternative splicing of multiple intellectual disability-associated genes and that the developing brain is sensitive to aberrant levels of HNRNPC. Hence, our data strongly support the inclusion of HNRNPC to the family of HNRNP-related neurodevelopmental disorders. [Display omitted] We identified genetic variants of HNRNPC in 13 individuals with intellectual disability and global developmental delay. Through a meta-analysis of multiple cell types, we found that loss of HNRNPC affects alternative splicing, in particular of intellectual disability-associated genes. In vivo assays confirmed that neurodevelopment was affected by aberrant HNRNPC levels.

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.54 Molecular & Cell Biology - Genetics; 1.54.469 Splicing
Web Of Science research areas: Genetics & Heredity
ESI research areas: Molecular Biology & Genetics

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Details

Title: HNRNPC haploinsufficiency affects alternative splicing of intellectual disability-associated genes and causes a neurodevelopmental disorder
Creators: Eva Niggl - Department of Clinical Genetics, Erasmus MC, 3015 GD Rotterdam, the Netherlands
Arjan Bouman - Department of Clinical Genetics, Erasmus MC, 3015 GD Rotterdam, the Netherlands
Lauren C. Briere - Massachusetts General Hospital
Remco M. Hoogenboezem - Department of Hematology, Erasmus MC, 3015 GD Rotterdam, the Netherlands
Ilse Wallaard - Department of Clinical Genetics, Erasmus MC, 3015 GD Rotterdam, the Netherlands
Joohyun Park - University of Tübingen
Jakob Admard - University of Tübingen
Martina Wilke - Department of Clinical Genetics, Erasmus MC, 3015 GD Rotterdam, the Netherlands
Emilio D.R.O. Harris-Mostert - Department of Clinical Genetics, Erasmus MC, 3015 GD Rotterdam, the Netherlands
Minetta Elgersma - Department of Clinical Genetics, Erasmus MC, 3015 GD Rotterdam, the Netherlands
Jennifer Bain - Columbia University
Meena Balasubramanian - Sheffield Children's NHS Foundation Trust
Siddharth Banka - Manchester University NHS Foundation Trust
Paul J. Benke - Joe DiMaggio Children's Hospital
Miriam Bertrand - University of Tübingen
Alyssa E. Blesson - Kennedy Krieger Institute
Jill Clayton-Smith - Manchester University NHS Foundation Trust
Jamie M. Ellingford - Manchester University NHS Foundation Trust
Madelyn A. Gillentine - Seattle Children's Hospital
Dana H. Goodloe - University of Alabama at Birmingham
Tobias B. Haack - University of Tübingen
Mahim Jain - Kennedy Krieger Institute
Ian Krantz - Children's Hospital of Philadelphia
Sharon M. Luu - Waisman Center, University of Wisconsin Hospitals and Clinics, Madison, WI 53704, USA
Molly McPheron - University of Indianapolis
Candace L. Muss - Dupont Hospital
Sarah E. Raible - Children's Hospital of Philadelphia
Nathaniel H. Robin - University of Alabama at Birmingham
Michael Spiller - Sheffield Children's NHS Foundation Trust
Susan Starling - Sisters of Mercy Health System
David A. Sweetser - Massachusetts General Hospital
Isabelle Thiffault - Sisters of Mercy Health System
Francesco Vetrini - University of Indianapolis
Dennis Witt - University of Tübingen
Emily Woods - Sheffield Children's NHS Foundation Trust
Dihong Zhou - Sisters of Mercy Health System
J.C. Ambrose
P. Arumugam
R. Bevers
M. Bleda
F. Boardman-Pretty
C.R. Boustred
H. Brittain
M.A. Brown
M.J. Caulfield
G.C. Chan
A. Giess
J.N. Griffin
A. Hamblin
S. Henderson
T.J.P. Hubbard
R. Jackson
L.J. Jones
D. Kasperaviciute
M. Kayikci
A. Kousathanas
L. Lahnstein
A. Lakey
S.E.A. Leigh
I.U.S. Leong
F.J. Lopez
F. Maleady-Crowe
M. McEntagart
F. Minneci
J. Mitchell
L. Moutsianas
M. Mueller
N. Murugaesu
A.C. Need
P. O‘Donovan
C.A. Odhams
C. Patch
D. Perez-Gil
M.B. Pereira
J. Pullinger
T. Rahim
A. Rendon
T. Rogers
K. Savage
K. Sawant
R.H. Scott
A. Siddiq
A. Sieghart
S.C. Smith
A. Sosinsky
A. Stuckey
M. Tanguy
A.L. Taylor Tavares
E.R.A. Thomas
S.R. Thompson
A. Tucci
M.J. Welland
E. Williams
K. Witkowska
S.M. Wood
M. Zarowiecki
Maria T. Acosta
David R. Adams
Raquel L. Alvarez
Justin Alvey
Aimee Allworth
Ashley Andrews
Euan A. Ashley
Ben Afzali
Carlos A. Bacino
Guney Bademci
Ashok Balasubramanyam
Dustin Baldridge
Jim Bale
Michael Bamshad
Deborah Barbouth
Pinar Bayrak-Toydemir
Anita Beck
Alan H. Beggs
Edward Behrens
Gill Bejerano
Hugo J. Bellen
Jimmy Bennet
Jonathan A. Bernstein
Gerard T. Berry
Anna Bican
Stephanie Bivona
Elizabeth Blue
John Bohnsack
Devon Bonner
Lorenzo Botto
Lauren C. Briere
Gabrielle Brown
Elizabeth A. Burke
Lindsay C. Burrage
Manish J. Butte
Peter Byers
William E. Byrd
John Carey
Olveen Carrasquillo
Thomas Cassini
Ta Chen Chang
Sirisak Chanprasert
Hsiao-Tuan Chao
Ivan Chinn
Gary D. Clark
Terra R. Coakley
Laurel A. Cobban
Joy D. Cogan
Matthew Coggins
F. Sessions Cole
Heather A. Colley
Heidi Cope
Rosario Corona
William J. Craigen
Andrew B. Crouse
Michael Cunningham
Precilla D'Souza
Hongzheng Dai
Surendra Dasari
Joie Davis
Jyoti G. Dayal
Margaret Delgado
Esteban C. Dell'Angelica
Katrina Dipple
Daniel Doherty
Naghmeh Dorrani
Argenia L. Doss
Emilie D. Douine
Dawn Earl
David J. Eckstein
Lisa T. Emrick
Christine M. Eng
Marni Falk
Elizabeth L. Fieg
Paul G. Fisher
Brent L. Fogel
Irman Forghani
Jiayu Fu
William A. Gahl
Ian Glass
Page C. Goddard
Rena A. Godfrey
Alana Grajewski
Meghan C. Halley
Rizwan Hamid
Neal Hanchard
Kelly Hassey
Nichole Hayes
Frances High
Anne Hing
Fuki M. Hisama
Ingrid A. Holm
Jason Hom
Martha Horike-Pyne
Alden Huang
Yan Huang
Sarah Hutchison
Wendy Introne
Rosario Isasi
Kosuke Izumi
Gail P. Jarvik
Jeffrey Jarvik
Suman Jayadev
Orpa Jean-Marie
Vaidehi Jobanputra
Emerald Kaitryn
Shamika Ketkar
Dana Kiley
Gonench Kilich
Shilpa N. Kobren
Isaac S. Kohane
Jennefer N. Kohler
Susan Korrick
Deborah Krakow
Donna M. Krasnewich
Elijah Kravets
Seema R. Lalani
Byron Lam
Christina Lam
Brendan C. Lanpher
Ian R. Lanza
Kimberly LeBlanc
Brendan H. Lee
Roy Levitt
Richard A. Lewis
Pengfei Liu
Xue Zhong Liu
Nicola Longo
Sandra K. Loo
Joseph Loscalzo
Richard L. Maas
Ellen F. Macnamara
Calum A. MacRae
Valerie V. Maduro
AudreyStephannie Maghiro
Rachel Mahoney
May Christine Malicdan
Laura A. Mamounas
Teri A. Manolio
Rong Mao
Ronit Marom
Gabor Marth
Beth A. Martin
Martin G. Martin
Julian A. Martínez-Agosto
Shruti Marwaha
Jacob McCauley
Allyn McConkie-Rosell
Alexa T. McCray
Elisabeth McGee
Matthew Might
Danny Miller
Ghayda Mirzaa
Eva Morava
Paolo Moretti
Marie Morimoto
John J. Mulvihill
Mariko Nakano-Okuno
Stanley F. Nelson
Shirley Nieves-Rodriguez
Donna Novacic
Devin Oglesbee
James P. Orengo
Laura Pace
Stephen Pak
J. Carl Pallais
Jeanette C. Papp
Neil H. Parker
Leoyklang Petcharet
John A. Phillips
Jennifer E. Posey
Lorraine Potocki
Barbara N. Swerdzewski
Aaron Quinlan
Deepak A. Rao
Anna Raper
Wendy Raskind
Genecee Renteria
Chloe Reuter
Lynette Rives
Amy K. Robertson
Lance H. Rodan
Jill A. Rosenfeld
Elizabeth Rosenthal
Francis Rossignol
Maura Ruzhnikov
Marla Sabaii
Ralph Sacco
Jacinda B. Sampson
Mario Saporta
Judy Schaechter
Timothy Schedl
Kelly Schoch
Daryl A. Scott
Elaine Seto
Prashant Sharma
Vandana Shashi
Emily Shelkowitz
Sam Sheppeard
Jimann Shin
Edwin Silverman
Janet Sinsheimer
Kathy Sisco
Edward Smith
Kevin Smith
Lilianna Solnica-Krezel
Ben Solomon
Rebecca Spillmann
Andrew Stergachis
Joan Stoler
Kathleen Sullivan
Jennifer Sullivan
Shirley Sutton
David A. Sweetser
Virginia Sybert
Holly K. Tabor
Queenie K.-G. Tan
Amelia L. Tan
Arjun Tarakad
Mustafa Tekin
Fred Telischi
Willa Thorson
Cynthia Tifft
Camilo Toro
Alyssa A. Tran
Rachel A. Ungar
Tiina K. Urv
Adeline Vanderver
Matt Velinder
Dave Viskochil
Tiphanie P. Vogel
Colleen E. Wahl
Melissa Walker
Nicole M. Walley
Jennifer Wambach
Jijun Wan
Lee-kai Wang
Michael F. Wangler
Patricia A. Ward
Daniel Wegner
Monika Weisz
Mark Wener
Tara Wenger
Monte Westerfield
Matthew T. Wheeler
Jordan Whitlock
Lynne A. Wolfe
Shinya Yamamoto
Zhe Zhang
Stephan Zuchner
Ype Elgersma - Department of Clinical Genetics, Erasmus MC, 3015 GD Rotterdam, the Netherlands
Annelot C.M. van Esbroeck - Department of Clinical Genetics, Erasmus MC, 3015 GD Rotterdam, the Netherlands
Genomics England Research Consortium
Publication Details: American journal of human genetics, Vol.110(8), pp.1414-1435
Publisher: Elsevier Inc
Academic Unit: Leadership Department; Miller School of Medicine; John P. Hussman Institute for Human Genomics; UMMG Department of Otolaryngology; UMMG Dept of Human Genetics - Clinical and Translational Genetics; UMMG Department of Neurology; UMMG Dept of Human Genetics (Dr. John T. Macdonald Foundation); Benefits - Other; Human Resources; UMMG Dept of Neurology - Neuromuscular Disorders Div
Language: English
Resource Type: Journal article
Record Identifier: 991031921619902976