TY - JOUR
T1 - HNRNPC haploinsufficiency affects alternative splicing of intellectual disability-associated genes and causes a neurodevelopmental disorder
AU - Genomics England Research Consortium
AU - Undiagnosed Diseases Network
AU - Niggl, Eva
AU - Bouman, Arjan
AU - Briere, Lauren C.
AU - Hoogenboezem, Remco M.
AU - Wallaard, Ilse
AU - Park, Joohyun
AU - Admard, Jakob
AU - Wilke, Martina
AU - Harris-Mostert, Emilio D.R.O.
AU - Elgersma, Minetta
AU - Bain, Jennifer
AU - Balasubramanian, Meena
AU - Banka, Siddharth
AU - Benke, Paul J.
AU - Bertrand, Miriam
AU - Blesson, Alyssa E.
AU - Clayton-Smith, Jill
AU - Ellingford, Jamie M.
AU - Gillentine, Madelyn A.
AU - Goodloe, Dana H.
AU - Haack, Tobias B.
AU - Jain, Mahim
AU - Krantz, Ian
AU - Luu, Sharon M.
AU - McPheron, Molly
AU - Muss, Candace L.
AU - Raible, Sarah E.
AU - Robin, Nathaniel H.
AU - Spiller, Michael
AU - Starling, Susan
AU - Sweetser, David A.
AU - Thiffault, Isabelle
AU - Vetrini, Francesco
AU - Witt, Dennis
AU - Woods, Emily
AU - Zhou, Dihong
AU - Ambrose, J. C.
AU - Arumugam, P.
AU - Bevers, R.
AU - Bleda, M.
AU - Boardman-Pretty, F.
AU - Boustred, C. R.
AU - Brittain, H.
AU - Brown, M. A.
AU - Caulfield, M. J.
AU - Chan, G. C.
AU - Giess, A.
AU - Griffin, J. N.
AU - Hamblin, A.
AU - Izumi, Kosuke
N1 - Publisher Copyright:
© 2023 American Society of Human Genetics
PY - 2023/8/3
Y1 - 2023/8/3
N2 - 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.
AB - 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.
KW - HNRNP
KW - HNRNPC
KW - NDD
KW - RNA processing
KW - alternative splicing
KW - heterogeneous ribonucleoprotein C
KW - iPSCs
KW - induced pluripotent stem cells
KW - intellectual disability
KW - neurodevelopmental disorder
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UR - http://www.scopus.com/inward/citedby.url?scp=85166598997&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2023.07.005
DO - 10.1016/j.ajhg.2023.07.005
M3 - Article
C2 - 37541189
AN - SCOPUS:85166598997
SN - 0002-9297
VL - 110
SP - 1414
EP - 1435
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 8
ER -