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 Blesson, Jill Clayton‐Smith, Jamie M. Ellingford, Madelyn A. Gillentine, Dana Goodloe, Tobias B. Haack, Mahim Jain, Ian D. Krantz, Sharon M. Luu, Molly McPheron, Candace Muss, Sarah E. Raible, Nathaniel H. Robin, Michael Spiller, Susan Starling, David A. Sweetser, Isabelle Thiffault, Francesco Vetrini, Dennis Witt, Emily Woods, Dihong Zhou, John C. Ambrose, Prabhu Arumugam, R. Bevers, Marta Bleda, F. Boardman-Pretty, C. R. Boustred, Helen Brittain, Matthew A. Brown, Mark J. Caulfield, G. C. Chan, Adam Giess, John N. Griffin, Angela Hamblin, Shirley Henderson, Tim Hubbard, R. Jackson, J. Louise Jones, Dalia Kasperavičiūtė, Melis Kayikci, Athanasios Kousathanas, L. Lahnstein, A. Lakey, S. E. A. Leigh, I. U. S. Leong, Fabrice Lopez, F. Maleady-Crowe, Meriel McEntagart, Federico Minneci, Jonathan Mitchell, Loukas Moutsianas, Michael Mueller, Nirupa Murugaesu, Anna C. Need, Peter O’Donovan, Christopher A. Odhams, C. Patch, D. Perez-Gil, Mariana Buongermino Pereira, J. Pullinger, T. Rahim, Augusto Rendon, T. Rogers, K. Savage, K. Sawant, Richard H. Scott, Afshan Siddiq, A. Sieghart, Samuel C. Smith, Alona Sosinsky, Alexander Stuckey, M. Tanguy, Ana Lisa Taylor Tavares, Ellen Thomas, Simon R. Thompson, Arianna Tucci, M. J. Welland, Eric O. Williams, Katarzyna Witkowska, S. M. Wood, Magdalena Zarowiecki, Maria T. Acosta, David R. Adams, Raquel L. Alvarez, Justin Alvey
Abstract
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.