SNUPN deficiency causes a recessive muscular dystrophy due to RNA mis-splicing and ECM dysregulation

Marwan Nashabat, Nasrinsadat Nabavizadeh, Hilal Pırıl Saraçoğlu, Burak Sarıbaş, Şahin Avcı, Esra Börklü, Emmanuel Beillard, Elanur Yılmaz, Seyide Ecesu Uygur, Cavit Kerem Kayhan, Luca Bosco, Zeynep Bengi Eren, Katharina Steindl, Manuela Friederike Richter, Guney Bademci, Anita Rauch, Zohreh Fattahi, Maria Lucia Valentino, Anne M. Connolly, Angela Bahr, Laura Viola, Anke Katharina Bergmann, Maria Eugenia Rocha, LeShon Peart, Derly Liseth Castro-Rojas, Eva Bültmann, Suliman Khan, Miriam Liliana Giarrana, Raluca Ioana Teleanu, Joanna Michelle Gonzalez, Antonella Pini, Ines Sophie Schädlich, Katharina Vill, Melanie Brugger, Stephan Zuchner, Andreia Pinto, Sandra Donkervoort, Stephanie Ann Bivona, Anca Riza, Ioana Streata, Dieter Gläser, Carolina Baquero-Montoya, Natalia Garcia-Restrepo, Urania Kotzaeridou, Theresa Brunet, Diana Anamaria Epure, Aida Bertoli-Avella, Ariana Kariminejad, Mustafa Tekin, Sandra Hardenberg, Carsten G. Bönnemann, Georg M. Stettner, Ginevra Zanni, Hülya Kayserili, Zehra Piraye Oflazer and Nathalie Escande-Beillard ()
Additional contact information
Marwan Nashabat: Koç University, School of Medicine (KUSoM)
Nasrinsadat Nabavizadeh: Koç University, School of Medicine (KUSoM)
Hilal Pırıl Saraçoğlu: Koç University, School of Medicine (KUSoM)
Burak Sarıbaş: Koç University, School of Medicine (KUSoM)
Şahin Avcı: Koç University Hospital
Esra Börklü: Koç University Hospital
Emmanuel Beillard: Centre Léon Bérard
Elanur Yılmaz: Koç University, School of Medicine (KUSoM)
Seyide Ecesu Uygur: Koç University, School of Medicine (KUSoM)
Cavit Kerem Kayhan: Acıbadem Maslak Hospital
Luca Bosco: Bambino Gesù Children’s Hospital, IRCCS
Zeynep Bengi Eren: Koç University, School of Medicine (KUSoM)
Katharina Steindl: University of Zurich
Manuela Friederike Richter: Children’s and Youth Hospital Auf der Bult
Guney Bademci: University of Miami Miller School of Medicine
Anita Rauch: University of Zurich
Zohreh Fattahi: University of Social Welfare and Rehabilitation Sciences
Maria Lucia Valentino: IRCCS Institute of Neurological Sciences of Bologna
Anne M. Connolly: The Ohio State University College of Medicine
Angela Bahr: University of Zurich
Laura Viola: Unit of Clinical Pediatrics, State Hospital
Anke Katharina Bergmann: Hannover Medical School
Maria Eugenia Rocha: CENTOGENE GmbH
LeShon Peart: University of Miami Miller School of Medicine
Derly Liseth Castro-Rojas: Center of Immunology and Genetics (CIGE), SURA Ayudas Diagnosticas
Eva Bültmann: Hannover Medical School
Suliman Khan: CENTOGENE GmbH
Miriam Liliana Giarrana: University Children’s Hospital Zurich
Raluca Ioana Teleanu: Dr Victor Gomoiu Children’s Hospital
Joanna Michelle Gonzalez: University of Miami Miller School of Medicine
Antonella Pini: IRCCS Institute of Neurological Sciences of Bologna
Ines Sophie Schädlich: University Medical Center Hamburg-Eppendorf
Katharina Vill: Ludwig-Maximilians-University
Melanie Brugger: Technical University of Munich, School of Medicine
Stephan Zuchner: University of Miami Miller School of Medicine
Andreia Pinto: CENTOGENE GmbH
Sandra Donkervoort: National Institutes of Health
Stephanie Ann Bivona: University of Miami Miller School of Medicine
Anca Riza: University of Medicine and Pharmacy
Ioana Streata: University of Medicine and Pharmacy
Dieter Gläser: Genetikum
Carolina Baquero-Montoya: SURA Ayudas Diagnosticas
Natalia Garcia-Restrepo: Universidad de Manizales
Urania Kotzaeridou: University Hospital Heidelberg
Theresa Brunet: Ludwig-Maximilians-University
Diana Anamaria Epure: Dr Victor Gomoiu Children’s Hospital
Aida Bertoli-Avella: CENTOGENE GmbH
Ariana Kariminejad: Kariminejad-Najmabadi Pathology & Genetics Centre
Mustafa Tekin: University of Miami Miller School of Medicine
Sandra Hardenberg: Hannover Medical School
Carsten G. Bönnemann: National Institutes of Health
Georg M. Stettner: University Children’s Hospital Zurich, University of Zurich
Ginevra Zanni: Bambino Gesù Children’s Hospital, IRCCS
Hülya Kayserili: Koç University Hospital
Zehra Piraye Oflazer: Koç University Hospital Muscle Center
Nathalie Escande-Beillard: Koç University, School of Medicine (KUSoM)

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract SNURPORTIN-1, encoded by SNUPN, plays a central role in the nuclear import of spliceosomal small nuclear ribonucleoproteins. However, its physiological function remains unexplored. In this study, we investigate 18 children from 15 unrelated families who present with atypical muscular dystrophy and neurological defects. Nine hypomorphic SNUPN biallelic variants, predominantly clustered in the last coding exon, are ascertained to segregate with the disease. We demonstrate that mutant SPN1 failed to oligomerize leading to cytoplasmic aggregation in patients’ primary fibroblasts and CRISPR/Cas9-mediated mutant cell lines. Additionally, mutant nuclei exhibit defective spliceosomal maturation and breakdown of Cajal bodies. Transcriptome analyses reveal splicing and mRNA expression dysregulation, particularly in sarcolemmal components, causing disruption of cytoskeletal organization in mutant cells and patient muscle tissues. Our findings establish SNUPN deficiency as the genetic etiology of a previously unrecognized subtype of muscular dystrophy and provide robust evidence of the role of SPN1 for muscle homeostasis.

Date: 2024
References: View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-024-45933-5 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45933-5

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-024-45933-5

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().