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

  • Marwan Nashabat (Shared first author)
  • Nasrinsadat Nabavizadeh (Shared first author)
  • Hilal Pırıl Saraçoğlu (Shared first author)
  • 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 von Hardenberg
  • Carsten G Bönnemann
  • Georg M Stettner
  • Ginevra Zanni
  • Hülya Kayserili
  • Zehra Piraye Oflazer
  • Nathalie Escande-Beillard
  • Undiagnosed Diseases Network

Related Research units


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.

Bibliographical data

Original languageEnglish
Publication statusPublished - 27.02.2024

Comment Deanary

© 2024. The Author(s).

PubMed 38413582