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


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.

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.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Children's Hospital Zurich > Medical Clinic
04 Faculty of Medicine > Institute of Medical Genetics
Dewey Decimal Classification:610 Medicine & health
570 Life sciences; biology
Scopus Subject Areas:Physical Sciences > General Chemistry
Life Sciences > General Biochemistry, Genetics and Molecular Biology
Physical Sciences > General Physics and Astronomy
Uncontrolled Keywords:Genetics (clinical), General Physics, General Biochemistry, Genetics and Molecular Biology, General Chemistry, Multidisciplinary, Disease genetics, Neuromuscular disease, RNA transport
Language:English
Date:27 February 2024
Deposited On:15 Mar 2024 10:49
Last Modified:31 May 2024 01:57
Publisher:Nature Publishing Group
ISSN:2041-1723
OA Status:Gold
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1038/s41467-024-45933-5
Related URLs:https://api.semanticscholar.org/CorpusID:268039113
http://www.ncbi.nlm.nih.gov/pmc/articles/pmc10899626/
PubMed ID:38413582
Other Identification Number:PMCID: PMC10899626 / Corpus ID: 268039113
Project Information:
  • Content: Published Version
  • Language: English
  • Licence: Creative Commons: Attribution 4.0 International (CC BY 4.0)
  • Content: Supplemental Material
  • Language: English
  • Description: Supplementary Information
  • Licence: Creative Commons: Attribution 4.0 International (CC BY 4.0)
  • Content: Supplemental Material
  • Language: English
  • Description: Description of Additional Supplementary Files
  • Licence: Creative Commons: Attribution 4.0 International (CC BY 4.0)
  • Content: Supplemental Material
  • Language: English
  • Description: Peer Review File
  • Licence: Creative Commons: Attribution 4.0 International (CC BY 4.0)
  • Content: Supplemental Material
  • Language: English
  • Description: Reporting Summary
  • Licence: Creative Commons: Attribution 4.0 International (CC BY 4.0)