Nature Communications (Feb 2024)
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,
- Undiagnosed Diseases Network,
- 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
Affiliations
- Marwan Nashabat
- Laboratory of Functional Genomics, Department of Medical Genetics, Koç University, School of Medicine (KUSoM)
- Nasrinsadat Nabavizadeh
- Laboratory of Functional Genomics, Department of Medical Genetics, Koç University, School of Medicine (KUSoM)
- Hilal Pırıl Saraçoğlu
- Laboratory of Functional Genomics, Department of Medical Genetics, Koç University, School of Medicine (KUSoM)
- Burak Sarıbaş
- Laboratory of Functional Genomics, Department of Medical Genetics, Koç University, School of Medicine (KUSoM)
- Şahin Avcı
- Diagnostic Center for Genetic Diseases, Department of Medical Genetics, Koç University Hospital
- Esra Börklü
- Diagnostic Center for Genetic Diseases, Department of Medical Genetics, Koç University Hospital
- Emmanuel Beillard
- Department of Biopathology, Centre Léon Bérard
- Elanur Yılmaz
- Laboratory of Functional Genomics, Department of Medical Genetics, Koç University, School of Medicine (KUSoM)
- Seyide Ecesu Uygur
- Laboratory of Functional Genomics, Department of Medical Genetics, Koç University, School of Medicine (KUSoM)
- Cavit Kerem Kayhan
- Pathology Laboratory, Acıbadem Maslak Hospital
- Luca Bosco
- Unit of Muscular and Neurodegenerative Disorders and Developmental Neurology, Bambino Gesù Children’s Hospital, IRCCS
- Zeynep Bengi Eren
- Laboratory of Functional Genomics, Department of Medical Genetics, Koç University, School of Medicine (KUSoM)
- Katharina Steindl
- Institute of Medical Genetics, University of Zurich
- Manuela Friederike Richter
- Department of Neonatology, Children’s and Youth Hospital Auf der Bult
- Guney Bademci
- Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine
- Anita Rauch
- Institute of Medical Genetics, University of Zurich
- Zohreh Fattahi
- Genetics Research Center, University of Social Welfare and Rehabilitation Sciences
- Maria Lucia Valentino
- IRCCS Institute of Neurological Sciences of Bologna
- Anne M. Connolly
- Division of Neurology, Nationwide Children’s Hospital, The Ohio State University College of Medicine
- Angela Bahr
- Institute of Medical Genetics, University of Zurich
- Laura Viola
- Unit of Clinical Pediatrics, State Hospital
- Anke Katharina Bergmann
- Department of Human Genetics, Hannover Medical School
- Maria Eugenia Rocha
- CENTOGENE GmbH
- LeShon Peart
- Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine
- Derly Liseth Castro-Rojas
- Genomics Laboratory, Center of Immunology and Genetics (CIGE), SURA Ayudas Diagnosticas
- Eva Bültmann
- Institute of Diagnostic and Interventional Neuroradiology, Hannover Medical School
- Suliman Khan
- CENTOGENE GmbH
- Miriam Liliana Giarrana
- Division of Sleep Medicine, University Children’s Hospital Zurich
- Raluca Ioana Teleanu
- Dr Victor Gomoiu Children’s Hospital
- Joanna Michelle Gonzalez
- Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine
- Antonella Pini
- Neuromuscular Pediatric Unit, IRCCS Institute of Neurological Sciences of Bologna
- Ines Sophie Schädlich
- Department of Neurology, University Medical Center Hamburg-Eppendorf
- Katharina Vill
- Department of Pediatric Neurology and Developmental Medicine and LMU Center for Children with Medical Complexity, Dr. von Hauner Children’s Hospital, LMU Hospital, Ludwig-Maximilians-University
- Melanie Brugger
- Department of Human Genetics, Technical University of Munich, School of Medicine
- Stephan Zuchner
- Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine
- Andreia Pinto
- CENTOGENE GmbH
- Sandra Donkervoort
- Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health
- Stephanie Ann Bivona
- Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine
- Anca Riza
- Human Genomics Laboratory, University of Medicine and Pharmacy
- Undiagnosed Diseases Network
- Ioana Streata
- Human Genomics Laboratory, University of Medicine and Pharmacy
- Dieter Gläser
- Genetikum
- Carolina Baquero-Montoya
- Pediatric department, Hospital Pablo Tobon Uribe, SURA Ayudas Diagnosticas
- Natalia Garcia-Restrepo
- Universidad de Manizales
- Urania Kotzaeridou
- Division of Child Neurology and Inherited Metabolic Diseases, Center for Pediatric and Adolescent Medicine, University Hospital Heidelberg
- Theresa Brunet
- Department of Pediatric Neurology and Developmental Medicine and LMU Center for Children with Medical Complexity, Dr. von Hauner Children’s Hospital, LMU Hospital, 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
- Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine
- Sandra von Hardenberg
- Department of Human Genetics, Hannover Medical School
- Carsten G. Bönnemann
- Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health
- Georg M. Stettner
- Neuromuscular Center Zurich and Department of Pediatric Neurology, University Children’s Hospital Zurich, University of Zurich
- Ginevra Zanni
- Unit of Muscular and Neurodegenerative Disorders and Developmental Neurology, Bambino Gesù Children’s Hospital, IRCCS
- Hülya Kayserili
- Diagnostic Center for Genetic Diseases, Department of Medical Genetics, Koç University Hospital
- Zehra Piraye Oflazer
- Department of Neurology, Koç University Hospital Muscle Center
- Nathalie Escande-Beillard
- Laboratory of Functional Genomics, Department of Medical Genetics, Koç University, School of Medicine (KUSoM)
- DOI
- https://doi.org/10.1038/s41467-024-45933-5
- Journal volume & issue
-
Vol. 15,
no. 1
pp. 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.
