SNUPN deficiency causes a recessive muscular dystrophy due to RNA mis-splicing and ECM dysregulation
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SNUPN deficiency causes a recessive muscular dystrophy due to RNA mis-splicing and ECM dysregulation. / Nashabat, Marwan; Nabavizadeh, Nasrinsadat; Saraçoğlu, Hilal Pırıl; Sarıbaş, Burak; Avcı, Şahin; Börklü, Esra; Beillard, Emmanuel; Yılmaz, Elanur; Uygur, Seyide Ecesu; Kayhan, Cavit Kerem; Bosco, Luca; Eren, Zeynep Bengi; Steindl, Katharina; Richter, Manuela Friederike; Bademci, Guney; Rauch, Anita; Fattahi, Zohreh; Valentino, Maria Lucia; Connolly, Anne M; Bahr, Angela; Viola, Laura; Bergmann, Anke Katharina; Rocha, Maria Eugenia; Peart, LeShon; Castro-Rojas, Derly Liseth; Bültmann, Eva; Khan, Suliman; Giarrana, Miriam Liliana; Teleanu, Raluca Ioana; Gonzalez, Joanna Michelle; Pini, Antonella; Schädlich, Ines Sophie; Vill, Katharina; Brugger, Melanie; Zuchner, Stephan; Pinto, Andreia; Donkervoort, Sandra; Bivona, Stephanie Ann; Riza, Anca; Streata, Ioana; Gläser, Dieter; Baquero-Montoya, Carolina; Garcia-Restrepo, Natalia; Kotzaeridou, Urania; Brunet, Theresa; Epure, Diana Anamaria; Bertoli-Avella, Aida; Kariminejad, Ariana; Tekin, Mustafa; von Hardenberg, Sandra; Bönnemann, Carsten G; Stettner, Georg M; Zanni, Ginevra; Kayserili, Hülya; Oflazer, Zehra Piraye; Escande-Beillard, Nathalie; Undiagnosed Diseases Network.
In: NAT COMMUN, Vol. 15, No. 1, 27.02.2024, p. 1758.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - SNUPN deficiency causes a recessive muscular dystrophy due to RNA mis-splicing and ECM dysregulation
AU - Nashabat, Marwan
AU - Nabavizadeh, Nasrinsadat
AU - Saraçoğlu, Hilal Pırıl
AU - Sarıbaş, Burak
AU - Avcı, Şahin
AU - Börklü, Esra
AU - Beillard, Emmanuel
AU - Yılmaz, Elanur
AU - Uygur, Seyide Ecesu
AU - Kayhan, Cavit Kerem
AU - Bosco, Luca
AU - Eren, Zeynep Bengi
AU - Steindl, Katharina
AU - Richter, Manuela Friederike
AU - Bademci, Guney
AU - Rauch, Anita
AU - Fattahi, Zohreh
AU - Valentino, Maria Lucia
AU - Connolly, Anne M
AU - Bahr, Angela
AU - Viola, Laura
AU - Bergmann, Anke Katharina
AU - Rocha, Maria Eugenia
AU - Peart, LeShon
AU - Castro-Rojas, Derly Liseth
AU - Bültmann, Eva
AU - Khan, Suliman
AU - Giarrana, Miriam Liliana
AU - Teleanu, Raluca Ioana
AU - Gonzalez, Joanna Michelle
AU - Pini, Antonella
AU - Schädlich, Ines Sophie
AU - Vill, Katharina
AU - Brugger, Melanie
AU - Zuchner, Stephan
AU - Pinto, Andreia
AU - Donkervoort, Sandra
AU - Bivona, Stephanie Ann
AU - Riza, Anca
AU - Streata, Ioana
AU - Gläser, Dieter
AU - Baquero-Montoya, Carolina
AU - Garcia-Restrepo, Natalia
AU - Kotzaeridou, Urania
AU - Brunet, Theresa
AU - Epure, Diana Anamaria
AU - Bertoli-Avella, Aida
AU - Kariminejad, Ariana
AU - Tekin, Mustafa
AU - von Hardenberg, Sandra
AU - Bönnemann, Carsten G
AU - Stettner, Georg M
AU - Zanni, Ginevra
AU - Kayserili, Hülya
AU - Oflazer, Zehra Piraye
AU - Escande-Beillard, Nathalie
AU - Undiagnosed Diseases Network
N1 - © 2024. The Author(s).
PY - 2024/2/27
Y1 - 2024/2/27
N2 - 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.
AB - 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.
KW - Child
KW - Humans
KW - Muscular Dystrophies/genetics
KW - Ribonucleoproteins, Small Nuclear/metabolism
KW - RNA/metabolism
KW - RNA Splicing/genetics
KW - Spliceosomes/genetics
U2 - 10.1038/s41467-024-45933-5
DO - 10.1038/s41467-024-45933-5
M3 - SCORING: Journal article
C2 - 38413582
VL - 15
SP - 1758
JO - NAT COMMUN
JF - NAT COMMUN
SN - 2041-1723
IS - 1
ER -