A Novel SIL1 Variant (p.E342K) Associated with Marinesco-Sjögren Syndrome Impairs Protein Stability and Function.
| Title: | A Novel SIL1 Variant (p.E342K) Associated with Marinesco-Sjögren Syndrome Impairs Protein Stability and Function. |
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| Authors: | Ruggieri AG; Department of Innovative Technologies in Medicine and Dentistry, 'G. d'Annunzio' University of Chieti-Pescara, 66100 Chieti, Italy.; Center for Advanced Studies and Technology (CAST), 'G. d'Annunzio' University of Chieti-Pescara, 66100 Chieti, Italy.; Marinakis NM; Laboratory of Medical Genetics, Medical School, St. Sophia's Children's Hospital, National and Kapodistrian University of Athens, 115 27 Athens, Greece.; Laboratory of Genetics, Department of Medicine, Democritus University of Thrace, 681 00 Alexandroupolis, Greece.; Amodei L; Department of Innovative Technologies in Medicine and Dentistry, 'G. d'Annunzio' University of Chieti-Pescara, 66100 Chieti, Italy.; Center for Advanced Studies and Technology (CAST), 'G. d'Annunzio' University of Chieti-Pescara, 66100 Chieti, Italy.; Potenza F; Department of Innovative Technologies in Medicine and Dentistry, 'G. d'Annunzio' University of Chieti-Pescara, 66100 Chieti, Italy.; Center for Advanced Studies and Technology (CAST), 'G. d'Annunzio' University of Chieti-Pescara, 66100 Chieti, Italy.; Kampouraki A; Laboratory of Medical Genetics, Medical School, St. Sophia's Children's Hospital, National and Kapodistrian University of Athens, 115 27 Athens, Greece.; Tilemis FN; Laboratory of Medical Genetics, Medical School, St. Sophia's Children's Hospital, National and Kapodistrian University of Athens, 115 27 Athens, Greece.; Pietrangelo L; Department of Medicine and Aging Sciences, 'G. d'Annunzio' University of Chieti-Pescara, 66100 Chieti, Italy.; Viele M; Department of Innovative Technologies in Medicine and Dentistry, 'G. d'Annunzio' University of Chieti-Pescara, 66100 Chieti, Italy.; Center for Advanced Studies and Technology (CAST), 'G. d'Annunzio' University of Chieti-Pescara, 66100 Chieti, Italy.; Di Marco F; Department of Innovative Technologies in Medicine and Dentistry, 'G. d'Annunzio' University of Chieti-Pescara, 66100 Chieti, Italy.; Center for Advanced Studies and Technology (CAST), 'G. d'Annunzio' University of Chieti-Pescara, 66100 Chieti, Italy.; Del Boccio P; Center for Advanced Studies and Technology (CAST), 'G. d'Annunzio' University of Chieti-Pescara, 66100 Chieti, Italy.; Department of Sciences, 'G. d'Annunzio' University of Chieti-Pescara, 66100 Chieti, Italy.; Di Cintio F; Center for Advanced Studies and Technology (CAST), 'G. d'Annunzio' University of Chieti-Pescara, 66100 Chieti, Italy.; Department of Medical, Oral and Biotechnological Sciences, 'G. d'Annunzio' University of Chieti-Pescara, 66100 Chieti, Italy.; Selenti N; Laboratory of Medical Genetics, Medical School, St. Sophia's Children's Hospital, National and Kapodistrian University of Athens, 115 27 Athens, Greece.; Valari M; Department of Dermatology, Medical School, St. Sophia's Children's Hospital, National and Kapodistrian University of Athens, 115 27 Athens, Greece.; Federici L; Department of Innovative Technologies in Medicine and Dentistry, 'G. d'Annunzio' University of Chieti-Pescara, 66100 Chieti, Italy.; Center for Advanced Studies and Technology (CAST), 'G. d'Annunzio' University of Chieti-Pescara, 66100 Chieti, Italy.; Miele AE; Department of Biochemical Sciences, Sapienza University of Rome, 00185 Rome, Italy.; Institute of Analytical Sciences, UMR 5280 ISA CNRS UCBL, Université Claude Bernard Lyon 1, 69100 Villeurbanne, France.; Sallese M; Department of Innovative Technologies in Medicine and Dentistry, 'G. d'Annunzio' University of Chieti-Pescara, 66100 Chieti, Italy.; Center for Advanced Studies and Technology (CAST), 'G. d'Annunzio' University of Chieti-Pescara, 66100 Chieti, Italy.; Makrythanasis P; Laboratory of Medical Genetics, Medical School, St. Sophia's Children's Hospital, National and Kapodistrian University of Athens, 115 27 Athens, Greece. |
| Source: | International journal of molecular sciences [Int J Mol Sci] 2025 Nov 22; Vol. 26 (23). Date of Electronic Publication: 2025 Nov 22. |
| Publication Type: | Journal Article; Case Reports |
| Language: | English |
| Journal Info: | Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Basel, Switzerland : MDPI, [2000- |
| MeSH Terms: | Spinocerebellar Degenerations*/genetics ; Spinocerebellar Degenerations*/metabolism ; Spinocerebellar Degenerations*/pathology; Child, Preschool ; Female ; Humans ; Exome Sequencing ; Protein Stability ; Guanine Nucleotide Exchange Factors |
| Abstract: | Marinesco-Sjögren syndrome (MSS) is a rare autosomal recessive neuromuscular disorder marked by ataxia, muscle weakness, cataracts, and often intellectual and skeletal abnormalities. It is commonly caused by loss-of-function variants in the SIL1 gene, which impair binding immunoglobulin protein (BiP) function, leading to protein misfolding and activation of the unfolded protein response. In a 2-year-old patient with typical MSS symptoms, we identified a previously unreported c.1024G>A (p.E342K) variant in SIL1 via whole-exome sequencing. The pathogenicity of this Sil1 variant was supported by evidence of structural changes revealed through in silico predictions, circular dichroism, and native gel electrophoresis. Patient-derived fibroblasts exhibited reduced Sil1 protein levels, likely due to misfolding and degradation, which was partially rescued by proteasome inhibition. Proteomics revealed a profile similar to known MSS cases and a distinctive MSS transcriptional signature. Ultrastructural analysis confirmed typical MSS features, such as autophagic vacuoles and lipid droplets. Although the p.E342K phenotype appears milder than the reference pathogenic variant R111X, our findings support the reclassification of this novel variant as pathogenic, in accordance with the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) 2015 guidelines and the refinements proposed by the Clinical Genome Resource Sequence Variant Interpretation (ClinGen SVI) recommendations. Furthermore, the overall evidence also provides important insights into the genotype-phenotype correlation and the underlying pathogenic mechanism of the p.E342K variant. |
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| Grant Information: | D75F21003210001 Ministero dell'università e della ricerca; GGP20092 Telethon Foundation; PNRR-MR1-2022-12375730 Funded by European Union |
| Contributed Indexing: | Keywords: VUS; ataxia; chaperones; myopathy; neurodegenerative disease; proteomics; variant of unknown significance |
| Substance Nomenclature: | 0 (SIL1 protein, human); 0 (Guanine Nucleotide Exchange Factors) |
| Entry Date(s): | Date Created: 20251211 Date Completed: 20251211 Latest Revision: 20260127 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC12691736 |
| DOI: | 10.3390/ijms262311310 |
| PMID: | 41373471 |
| Database: | MEDLINE |
Journal Article; Case Reports