A Novel SIL1 Variant (p.E342K) Associated with Marinesco–Sjögren Syndrome Impairs Protein Stability and Function

Ruggieri, Anna Giulia; Marinakis, Nikolaos M.; Amodei, Laura; Potenza, Francesca; Kampouraki, Afrodite; Tilemis, Faidon-Nikolaos; Pietrangelo, Laura; Viele, Marianna; Di Marco, Federica; Del Boccio, Piero; Di Cintio, Federica; Selenti, Nikoletta; Valari, Manthoula; Federici, Luca; Miele, Adriana Erica; Sallese, Michele; Makrythanasis, Periklis

doi:10.3390/ijms262311310

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A Novel SIL1 Variant (p.E342K) Associated with Marinesco–Sjögren Syndrome Impairs Protein Stability and Function

by

Anna Giulia Ruggieri

^1,2,†,

Nikolaos M. Marinakis

^3,4,†

,

Laura Amodei

^1,2

,

Francesca Potenza

^1,2,

Afrodite Kampouraki

³,

Faidon-Nikolaos Tilemis

³

,

Laura Pietrangelo

⁵

,

Marianna Viele

^1,2,

Federica Di Marco

^1,2

,

Piero Del Boccio

^2,6

,

Federica Di Cintio

^2,7

,

Nikoletta Selenti

³,

Manthoula Valari

⁸,

Luca Federici

^1,2,

Adriana Erica Miele

^9,10

,

Michele Sallese

^1,2,*,‡

and

Periklis Makrythanasis

^3,‡

¹

Department of Innovative Technologies in Medicine and Dentistry, “G. d’Annunzio” University of Chieti-Pescara, 66100 Chieti, Italy

²

Center for Advanced Studies and Technology (CAST), “G. d’Annunzio” University of Chieti-Pescara, 66100 Chieti, Italy

³

Laboratory of Medical Genetics, Medical School, St. Sophia’s Children’s Hospital, National and Kapodistrian University of Athens, 115 27 Athens, Greece

⁴

Laboratory of Genetics, Department of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece

⁵

Department of Medicine and Aging Sciences, “G. d’Annunzio” University of Chieti-Pescara, 66100 Chieti, Italy

⁶

Department of Sciences, “G. d’Annunzio” University of Chieti-Pescara, 66100 Chieti, Italy

⁷

Department of Medical, Oral and Biotechnological Sciences, “G. d’Annunzio” University of Chieti-Pescara, 66100 Chieti, Italy

⁸

Department of Dermatology, Medical School, St. Sophia’s Children’s Hospital, National and Kapodistrian University of Athens, 115 27 Athens, Greece

⁹

Department of Biochemical Sciences, Sapienza University of Rome, 00185 Rome, Italy

¹⁰

Institute of Analytical Sciences, UMR 5280 ISA CNRS UCBL, Université Claude Bernard Lyon 1, 69100 Villeurbanne, France

^*

Author to whom correspondence should be addressed.

^†

These authors contributed equally as first authors.

^‡

These authors contributed equally as last authors.

Int. J. Mol. Sci. 2025, 26(23), 11310; https://doi.org/10.3390/ijms262311310 (registering DOI)

Submission received: 1 October 2025 / Accepted: 18 November 2025 / Published: 22 November 2025

(This article belongs to the Section Biochemistry)

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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.

Keywords: neurodegenerative disease; ataxia; myopathy; chaperones; proteomics; variant of unknown significance; VUS

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MDPI and ACS Style

Ruggieri, A.G.; Marinakis, N.M.; Amodei, L.; Potenza, F.; Kampouraki, A.; Tilemis, F.-N.; Pietrangelo, L.; Viele, M.; Di Marco, F.; Del Boccio, P.; et al. A Novel SIL1 Variant (p.E342K) Associated with Marinesco–Sjögren Syndrome Impairs Protein Stability and Function. Int. J. Mol. Sci. 2025, 26, 11310. https://doi.org/10.3390/ijms262311310

AMA Style

Ruggieri AG, Marinakis NM, Amodei L, Potenza F, Kampouraki A, Tilemis F-N, Pietrangelo L, Viele M, Di Marco F, Del Boccio P, et al. A Novel SIL1 Variant (p.E342K) Associated with Marinesco–Sjögren Syndrome Impairs Protein Stability and Function. International Journal of Molecular Sciences. 2025; 26(23):11310. https://doi.org/10.3390/ijms262311310

Chicago/Turabian Style

Ruggieri, Anna Giulia, Nikolaos M. Marinakis, Laura Amodei, Francesca Potenza, Afrodite Kampouraki, Faidon-Nikolaos Tilemis, Laura Pietrangelo, Marianna Viele, Federica Di Marco, Piero Del Boccio, and et al. 2025. "A Novel SIL1 Variant (p.E342K) Associated with Marinesco–Sjögren Syndrome Impairs Protein Stability and Function" International Journal of Molecular Sciences 26, no. 23: 11310. https://doi.org/10.3390/ijms262311310

APA Style

Ruggieri, A. G., Marinakis, N. M., Amodei, L., Potenza, F., Kampouraki, A., Tilemis, F.-N., Pietrangelo, L., Viele, M., Di Marco, F., Del Boccio, P., Di Cintio, F., Selenti, N., Valari, M., Federici, L., Miele, A. E., Sallese, M., & Makrythanasis, P. (2025). A Novel SIL1 Variant (p.E342K) Associated with Marinesco–Sjögren Syndrome Impairs Protein Stability and Function. International Journal of Molecular Sciences, 26(23), 11310. https://doi.org/10.3390/ijms262311310

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A Novel SIL1 Variant (p.E342K) Associated with Marinesco–Sjögren Syndrome Impairs Protein Stability and Function

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