PXD062620-1

PXD062620 is an original dataset announced via ProteomeXchange.

Title	Structural and functional analysis of the novel pathological variant c.1024G>A in the SIL1 gene causing Marinesco-Sjögren syndrome
Description	Marinesco-Sjögren syndrome (MSS) is a rare autosomal recessive neuromuscular disease. MSS patients suffer from ataxia, muscle weakness and cataracts; mental retardation and skeletal abnormalities are often present. In many cases the syndrome is caused by loss of function variant in the SIL1 gene, which encodes for an endoplasmic reticulum-localised BiP nucleotide exchange factor. The loss of Sil1 impairs BiP functions, which in turn leads to the accumulation of unfolded proteins and thus activation of unfolded protein response (UPR). This response most likely participates in the degeneration of Purkinje neurons and myopathy. Different SIL1 variants were reported so far, but a clear relationship with the phenotype was not established. We examined a 2-year-old patient presenting with ataxia, muscle weakness, and cataracts, the classic triad used to make a clinical diagnosis of MSS. Whole exome sequencing revealed a previously undescribed c.1024G>A variant in the SIL1 gene. Multiple in-silico analysis suggested that this variant of unknown significance (VUS) is likely pathogenic. The disruption of the three-dimensional organisation of the recombinant mutant protein (p.E342K) was revealed by circular dichroism and native gel electrophoresis. Primary skin fibroblasts isolated from the patient carrying the new SIL1 variant showed ten times less Sil1 protein than healthy control fibroblasts, most likely because the protein is misfolded and thus degraded. In fact, inhibition of proteasome activity increased the amount of Sil1 protein. Proteomic analysis of these fibroblasts revealed a typical protein expression pattern and ontologies enrichment resembling that of an MSS patient carrying the R111X variant and the Sil1Gt mouse model of MSS. In addition, these fibroblasts showed a transcription signature characteristic of MSS. Finally, ultrastructural analysis revealed the presence of autophagic vacuoles and accumulation of lipid droplets mirroring the features seen in fibroblasts from a patient with a declared MSS. Overall, these evidences support the hypothesis that the novel p.E342K variant is pathological and thus explain the clinical manifestation observed in the patientcarrying this variant.
HostingRepository	PRIDE
AnnounceDate	2025-12-22
AnnouncementXML	Submission_2025-12-21_16:17:00.395.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Federica Di Marco
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	monohydroxylated residue; deaminated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2025-04-04 10:00:18	ID requested
⏵ 1	2025-12-21 16:17:01	announced

Ruggieri AG, Marinakis NM, Amodei L, Potenza F, Kampouraki A, Tilemis FN, Pietrangelo L, Viele M, Di Marco F, Del Boccio P, Di Cintio F, Selenti N, Valari M, Federici L, Miele AE, Sallese M, Makrythanasis P, gren Syndrome Impairs Protein Stability and Function. Int J Mol Sci, 26(23):(2025) [pubmed]

10.3390/ijms262311310;

submitter keyword: SIL1, rare disease,Marinesco-Sjögren syndrome, proteomics, VUS

Michele Sallese
contact affiliation	Department of Innovative Technologies in Medicine and Dentistry, Chieti, Italy Center for Advanced Studies and Technology (CAST), Chieti, Italy
contact email	michele.sallese@unich.it
lab head
Federica Di Marco
contact affiliation	University of "G. d' Annunzio" Chieti - Pescara
contact email	federica.dimarco@unich.it
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD062620
     1. Label: PRIDE project
     2. Name: Structural and functional analysis of the novel pathological variant c.1024G>A in the SIL1 gene causing Marinesco-Sjögren syndrome