Novel compound heterozygous SIL1 variants associated with Marinesco-Sjögren syndrome in a Chinese family.

BACKGROUND: Marinesco-Sjögren syndrome (MSS) is a rare and disabling genetic disorder caused primarily by pathogenic variants in the SIL1 gene. SIL1 functions as a nucleotide exchange factor for the molecular chaperone BiP within the endoplasmic reticulum (ER), which is essential for protein folding. This study aims to characterize a novel SIL1 compound heterozygous pathogenic mutation and investigate its disease-causing mechanism. METHODS: We determined a novel SIL1 compound heterozygous mutation information using whole exome sequencing and Sanger sequencing. RNA-seq, RT-qPCR and Western blot were employed to assess the impact of mutations on SIL1 RNA and protein levels. Immunofluorescence was used to monitor localization changes at the cellular level. Structural prediction and coimmunoprecipitation were utilized to investigate the effects of mutations on protein interactions. RESULTS: We identified a 6-year-old girl with MSS carrying novel compound heterozygous variants in the SIL1 gene (c.570_572delCAA (p. Asn190del) and c.740C>T (p. Ala247Val)). Subsequent functional experiments revealed that the mutations show a reduction in SIL1 mRNA and protein levels. Structural prediction and coimmunoprecipitation indicate that the compound variants may be associated with the development of MSS by weakening SIL1-BiP binding. CONCLUSIONS: These findings expand the SIL1 variant spectrum and provide preliminary functional evidence that the identified variants may affect SIL1 abundance and SIL1-BiP interaction, supporting their relevance to the MSS phenotype in this family.