Dataset Information

RNA sequencing of Normal Human Fibroblasts and Patient Fibroblasts with Novel SCP2 Variant

ABSTRACT: RNA sequencing of Normal Human Fibroblasts and Patient Fibroblasts with Novel SCP2 Variant

PROVIDER: PRJNA820882 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR18509012_1.fastq.gz	Fastqsanger.gz
	SRR18509012_2.fastq.gz	Fastqsanger.gz
	SRR18509013_1.fastq.gz	Fastqsanger.gz
	SRR18509013_2.fastq.gz	Fastqsanger.gz
	SRR18509014_1.fastq.gz	Fastqsanger.gz

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Project 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.

Dataset Information

RNA sequencing of Normal Human Fibroblasts and Patient Fibroblasts with Novel SCP2 Variant

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