Serum microRNA as indicators of Wolfram syndrome's progression in neuroimaging studies

Abstract

Introduction: Patients with the ultra-rare Wolfram syndrome (WFS) develop insulin-dependent diabetes and progressive neurodegeneration. The aim of the study was to quantify microRNAs (miRNAs) in sera from patients with WFS, correlate their expression with neurological imaging over time and compare miRNA levels with those observed in patients with type 1 diabetes mellitus (T1DM).

Research design and methods: We quantified miRNA expression (Qiagen, Germany) in two groups of patients: with WFS at study entry (n=14) and after 2 years of follow-up and in 15 glycated hemoglobin-matched (p=0.72) patients with T1DM.

Results: We observed dynamic changes in the expression of multiple miRNAs in patients with WFS parallel to disease progression and in comparison to the T1DM patients group. Among miRNAs that differed between baseline and follow-up WFS samples, the level of 5 increased over time (miR-375, miR-30d-5p, miR-30e-30, miR-145-5p and miR-193a-5p) and was inversely correlated with macular average thickness, while the expression of 2 (let-7g-5p and miR-22-3p) decreased and was directly correlated with neuroimaging indicators of neurodegeneration.

Conclusions: Our findings show for the first time that serum miRNAs can be used as easily accessible indicators of disease progression in patients with WFS, potentially facilitating clinical trials on mitigating neurodegeneration.

Keywords: biomarkers; diabetes mellitus; genetic diseases; inborn; type 1.

Figure 1

Profile of differentially expressed (at p<0.05) microRNAs (miRNAs) distinguish baseline and follow-up samples from patients with Wolfram syndrome (WFS). (A) Heatmap and hierarchical clustering of differentially expressed miRNAs. (B) Principal component analysis of patient samples based on the expression of differentially expressed miRNAs. Numbers designate samples from the same patient.

Figure 2

Correlations of microRNA (miRNA) levels with optical coherence tomography (OCT) or MRI parameters in patients with Wolfram syndrome (WFS): (A) miR-375 with macular average thickness (MAT), (B) miR-30d-5p with macular average thickness, (C) miR-193-5p with macular average thickness, (D) baseline miR-145-5p with brainstem volume, (E) follow-up miR-30e-3p with baseline macular average thickness, (F) miR-22-3p with macular average thickness, (G) follow-up let-7g-5p with brainstem volume. White circles represent WFS baseline measurements, black dots—WFS follow-up, rhombi—follow-up miR measurements with baseline MAT; measurements of the same patients are matched with black lines.

Figure 3

Levels of microRNAs (miRNAs) in Wolfram syndrome (WFS) and patients with type 1 diabetes mellitus (T1DM) presented in relation to age: (A) miR-375, (B) miR-30d-5p, (C) miR-193-5p, (D) miR-145-5p, (E) miR-30e-3p, (F) miR-22-3p, (G) let-7g-5p. X signs represent patients with T1DM, white circles—WFS baseline and black dots—WFS follow-up; baseline and follow-up measurements of the same patients are matched with black lines.

Figure 4

Levels of microRNAs (miRNAs) in paired Wolfram syndrome (WFS) and type 1 diabetes mellitus (T1DM) samples: (A) miR-375, (B) miR-30d-5p, (C) miR-193-5p, (D) miR-145-5p, (E) miR-30e-3p, (F) miR-22-3p, (G) let-7g-5p. *P<0.05 in t-test for T1DM versus WFS comparisons or in paired t-test for WFS baseline versus WFS follow-up comparisons.