Clinical Characteristics and Induced Pluripotent Stem Cells (iPSCs) Disease Model of Fabry Disease Caused by a Novel GLA Mutation.

BACKGROUND: Fabry disease (FD) is a rare X-linked inherited disease caused by mutations in the GLA gene. We established a cohort of FD patients and performed whole-exome sequencing (WES) to identify some novel mutations. AIM: The aim of this study is to investigate the etiology of the novel mutation (c.72G > A, p.Trp24*）in the GLA gene in affected patients by using induced pluripotent stem cells (iPSCs) as a valuable tool. METHODS: We explored the clinical implications of this proband and examined the deleteriousness and conservation of the mutation site through bioinformatics analysis. Simultaneously, we collected the peripheral blood mononuclear cells (PBMCs) of the affected patient, then reprogrammed them into iPSCs and assessed their enzymatic activity to confirm the function of lysosomal enzyme α-galactosidase A (α-Gal A). RESULTS: Clinical examination of the patient demonstrated a classical FD, such as neuropathic pain, gastrointestinal disorders, deficiency of α-Gal A activity, and accumulation of Lyso-Gb-3. The novel mutation located on the N-terminal region, leading to a truncation of the protein and remaining only 24 amino acids. The α-Gal A activity of the patient-specific iPSC (iPS-FD) was significantly lower (60%) than that of normal iPSCs derived from healthy donors (iPS-B1). CONCLUSION: This work not only elucidated the etiology of novel mutations in affected patients but also highlighted the utility of iPSCs as a valuable tool for clarifying the molecular mechanisms and providing new insights into the therapy of FD.

Lipidomic profiles in serum and urine in children with steroid sensitive nephrotic syndrome.

BACKGROUND: Steroid-sensitive nephrotic syndrome (SSNS) accounts for approximately 80% of cases of nephrotic syndrome. The involvement of aberrant lipid metabolism in early SSNS is poorly understood, warranting further investigation. This study aimed to explore alterations in lipid metabolism associated with SSNS pathogenesis. METHODS: A screening cohort containing serum (50 SSNS, 37 controls) and urine samples (27 SSNS, 26 controls) was analyzed by untargeted lipidomic profiling using UHPLC-QTOF-MS. Then, a validation cohort (20 SSNS, 56 controls) underwent further analysis to check the potential clinical application by ROC curve analysis. RESULTS: Lipidomic profiling of serum and urine samples revealed significant lipid alterations in SSNS patients, with the alterations in the serum samples being more significant. An elevated concentration of PE and PG and downregulated concentration of FA were observed in SSNS serum. A total of 38 dysregulated lipids and 5 lipid metabolic pathways were identified in the serum samples in SSNS patients. Validation in the second cohort confirmed differential regulation of nine kinds of lipids, including 5 up-regulated substances [SM d33:2 (m/z = 686.5361), SHexCer d34:1 (m/z = 779.521), PI 20:4_22:4 (m/z = 934.5558), Cer_NS d18:1_23:0 (m/z = 635.6216), and GM3 d36:1 (m/z = 1180.7431)], as well as 4 down-regulated substances: [CE 18:1 (m/z = 650.601), PE 38:6 (m/z = 763.5205), PC 17:0_20:4 (m/z = 795.5868) and EtherPC 16:2e_20:4 (m/z = 763.5498)]. CONCLUSIONS: Untargeted lipidomic analysis successfully identified specific lipid class changes in patients with SSNS, providing a deeper understanding of lipid alterations and underlying mechanisms associated with SSNS.