SUMF1

Multiple sulfatase deficiency (MSD) is an ultra-rare, inherited lysosomal storage disease caused by mutations in the gene sulfatase modifying factor 1 (SUMF1). MSD is characterized by the functional deficiency of all sulfatase enzymes, leading to the storage of sulfated substrates including glycosaminoglycans (GAGs), sulfolipids, and steroid sulfates. Patients with MSD experience severe neurological impairment, hearing loss, organomegaly, corneal clouding, cardiac valve disease, dysostosis multiplex, contractures, and ichthyosis. Here, we generated a novel human model of MSD by reprogramming patient peripheral blood mononuclear cells to establish an MSD induced pluripotent stem cell (iPSC) line (SUMF1 p.A279V). We also generated an isogenic control iPSC line by correcting the pathogenic variant with CRISPR/Cas9 gene editing. We successfully differentiated these iPSC lines into neural progenitor cells (NPCs) and NGN2-induced neurons (NGN2-iN) to model the neuropathology of MSD. Mature neuronal cells exhibited decreased SUMF1 gene expression, increased lysosomal stress, impaired neurite outgrowth and maturation, reduced sulfatase activities, and GAG accumulation. Interestingly, MSD iPSCs and NPCs did not exhibit as severe of phenotypes, suggesting that as neurons differentiate and mature, they become more vulnerable to loss of SUMF1. In summary, we demonstrate that this human iPSC-derived neuronal model recapitulates the cellular and biochemical features of MSD. These cell models can be used as tools to further elucidate the mechanisms of MSD pathology and for the development of therapeutics.

Selenoneine (SEN) is a natural histidine derivative with radical-scavenging activity and shows higher antioxidant potential than its sulfur-containing isolog ergothioneine (EGT). Recently, the SEN biosynthetic pathway in Variovorax paradoxus was reported. Resembling EGT biosynthesis, the committed step of SEN synthesis is catalyzed by a nonheme Fe-dependent oxygenase termed SenA. This enzyme catalyzes oxidative carbon‑selenium (C-Se) bond formation to conjugate N-α-trimethyl histidine (TMH) and selenosugar to yield selenoxide; the process parallels the EGT biosynthetic route, in which sulfoxide synthases known as EgtB members catalyze the conjugation of TMH and cysteine or γ-glutamylcysteine to afford sulfoxides. Here, we report the crystal structures of SenA and its complex with TMH and thioglucose (SGlc), an analog of selenoglucose (SeGlc) at high resolution. The overall structure of SenA adopts the archetypical fold of EgtB, which comprises a DinB-like domain and an FGE-like domain. While the TMH-binding site is highly conserved to that of EgtB, a various substrate-enzyme interaction network in the selenosugar-binding site of SenA features a number of water-mediated hydrogen bonds. The obtained structural information is beneficial for understanding the mechanism of SenA-mediated C-Se bond formation.

Cuproptosis has been reported to affect a variety of diseases. Therefore, we aimed to examine the role of cuproptosis-related genes in active ulcerative colitis (UC). We acquired 2 datasets of active UC from the Gene Expression Omnibus database and created immune cell infiltrations to research immune cell dysregulation. Based on the cuproptosis gene set and differentially expressed genes (DEGs), we identified the differentially expressed genes of cuproptosis (CuDEGs). We then used 2 machine learning methods to screen hub CuDEGs. Subsequently, we performed validation on additional datasets and investigated the relationship between hub CuDEGs and drug treatments. Thirty-five controls with inactive UC and 90 patients with active UC were obtained from the training sets. A total of 9157 DEGs and 27 CuDEGs were identified, respectively. Immune cell infiltration analysis revealed that patients with active UC exhibited higher levels of activated dendritic cells and neutrophils as well as lower levels of CD8+ T cells, regulatory T cells (Tregs), and macrophage M2. A six-gene cuproptosis signature was identified using machine learning algorithms. We further validated that the 6 hub CuDEGs showed a strong correlation with active UC and acted as cuproptosis-related biomarkers of active UC. Moreover, the expression of ATOX1 was downregulated, and SUMF1, MT1G, ATP7B, FDX1, and LIAS expression was upregulated in the colonic mucosa of active UC patients who responded to golimumab or vedolizumab therapy. With the exception of ATP7B, the expression patterns of hub CuDEGs before and after infliximab treatment of patients with active UC were similar to those of golimumab and vedolizumab. Cuproptosis and active UC have a complex relationship, as illustrated in our study. ATOX1, SUMF1, MT1G, ATP7B, FDX1, and LIAS are cuproptosis-related hub genes of active UC. Our study opens new avenues for investigating UC progression and developing novel therapeutic potential targets for the disease.