bims-supasi 2026-07-26 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2026–07–26
thirteen papers selected by
Jonathan Wolf Mueller, University of Birmingham

Heparan sulfate and glycomimetics: Advances in synthesis and biological applications for post-stroke neurorepair.
Structure characterization and multi-target inhibitory activities of fucosylated chondroitin sulfate from sea cucumber Thelenota anax.
Structural Characterization and Wound Healing Activity of Sulfated Glycosaminoglycans from Acipenser Baerii Cartilage: Potential Regulation of Fibroblast Function.
Structural characterization and immunomodulatory activity of sulfated polysaccharides from the green microalgae Tetraselmis suecica.
Rational Design and Characterization of a Mutated Nanobody for Specific Targeting of Heparan Sulfate.
A glycosaminoglycan-binding LecA-like lectin from Xenorhabdus nematophila: structural and biophysical characterization.
Charge reversal in the heparin-binding pocket enhances the stability and activity of the human FGF1.
Host-microbial co-metabolites: from biogenesis to immunomodulation and implications for health and disease.
Comparative Metabolomics Reveals the Production of Sulfated Metabolites by Human Gut Bacteria.
The multilayered cuticle underlying structural coloration in red algae shares features with the metazoan extracellular matrix.
Immunogenic Risk Assessment of Porcine, Bovine, and Ovine Heparins for Diversifying the Global Heparin Supply.
Sulfated galactans from Gracilaria corticata reprogram metabolism, activate Immunity, promote regeneration, and exhibit anti-melanoma activity.
Mucopolysaccharidosis type II in tunisian families: IDS gene variations disrupting substrate binding and a novel deep intronic deletion reducing IDS expression.

Neuroprotection. 2026 Jul 02.

Heparan sulfate and glycomimetics: Advances in synthesis and biological applications for post-stroke neurorepair.

Mozammel H Bhuiyan, Madeleine J Smith, Simon F R Hinkley, Andrew N Clarkson.

  Heparan sulfate, a structurally diverse glycosaminoglycan that is abundant in the central nervous system (CNS), orchestrates essential processes fundamental to neural plasticity, neurorepair, and neuroprotection. The ability of heparan sulfate to promote regeneration, in stark contrast to the inhibitory effects of chondroitin sulfate and related glycosaminoglycans, has sparked a growing interest in harnessing heparan sulfate and synthetic glycomimetics for post-stroke neurorepair, as well as numerous other neurodegenerative diseases. However, significant gaps persist in our understanding of how sulfation patterns of heparan sulfate can govern functional outcomes, and major barriers remain for clinical translation. Here, we critically review advances in the synthesis and application of heparan sulfate-based glycomimetics, delineate the mechanistic duality of glycosaminoglycans in CNS diseases, and highlight how new preclinical and emerging clinical data are reshaping prospects for bioengineered extracellular matrix therapies. We identify unresolved challenges in delivery, specificity and efficacy, and propose future research directions to bridge these translational divides.

Keywords:  chondroitin sulfate proteoglycan; extracellular matrix; glycoasaminoglycans; heparan sulfate proteoglycans; inflammation; intercellular signalling peptides and proteins; neurodegenerative diseases

DOI:  https://doi.org/10.1002/nep3.70043
Carbohydr Polym. 2026 Sep 15. pii: S0144-8617(26)00708-3. [Epub ahead of print]388 125591

Structure characterization and multi-target inhibitory activities of fucosylated chondroitin sulfate from sea cucumber Thelenota anax.

Ying Hong, Ying Pan, Guangyu Zhu, Jing Wen, Rou Chen, Lige Cui, Huilin Chen, Tong Wu, Ronghua Yin, Jinhua Zhao.

  A fucosylated chondroitin sulfate (FCS) was extracted from the body wall of Thelenota anax (FCSTx). Physicochemical characterization confirmed its typical FCS structural features, and monosaccharide composition analysis revealed the presence of Gal. Combined NMR spectroscopic analysis of native FCSTx and fifteen oligosaccharides prepared by partial acid hydrolysis and β-elimination depolymerization comprehensively established that FCSTx possesses a chondroitin sulfate E backbone with branches composed of 60% Fuc2S4S, 8% Fuc4S, and 32% D-Gal4S(6S)-α1,2-L-Fuc3S, all attached at the O-3 of GlcA. Notably, this represents the second confirmation in nature of D-Gal-α1,2-L-Fuc-type disaccharide branches, following the initial report from T. ananas. This branch type has thus far been identified exclusively in the genus Thelenota, providing valuable clues for investigating the relationship among FCS structure, biosynthesis, and species taxonomy. Pharmacologically, FCSTx exhibited potent inhibition against intrinsic Xase (iXase), heparanase, and P-selectin, with the strongest inhibition observed against iXase. SAR analysis of low-molecular-weight derivatives revealed distinct molecular weight-dependent patterns: heparanase and P-selectin inhibitory activities increased with chain length, whereas iXase inhibitory activity initially increased upon depolymerization followed by a decrease. Further glycosylation of fucose branch diminished the inhibition potency. Notably, fractions with molecular weights above approximately 6 kDa exhibited stronger iXase inhibitory activity than native FCSTx.

Keywords:  Anticoagulation; Fucosylated chondroitin sulfate; Heterodisaccharide branch; Inhibition; Oligosaccharide; Thelenota anax

DOI:  https://doi.org/10.1016/j.carbpol.2026.125591
Macromol Biosci. 2026 Jul;26(7): e70225

Structural Characterization and Wound Healing Activity of Sulfated Glycosaminoglycans from Acipenser Baerii Cartilage: Potential Regulation of Fibroblast Function.

Choirul Anwar, Pitchurajan Krishna Perumal, Chun-Wei Tu, Hsing-Chun Kuo, Pei-Pei Sun, Mei-Ling Tsai.

  Sulfated glycosaminoglycans derived from sturgeon cartilage exhibit unique structural features and diverse biological activities. This study investigated the chemical, structural, and wound-healing properties of sulfated glycosaminoglycans from Acipenser baerii cartilage (ACGs). Disaccharide analysis revealed Δdi-6S (80%) and Δdi-4S (20%), while FTIR confirmed the characteristic functional groups of chondroitin sulfate. Structural characterization using 1H, 13C, and HSQC NMR demonstrated that ACGs consist of repeating CS-C and CS-A units with glycosidic linkages of →4-β-D-GlcA-(1→3)- β-D-GalNAc(6-OSO3 -)-(1→, and →4-β-D-GlcA-(1→3)- β-D-GalNAc(4-OSO3 -)-(1→. As the wound-healing potential of ACGs had not been previously explored, their effects on cell proliferation, migration, and tissue repair were evaluated. In vitro, ACGs enhanced HDFa cell proliferation and migration by regulating MMP2 and Collagen 3A1 signaling. In vivo, topical ACG application accelerated wound closure in a dose-dependent manner, reducing the wound area to 3.97 ± 5.71% and achieving a 95.95 ± 5.97% healing rate by day 10 at 500 µg/cm2. Notably, collagen deposition in the wounded sites increased to 220.36 ± 10.64% on day 10 at 100 µg/cm2, while the control remained at 100.00 ± 10.89%. Moreover, ACGs promoted re-epithelialization and hair follicle regeneration in the wounded sites. Overall, ACG effectively promoted wound healing by modulating fibroblast functions.

Keywords:  Acipenser baerii; chondroitin sulfate; fibroblast function; glycosaminoglycan; wound healing

DOI:  https://doi.org/10.1002/mabi.70225
Fitoterapia. 2026 Jul 22. pii: S0367-326X(26)00330-8. [Epub ahead of print] 107411

Structural characterization and immunomodulatory activity of sulfated polysaccharides from the green microalgae Tetraselmis suecica.

ChangSheng Li, Periyannan Rajasekar, Ju Hun Lee, Jin-Chul Kim, Subramanian Palanisamy, SangGuan You, Dong-Jin Lee.

  Marine microalgae, including Tetraselmis suecica, are promising sources of bioactive sulfated polysaccharides (SPs) with potential applications in functional foods and biomedicine. However, the structural characteristics and immunomodulatory activities of SPs from T. suecica remain largely unexplored. In this study, water-soluble polysaccharides were extracted from T. suecica, fractionated by anion-exchange chromatography into two major fractions (F1 and F2), and evaluated for their structural characteristics and immunomodulatory effects on RAW264.7 macrophages. The crude polysaccharide contained 62.7% carbohydrates, 14.1% proteins, 8.0% sulfates, and 0.9% uronic acids. The purified fractions (F1 and F2) contained 58.3-72.0% carbohydrates, 3.2-6.2% proteins, 3.1-13.7% sulfates, and 1.3-2.6% uronic acids. All three polysaccharide samples contained sulfate groups but differed markedly in sulfate content and structural characteristics. Compared with F1, F2 contained substantially higher sulfate (13.7% vs. 3.1%) and uronic acid (2.6% vs. 1.3%) contents and exhibited a distinct molecular weight distribution. Structural characterization revealed that F2 consisted predominantly of α-(1 → 4)-linked d-glucopyranosyl residues with occasional α-(1 → 4,6)-linked glucopyranosyl branch points and that the sulfate group was proposed to be attached at the O-6 position. Functionally, only F2 significantly enhanced nitric oxide (NO) and IL-6 and IL-10 production in RAW264.7 macrophages. Antibody neutralization assays suggested that this activity is mediated primarily through complement receptor 3 (CR3). To the best of our knowledge, this is the first study to structurally characterize sulfated polysaccharides from T. suecica and demonstrate their CR-3-mediated immunomodulatory activity, highlighting their potential as natural immunomodulatory ingredients for functional foods and biomedical applications.

Keywords:  Immunomodulatory properties; RAW264.7 macrophages; Sulfated polysaccharides (SPs); Tetraselmis suecica

DOI:  https://doi.org/10.1016/j.fitote.2026.107411
Antibodies (Basel). 2026 Jun 23. pii: 52. [Epub ahead of print]15(4):

Rational Design and Characterization of a Mutated Nanobody for Specific Targeting of Heparan Sulfate.

Junfang Hao, Qian Xu, Yanyan Cui, Wenlong Wang, Kai Huang.

   BACKGROUND: Viral attachment mediated by host cell surface receptors is the first step in viral infection. As a key cell surface receptor, heparan sulfate (HS) mediates the attachment and entry of numerous non-enveloped viruses in livestock, thereby serving as a crucial molecular target for studying virus-host interactions.
METHODS: Based on the structural scaffold of a nanobody (Nb; PDB: 7TJC), we rationally designed and constructed a mutant Nb targeting HS, designated HS-Mut-Nb1, using molecular docking, site-directed mutagenesis, molecular dynamics (MD) simulations, and experimental characterization.
RESULTS: Molecular docking indicated that the active site of wild-type Nb for HS binding was located within the cavity jointly formed by the complementarity-determining region 3 (CDR3) and the framework regions (FRs) of the wild-type Nb. A comprehensive analysis integrating virtual alanine scanning, site-directed mutagenesis, and MD simulations revealed that the combination of three point mutations (Phe47Arg, Asp99Tyr, and Tyr108Pro) significantly enhanced the binding affinity of Mut-Nb1 for HS, with a calculated binding free energy (ΔG) of -83.26 ± 3.06 kcal/mol. Enzyme-linked immunosorbent assay (ELISA) results further confirmed that Mut-Nb1 exhibited high affinity for HS (KD = 65.87 nM) and specificity (positive/negative ratio, P/N = 3.84; cross-reactivity, CR < 6.60%).
CONCLUSIONS: This study not only provides novel candidate molecules for elucidating the mechanism of HS-virus interactions and developing related inhibitors but also offers a reference for the rapid construction of mutant Nbs.

Keywords:  heparan sulfate; nanobody; rational design; virus attachment

DOI:  https://doi.org/10.3390/antib15040052
Carbohydr Polym. 2026 Sep 15. pii: S0144-8617(26)00674-0. [Epub ahead of print]388 125557

A glycosaminoglycan-binding LecA-like lectin from Xenorhabdus nematophila: structural and biophysical characterization.

Marek Korsák, Jan Komárek, Josef Houser, Imlirenla Pongener, Gavin J Miller, Michaela Wimmerová.

  Glycosaminoglycan (GAG)-binding lectins represent a rare class of carbohydrate-binding proteins with the ability to recognize and organize linear polysaccharide chains. Here, we describe XN-IL, a novel calcium-dependent lectin from the Gram-negative bacterium Xenorhabdus nematophila, which exhibits an unusual specificity for glycosaminoglycans. X. nematophila is an entomopathogenic bacterium and a symbiont of insect-parasitic Steinernema nematodes. Glycan array screening, analytical ultracentrifugation, and differential scanning fluorimetry revealed that XN-IL selectively binds hyaluronan and low-sulfated heparan sulfate, while showing negligible affinity for monosaccharides and galactosylated glycans. GAG binding is mediated exclusively by calcium ions, enabling the reversible crosslinking and precipitation of hyaluronan polymers. Crystal structures of the apo and ligand-bound forms reveal a conserved LecA-like fold with a widened, calcium-dependent binding pocket that accommodates extended GAG chains without major conformational rearrangements. XN-IL is the first member of the LecA family with defined GAG specificity and the first lectin identified in the genus Xenorhabdus. Its divergence from galactophilic LecA homologues reflects an evolutionary adaptation towards calcium-driven recognition and reversible assembly of linear polysaccharides. These findings expand the functional diversity of the LecA family and introduce XN-IL as a new tool for probing and manipulating GAG-based polymer systems.

Keywords:  Calcium-dependent binding; Glycosaminoglycans; Lectin; Protein–carbohydrate interactions, Xenorhabdus nematophila; X-ray crystallography

DOI:  https://doi.org/10.1016/j.carbpol.2026.125557
Biophys J. 2026 Jul 22. pii: S0006-3495(26)00478-9. [Epub ahead of print]

Charge reversal in the heparin-binding pocket enhances the stability and activity of the human FGF1.

Julie Eberle Davis, Rebecca Kerr, Jeevapani J Hettige, Shivakumar Sonnaila, Shadi A Badiee, Gayatri Suresh Kumar, Shilpi Agrawal, Bhanuprashanth Koppulu, Srinivas Jayanthi, David A Zaharoff, Mahmoud Moradi, Thallapuranam Krishnaswamy Suresh Kumar.

  Human fibroblast growth factor 1 (hFGF1) is a potent signaling molecule whose role in cell growth, differentiation, and migration has made it an excellent candidate for wide-ranging biomedical applications. hFGF1 binds heparan sulfate proteoglycans, which stabilize the protein and play a crucial role in growth factor-induced signaling. Within the heparin-binding region of hFGF1 lies a thrombin cleavage site at arginine-136, which, although not part of the canonical thrombin recognition sequence (LVPRGS), is nevertheless cleaved by thrombin, leading to reduced biological activity. In our previous study, R136 was identified as the primary thrombin cleavage site and was mutated to several hFGF1 variants-R136E, R136K, R136G, R136L, and R136Q-to assess the structural and functional impact of charge and residue substitution. We confirmed that altering the positively charged R136 residue enhances resistance to proteases, thermal stability, and cell proliferation activity. However, the structural basis for the increased stability observed in the R136E mutant remained unclear. Here, NMR experiments reveal that structural perturbations in all variants are largely localized near the mutation site, indicating that the global fold of hFGF1 remains intact. 2D NMR experiments have also identified 14 residues whose amide protons do not undergo exchange with D2O in the variant, suggesting their contribution to enhancing structural rigidity. Microsecond-level molecular dynamics simulations reveal that the increased structural stability of the variant arises from new electrostatic interactions (E136-R133, E136-K132, and E136-K126) and hydrogen bonds (S130-N128 and K127-N32) within the heparin binding region. A stability comparison study of the R136E and R136D variants further suggests that the side-chain length of the acidic residue at position 136 is critical for conferring inherent stability to the hFGF1 protein. Overall, these findings attribute the enhanced stability of the R136E variant to unique electrostatic and hydrogen-bonding interactions absent in wild-type hFGF1.

Keywords:  cross correlation map; fibroblast growth factor; molecular dynamics simulation; nuclear magnetic spectroscopy; stability

DOI:  https://doi.org/10.1016/j.bpj.2026.06.037
Front Immunol. 2026 ;17 1775938

Host-microbial co-metabolites: from biogenesis to immunomodulation and implications for health and disease.

Ying Wang, Liangliang Zhao, Ying Zou, Lili Nie.

  Host-microbial co-metabolites are small bioactive molecules generated through obligatory sequential or complementary enzymatic transformations by both gut microbiota and host tissues, including secondary bile acids, trimethylamine N-oxide (TMAO), indoxyl sulfate, p-cresyl sulfate, phenylacetylglutamine, and hippurate. The dysregulation of this co-metabolic axis, often through gut microbial dysbiosis, contributes to chronic low-grade inflammation and has been implicated in inflammatory bowel disease, metabolic disorders, cardiovascular disease, kidney disease, neurological disorders, and cancer. This review synthesizes the definition, biogenesis, immunomodulatory mechanisms, disease relevance, and translational biomarker potential of strict host-microbial co-metabolites.

Keywords:  bile acids; biomarker; co-metabolites; gut-brain axis; hippurate; immunomodulation; indoxyl sulfate; p-cresyl sulfate

DOI:  https://doi.org/10.3389/fimmu.2026.1775938
J Am Chem Soc. 2026 Jul 20.

Comparative Metabolomics Reveals the Production of Sulfated Metabolites by Human Gut Bacteria.

Gabriel D D'Agostino, Cecilia H Kim, Jinseok Park, Yancong Zhang, Bashar Amer, Eric A Franzosa, Susan S Bird, Curtis Huttenhower, Jun R Huh, A Sloan Devlin.

The sulfated metabolome─the collection of sulfate-containing metabolites─is an emerging source of structurally unique bioactive compounds that influence metabolism, immune responses, and neurological function. Recent studies have shown that, in addition to host enzymes, gut bacteria also encode sulfotransferase enzymes (SULTs) that generate sulfated metabolites. However, the substrate scope of characterized gut bacterial SULTs remains narrow, and comprehensive discovery is limited by a lack of methods to detect and assign sulfated metabolites in complex samples. Here, we develop a comparative metabolomics workflow that leverages the universal SULT cofactor 3'-phosphoadenosine-5'-phosphosulfate (PAPS) to incorporate heavy (34S) or light (32S) sulfur into sulfated metabolites, enabling discovery of microbiome-dependent sulfated compounds. By applying this approach in both "bottom-up" bacterial culture and "top-down" in vivo studies, we find that gut bacteria sulfonate hydroxy fatty acids. We identify a gut commensal microbe, Eubacterium ramulus, that performs this transformation, as well as an enzyme in this bacterium that performs this sulfonation, ErSULT. Metagenomic analyses reveal that ErSULT is prevalent across diverse human gut microbiomes. Together, this workflow and its application demonstrate that sulfated metabolite production by gut bacteria is more widespread than previously appreciated and provide a platform for future studies investigating the biosynthesis and biological functions of microbiome-derived sulfated small molecules.

DOI: https://doi.org/10.1021/jacs.6c02487
Proc Natl Acad Sci U S A. 2026 Jul 28. 123(30): e2610789123

The multilayered cuticle underlying structural coloration in red algae shares features with the metazoan extracellular matrix.

Glenn Philippe, Olivier Godfroy, Frederic Beisson, Ambre Gautier, Diane Jouanneau, Sophie Le Panse, Emmanuelle Com, Ludovic Delage, Mirjam Czjzek, Elizabeth Ficko-Blean, Jonas Collén.

  Structural coloration, a physical phenomenon observed in many living organisms, may arise from the interference of light with highly organized surface nanostructures. In some seaweeds, these nanostructures consist of cuticular lamellae in the outer part of the extracellular matrix (ECM) of the epidermis. However, the chemical composition of seaweed cuticles is poorly understood and the molecular components of lamellae remain unidentified. Here, we use integrated genomic, transcriptomic, proteomic, and metabolomic approaches together with analytical profiling of carbohydrates to determine the composition of the multilayered cuticle in the red alga Chondrus crispus and assess its evolutionary conservation. The structural assembly reveals common features with the ECM of animals. The carbohydrate fraction includes a complex mixture of carrageenans and glycosaminoglycan-like compositions. A major von Willebrand factor A domain protein, Lamellae Cohesive Protein, plays a critical role in protein-protein interactions and binding to sulfated polysaccharides. We have further identified the major proteins of the algal cuticle, providing a framework for addressing the evolutionary origins of the cuticle and raising important questions regarding its role, particularly across the red algal life cycle marked by major structural differences in its ECM.

Keywords:  Rhodophyta; algal cuticle; sulfated polysaccharides; thin-films; von Willebrand factor A

DOI:  https://doi.org/10.1073/pnas.2610789123
J Thromb Haemost. 2026 Jul 18. pii: S1538-7836(26)00439-3. [Epub ahead of print]

Immunogenic Risk Assessment of Porcine, Bovine, and Ovine Heparins for Diversifying the Global Heparin Supply.

Bin Zhang, Changkai Bu, Yuxin Geng, Zizhe An, Lexin Chen, Qunye Zhang, Fuming Zhang, Deling Shi, Lianli Chi.

   BACKGROUND: The global heparin supply relies heavily on porcine mucosa, prompting renewed interest in ruminant-derived alternatives. However, concerns regarding heparin-induced thrombocytopenia (HIT) remain a major barrier to their clinical reintroduction.
OBJECTIVES: To systematically evaluate the platelet factor 4 (PF4)-dependent immunogenic potential of porcine mucosal heparin (PMH), bovine lung heparin (BLH), and ovine mucosal heparin (OMH), as well as their low-molecular-weight heparin (LMWH) derivatives, and to delineate the structural features governing these interactions.
METHODS: Size-exclusion chromatography and a competitive ELISA established in this study were used to monitor PF4-heparin complex stoichiometry and antibody recognition. Flow cytometry quantified functional heparin-induced platelet activation (CD62P/CD63 expression). PF4 affinity chromatography-hydrophilic interaction liquid chromatography-mass spectrometry (HILIC-MS) and molecular docking characterized high-affinity glycan features and evaluated sulfation patterns in stabilizing PF4-heparin interactions.
RESULTS: Under equipotent dosing conditions, PF4 complex formation antibody recognition, and platelet activation followed the order BLH > OMH > PMH. Differences among heparins were largely explained by molecular weight-dependent stoichiometry. In contrast, source-dependent differences among LMWHs persisted after potency normalization, with bovine LMWH (BLE) forming significantly more PF4 complexes and triggering the most robust platelet activation. Affinity profiling identified dp6-dp8 as minimal PF4-binding units and revealed that increased sulfation and reduced N-acetylation enhance PF4 affinity. Molecular docking confirmed that N-sulfation stabilizes PF4-heparin interactions.
CONCLUSION: Heparins derived from different animal sources exhibit distinct PF4-binding properties and immunogenic profiles. These findings provide mechanistic insight into species-dependent HIT risk-driven by stoichiometry in heparin and fine structural features in LMWH-and support diversification of the global heparin supply.

Keywords:  Heparin; Heparin-induced thrombocytopenia (HIT); Immunogenicity risk; Ruminant source

DOI:  https://doi.org/10.1016/j.jtha.2026.07.009
iScience. 2026 Aug 21. 29(8): 116692

Sulfated galactans from Gracilaria corticata reprogram metabolism, activate Immunity, promote regeneration, and exhibit anti-melanoma activity.

Amal D Premarathna, Katarzyna M Dziubinska-Kuehn, Anti Sooäär, Nambukara Palliyaguruge Pushpitha, Clarisa Naa Shormeh Darko, Renu Geetha Bai, Indrek Reile, Rando Tuvikene.

  Sulfated polysaccharides from marine algae hold therapeutic potential, but their mechanisms remain underexplored. This study investigates how distinct sulfated galactans from the red seaweed Gracilaria corticata reprogram cellular metabolism to drive specific biological responses. Six fractions (GC-1A/B, GC-2A/B, GC-3A/B) obtained by sequential cold and hot extraction were structurally characterized using NMR and FTIR. Cold-extracted fractions (GC-1A/B) enhanced macrophage phagocytosis and nitric oxide production, indicating immunostimulation. Hot-extracted fractions (GC-2A/3A) promoted human skin cell proliferation and migration while inhibiting B16-F10 melanoma cell growth. Targeted metabolomics revealed that these effects arise from cell-type-specific metabolic reprogramming, including changes in amino acid and lipid profiles. In skin cells, the active fractions also increased antioxidant enzyme activity and modulated wound healing genes. These findings establish sulfated galactans as metabolic modulators whose bioactivity depends on the extraction method. This work provides a framework for developing marine polysaccharides into targeted therapies for immune disorders, tissue regeneration, and cancer.

Keywords:  Gracilaria corticata; agar-type sulfated galactans; antioxidant activity; immunomodulation; melanoma; structure-activity relationship; wound healing

DOI:  https://doi.org/10.1016/j.isci.2026.116692
Mol Biol Rep. 2026 Jul 23. pii: 1250. [Epub ahead of print]53(1):

Mucopolysaccharidosis type II in tunisian families: IDS gene variations disrupting substrate binding and a novel deep intronic deletion reducing IDS expression.

Roua Ltaifa, Chayma Sahli, Hela Boudabous, Taieb Massoud, Hassen Ben Abdennebi, Salima Ferchichi, Latifa Chkioua.

   BACKGROUND: Hunter syndrome, also known as mucopolysaccharidosis type II (MPS II), is a rare X-linked lysosomal storage disorder caused by iduronate-2-sulfatase (IDS) deficiency, leading to the accumulation of dermatan sulfate and heparan sulfate. This study aimed to investigate the molecular defects underlying MPS II in tP2ee unrelated Tunisian patients.
METHODS: The IDS gene was analyzed by direct DNA sequencing. The functional consequence of a large intronic deletion was assessed by quantitative real-time PCR. Structural and functional impacts of missense variants were evaluated using 3D modeling with Swiss-PdbViewer and PyMOL.
RESULTS: Three distinct mutations were identified. Two patients (P1 and P2) with severe phenotypes were hemizygous for the missense variants p.R88P and p.H138Y. A third patient P3 carried a novel 1310-pb intronic deletion associated with significantly reduced IDS transcript levels, suggesting impaired splicing or transcript stability. The identified variant was described according to HGVS nomenclature as NC_000023.11:g.149501061_149502370del, corresponding to a 1310 deep intronic deletion within intron 3 of the IDS. Structural analysis indicated that both missense mutations induce conformational alterations affecting the substrate-binding region. The p.H138Y substitution modifies the local chemical environment near the catalytic pocket, potentially impairing substrate interaction and enzymatic activity. In contrast, the p.R88P variant introduces structural constraints that disrupt local folding and destabilize interactions, indirectly affecting the positioning of the catalytic formylglycine residue. Moreover, we identified a large number of single-nucleotide sequence variants in hemizygous status in patient P3.
CONCLUSION: This study identifies a novel deep intronic deletion in the IDS gene and highlights the structural and functional impact of missense mutations in Tunisian MPS II patients. These findings expand the mutational spectrum of IDS and improve understanding of genotype-phenotype correlations, contributing to accurate molecular diagnosis.

Keywords:  Hunter syndrome; IDS; bioinformatics analysis; deep intronic deletion; mucopolysaccharidosis type II

DOI:  https://doi.org/10.1007/s11033-026-12421-6