bims-actimu 2025-06-22 papers

Issue of 2025–06–22
two papers selected by
Elodie Busch, University of Strasbourg

Int Immunopharmacol. 2025 Jun 12. pii: S1567-5769(25)01019-7. [Epub ahead of print]161 115029

Unraveling a novel missense mutation (c.A248C) in Wiskott-Aldrich syndrome gene by whole exome sequencing: Insights from dynamic simulation, molecular docking and in-silico studies.

Fatemeh Mohammad-Rezaei, Javad Saffari-Chaleshtori, Kolsoum InanlooRahatloo, Roya Sherkat, Mansoor Salehi.

Wiskott-Aldrich syndrome (WAS) is an uncommon genetic condition that is inherited via the X chromosome and is caused by mutations in the Wiskott-Aldrich syndrome (WAS) gene. This disease is defined by the presence of persistent thrombocytopenia, eczema, and immunological dysfunction. It is also linked to a higher likelihood of developing autoimmunity and cancer. Using whole-exome sequencing (WES) on the genomic DNA of a family that had two affected members, we detected a new missense hemizygous mutation (c.A248C, Y83S) in the Wiskott-Aldrich syndrome gene (WAS, Xp11.23). The tyrosine residue at position 83 (Y83) changes to serine (S) owing to the missense mutation in exon 2 (c.A248C). Furthermore, a simulation study employing the root mean square fluctuation (RMSF), radius of gyration, and root mean square deviation (RMSD) tools demonstrated that the p.Y83S variant causes changes in the structures of the protein and molecular dynamic characteristics. Since structural alterations have an impact on protein activity, these variations in protein structure may result in a decrease in the stability and function of mutant WASP. In conclusion, this research describes a novel WAS mutation's clinical and molecular characteristics. This mutation causes instability in the WASP protein and reduces its function, and eventually leading to the disease phenotype.

Keywords: Dynamic simulation; Mutation; Novel variant; Whole exome sequencing; Wiskott–Aldrich syndrome

DOI: https://doi.org/10.1016/j.intimp.2025.115029

Clin Exp Immunol. 2025 Jan 21. pii: uxaf024. [Epub ahead of print]219(1):

An atypical adolescent case of leukocyte adhesion deficiency I caused by a novel ITGB2 splicing variant with successful immune reconstitution following hematopoietic stem cell transplantation.

Leukocyte adhesion deficiency I (LAD-I) is an autosomal recessive immunodeficiency caused by mutations in the ITGB2 gene, characterized by recurrent severe infections, impaired pus formation, and delayed wound healing. In this study, we describe a late-onset presentation of LAD-I in a 22-year-old male who initially exhibited marked leukocytosis and neonatal omphalitis, followed by recurrent upper respiratory tract infections from 9 months of age. At age 13, the patient developed abdominal and left iliac fossa abscesses, which progressed to a vesicocutaneous fistula after a prolonged febrile episode. Extended catheterization and antibiotic treatment led to the formation of characteristic tin foil-like scarring. Recurrent purulent skin and soft tissue infections led to widespread scarring and pigmentary changes. Next-generation sequencing (NGS) identified a novel homozygous splice-site mutation in ITGB2 (NM_000211.5, c.1225-1G > A, IVS10-1G > A). In silico analysis predicted disruption of the acceptor site, while a minigene assay demonstrated two aberrant splicing events, namely a 12-bp deletion and complete skipping of exon 11 (188 bp). Flow cytometry analysis at age 13 showed CD18 expression reduced to less than 1% across granulocytes, monocytes, and lymphocytes, with concomitant decreases in β2-integrin α subunits (CD11a, CD11b, and CD11c). At 15 years of age, the patient underwent hematopoietic stem cell transplantation (HSCT) from a fully HLA-matched (10/10) heterozygous sister donor following a modified myeloablative conditioning regimen. Although initial chimerism fluctuated, full donor chimerism was ultimately achieved, restoring CD18 expression and normalizing ɑ-integrin levels. This study highlights the therapeutic efficacy of HSCT in correcting the molecular defects associated with LAD-I.

Keywords: ITGB2 gene; hematopoietic stem cell transplantation; immune reconstitution; leukocyte adhesion deficiency I; modified myeloablative conditioning; splicing variants

DOI: https://doi.org/10.1093/cei/uxaf024