Laboratoire de Chimie Organique et Bioorganique, Université de Haute-Alsace, ENSCMu , 3 Rue A. Werner, 68093 Mulhouse Cedex, France.
Published: September 2014
AI Article Synopsis
Article Abstract
Mycolactone is a complex macrolide toxin produced by Mycobacterium ulcerans, the causative agent of skin lesions called Buruli ulcers. Mycolactone-mediated activation of neural (N) Wiskott-Aldrich syndrome proteins (WASP) induces defects in cell adhesion underpinning cytotoxicity and disease pathogenesis. We describe the chemical synthesis of 23 novel mycolactone analogues that differ in structure and modular assembly of the lactone core with its northern and southern polyketide side chains. The lactone core linked to southern chain was the minimal structure binding N-WASP and hematopoietic homolog WASP, where the number and configuration of hydroxyl groups on the acyl side chain impacted the degree of binding. A fluorescent derivative of this compound showed time-dependent accumulation in target cells. Furthermore, a simplified version of mycolactone mimicked the natural toxin for activation of WASP in vitro and induced comparable alterations of epithelial cell adhesion. Therefore, it constitutes a structural and functional surrogate of mycolactone for WASP/N-WASP-dependent effects.
Wiskott-Aldrich syndrome (WAS) is a severe X-linked disorder caused by loss-of-function mutations in the WAS gene, responsible for encoding WASP, a key regulator of actin cytoskeleton in all hematopoietic cells except red blood cells. The mechanism underlying microthrombocytopenia, a distinctive feature of WAS and a major contributor to mortality, remains not fully elucidated. In this study, using different gene editing strategies, we corrected mutations in patient-derived WAS-induced pluripotent stem cell lines, generating isogeneic WAS iPSC lines.
Purpose: Wiskott-Aldrich syndrome (WAS) is an X-linked genetic disorder characterized by distinctive features including microthrombocytopenia, eczema and recurrent infections. In the present study we report clinical, immunological and molecular spectrum of 41 WAS patients diagnosed over last five years.
Methods: Clinical and family history was collected from case records.
Cortical condensates are transient structures that form in the actin cortex of oocytes and are rich in actin and N-WASP, forming through a phase separation process influenced by chemical kinetics.
The study reveals that N-WASP can undergo surface condensation on lipid bilayers, which is a key factor in the formation of these condensates.
The dynamics of condensate formation are regulated by a balance between their creation at the surface and the polymerization of actin, shedding light on the control of complex intracellular structures.
We present a case of X-linked thrombocytopenia (XLT) with a novel WAS gene variant expressing a normal amount of Wiskott-Aldrich syndrome protein (WASp) in lymphocytes. XLT usually decreases WASp expression not only in platelets, but also in lymphocytes. However, there were cases, such as the present one, in which WASp was expressed normally in lymphocytes and absent only in platelets.
Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), Università degli Studi di Genova, Genova, Italy.
Multisystem inflammatory syndrome in children (MIS-C) has been reported in patients with inborn errors of immunity (IEI), providing insights into disease pathogenesis. Here, we present the first case of MIS-C in a child affected by Wiskott-Aldrich syndrome (WAS) gene mutation, elucidating underlying predisposing factors and the involved inflammatory pathways. Genetic analysis revealed a frameshift truncating variant in the WAS gene, resulting in WAS protein expression between mild and severe forms, despite a clinical phenotype resembling X-linked thrombocytopenia (XLT).
