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    • The second patient had a homozygous

    2021-12-02

    The second patient had a homozygous substitution within exon 6 (c.538C>T). The parents were heterozygous and showed no clinical or immunological defect. The mutation has been predicted to alter a potential exonic splicing enhancer (ESE) site. Therefore, exon 6 skipping could be explained by the ESE-loss model in which the c.538C>T substitution disrupts the ESE that is bound by the SR protein SF2/ASF splicing activator [32], [33]. Interestingly, rather than functioning as an ESE according to in silico prediction, the region where the c.538C>T mutation falls has been previously characterized as an uridine-rich exonic sequence (consensus UCUU within a pyrimidine-rich context) in FAS exon 6 (URE6) functioning as an exonic splicing silencer [34]. Indeed, the URE6 sequence of human FAS pre-mRNA is a significant cis-acting regulating bromhexine of Fas alternative splicing which recruits trans-acting factors to modulate exon 6 skipping/inclusion. This element is bound by the polypyrimidine tract binding protein (PTB) [34]. PTB acts through this exonic splicing silencer by interfering with the molecular bridges between spliceosome components such as U1 snRNP (at the 5′ splice site of intron 6) and U2AF (at the 3′ splice site of intron 5) that lead to exon definition [34]. Thus, PTB binding promotes exon 6 skipping [34]. Based on these data, one could speculate that the c.538C>T mutation could disrupt the URE6 element preventing PTB binding and leading to interaction of the latter with U1 snRNP. The PTB/U1 snRNP forms a repressor complex around the 5′ splice site which is not competent to establish exon definition but rather enhance exon skipping since it prevents further assembly of the U1 snRNP with spliceosomal components downstream [34], [35]. These findings offer a comprehensive mechanistic basis to functional consequences of this rare mutation. Although these two rare splicing defects of Fas have been successfully identified using Sanger sequencing, one could speculate whether such mutations in this or in other genes would have been detected or escaped detection by whole exome sequencing (WES) [36]. At least for the BP mutation, a whole genome sequencing (WGS) would have been required since WES encompasses exons and splice sites only. In summary, we report two novel FAS mutations associated with severe clinical phenotype. These findings expand the spectrum of homozygous mutations with lack of Fas expression and illustrate the importance of such studies in highly consanguineous populations. Rare mechanisms are proposed to underly the splicing defects of FAS exon 6 observed in both patients highlighting the requirement of tight regulation of FAS exon 6 splicing for balanced alternative splicing.
    Conflict of interest
    Acknowledgements
    Introduction Renal transplantation is the treatment of choice for pediatric patients with end-stage l, disease, for the improvement in quality of life when compared to dialysis and the better cardiovascular and mortality outcomes [1], [2]. Allograft rejection depends mainly on human leukocyte antigen (HLA) polymorphism between donor and recipient and subsequent T cell recognition, either by direct recognition of allogeneic HLA on donor antigen-presenting cells (APC) or by indirect recognition of donor HLA-derived peptides presented by major histocompatibility complex class II antigens on recipient APCs [3].It is a complex multistage process involving T cells and immune components that are encoded by polymorphic genes [1]. Acute rejection (AR) is expected for the first week after transplantation on and is a cellular rejection involving T cell activation that involves morphologically a mononuclear cell predominant cellular inflammation [4], [5]. Although incidence of acute rejection was having a decreasing over the last decade, it is still a main problem in kidney transplantation. Delayed graft function (DGF), which often happens due to deceased-donor kidney transplantation, may last a few days or weeks. It is accompanied with an increased incidence of AR and produces injurious effects on patient and graft survival [5].