Characterization of Y-linked Autoimmune Accelerator Yaa

Jackson Laboratory, Bar Harbor ME

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Abstract

[unreadable] DESCRIPTION (provided by applicant): Susceptibility to systemic lupus erythematosus (SLE) has a genetic component, however, the complex genetic variation that results in risk for initiation and progression of this syndrome remains poorly understood. Mouse models for SLE continue to provide key insights into the genetic and phenotypic etiology of this complex disease syndrome. Among them, the BXSB.Yaa mouse model is intriguing both from a genetic and disease perspective. BXSB.Yaa male mice develop a quite severe autoimmune syndrome as a consequence of epistatic interactions between BXSB-background SLE-predisposition alleles and the Y-chromosome-linked autoimmune accelerator locus (Yaa). This ultimately results in severe autoimmunity, leading to death by acute renal failure. Yaa is, arguably, the most substantial SLE risk factor identified in mice, and also the most intractable. Yaa dramatically enhances overall autoimmune responses against autoantigens through its intrinsic effect on B-cell activation, presumably by decreasing the threshold for antigen receptor-dependent stimulation. Through a combination of genetic, genomic, transcriptional, and functional analyses, we have identified a very strong candidate gene for Yaa. Midline 1 (Midin) normally maps near the pseudoautosomal boundary of the X chromosome. Its protein is normally associated with cell proliferation and differentiation, has been shown to bind to the B-cell receptor associated signaling protein, Igbpl, and interacts with a rapamycin sensitive signaling pathway. We have found that this positive regulator of B-cell activation has been transferred from the X to the Y chromosome by an interchromosomal translocation event in male Yaa mice. This duplication, designated Midy, results in an overall elevation of Midin transcriptional expression in male Yaa mice. Our overall hypothesis is that the transposition of Midin onto the Yaa chromosome explains the Yaa phenotype. Mechanistically, we propose that the elevation of Midin expression caused by this translocation results in B-cell hyperactivity by decreasing phosphatase activity that normally represses action of a major cell kinase. We will (1) genomically characterize the structure of Midy, (2) determine the effect of transgenically elevated Midin expression on B-cell signaling and autoimmunity, and (3) inactivate Midy to evaluate its potential for generating the Yaa phenotype. These studies will clarify the molecular mechanisms by which Midin could impact B-cell signaling pathways generally leading to SLE pathogenesis both in mice and humans. Relevance to public health. SLE is one of the most challenging of all autoimmune disorders to predict and effectively treat. Mouse models can be used advantageously to understand how genetics influence this disease, to predict genetic predisposition, and to identify therapeutic targets. We have identified a key gene for mouse SLE. Understanding it will provide substantial insight into human SLE syndromes. [unreadable] [unreadable] [unreadable] [unreadable]