Abstract
The Sle2c1rec1c (rec1c) sublocus is derived from the mouse lupus susceptibility 2 (Sle2) locus identified in the NZM2410 model. Our current study dissected the functional characters and the genetic basis of the rec1c locus relative to lupus when co-expressed with the Faslpr mutation, an established inducer of autoimmunity. The rec1c.lpr mice exhibited mild expansion of lymph nodes and had a normal T cell cellularity, but developed significantly kidney and lung inflammation, indicating that the rec1c amplifies lpr-induced autoimmune pathogenesis. A variant of somatic nuclear autoantigenic sperm protein (sNASP) was identified from the rec1c interval as a substitution of two consecutive amino acid residues in the histone-binding domain, resulting in an increased binding affinity to histone H4 and H3.1/H4 tetramer. To determine the role of the sNASP rec1c allele in mouse lupus, a novel strain was generated by introducing the rec1c mutations into the B6 genome. In this transgenic model, the sNASP allele synergized with the lpr mutation leading to moderate autoimmune phenotypes and aggravating inflammatory pathology alterations in kidney and lung that were similar to those observed in the rec1c.lpr mice. These results establish that the sNASP allele is a pathogenic genetic element in the rec1c sublocus, which not only promotes autoimmunity, but also exacerbates the inflammation reaction of end organs in mouse lupus pathogenesis. It also shows the complexity of the Sle2c locus, initially mapped as the major locus associated with B1a cell expansion. In addition to Cdkn2c, which regulates this expansion, we have now identified in the same locus a protective allele of Csf3r, a variant of Skint6 associated with T cell activation, and now a variant of sNASP that amplifies autoimmunity and tissue damage.
Highlights
Mouse models of systemic lupus erythematosus (SLE) have greatly contributed to the understanding of SLE pathogenesis, including by the identification of genetic pathways whose alterations lead to increased disease susceptibility or resistance [1]
Since the rec1c interval is of NZB origin [8], we refined its map and defined its ends by genotyping all available markers that are polymorphic between the NZB and B6 genomes (Figure 1), including microsatellite Mit and singlenucleotide polymorphisms (SNPs) markers collected from the Mouse Genome Informatics (MGI), the National Center for Biotechnology Information (NCBI) or identified through our own genomic sequencing
We identified a variant of somatic nuclear autoantigenic sperm protein gene these results identify the sNSAP allele as a candidate gene for the rec1c interval through its possibly altered binding to histones, and show that this allele is shared among several lupus-prone mouse genomes. with two mutations in exon 10: Chr4:g116,276,661 G>A and Chr4:g116,276,664 C>T (NCBI m37 assembly), which correspond to 841G>A and 844C>T, respectively, in the sNASP cDNA sequence (Figure 4A)
Summary
Mouse models of systemic lupus erythematosus (SLE) have greatly contributed to the understanding of SLE pathogenesis, including by the identification of genetic pathways whose alterations lead to increased disease susceptibility or resistance [1]. Great efforts have been invested in the genetic analysis of spontaneous lupus mouse models, only a few lupus susceptibility genes have been identified with a putative causative etiology [2, 3]. Polymorphisms in these genes so far do not seem to be directly involved in human lupus, they fit into pathways that. The coexpression of Sle with the lpr mutation in the Fas gene in the B6.Sle2.lpr mice resulted in more severe lupus nephritis and marked lymphadenopathy compared with B6.lpr mice [7]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
