Olmsted syndrome (OS) is a rare congenital disorder characterized by palmoplantar and periorificial keratoderma, alopecia in most cases, and severe itching. The genetic basis for OS remained unidentified. Using whole-exome sequencing of case-parents trios, we have identified a de novo missense mutation in TRPV3 that produces p.Gly573Ser in an individual with OS. Nucleotide sequencing of five additional affected individuals also revealed missense mutations in TRPV3 (which produced p.Gly573Ser in three cases and p.Gly573Cys and p.Trp692Gly in one case each). Encoding a transient receptor potential vanilloid-3 cation channel, TRPV3 is primarily expressed in the skin, hair follicles, brain, and spinal cord. In transfected HEK293 cells expressing TRPV3 mutants, much larger inward currents were recorded, probably because of the constitutive opening of the mutants. These gain-of-function mutations might lead to elevated apoptosis of keratinocytes and consequent skin hyperkeratosis in the affected individuals. Our findings suggest that TRPV3 plays essential roles in skin keratinization, hair growth, and possibly itching sensation in humans and selectively targeting TRPV3 could provide therapeutic potential for keratinization or itching-related skin disorders.

These data may demonstrate that autophagy is involved in the pathogenesis of SLE and imply a common biological pathway in autoimmunity.

Objective Although the number of convincingly established genetic associations with systemic lupus erythematosus (SLE) has increased sharply over the last few years, refinement of these associations is required, and their potential roles in gene–gene interactions need to be further investigated. Recent genome-wide association studies (GWAS) in SLE have produced renewed interest in B cell/T cell responses and the NF-κB signaling pathway. The aim of this study was to search for possible gene–gene interactions based on identified single-nucleotide polymorphisms (SNPs), in using an approach based on the role of signaling pathways. Methods The SNPs in BLK, TNFSF4, TRAF1, TNFAIP3, and REL were replicated in order to evaluate genetic associations with SLE. TaqMan genotyping was conducted in 804 Chinese patients with SLE and 722 matched control subjects. A multiple logistic regression model was used to estimate the multiplicative interaction effect of the SNPs, and additive interactions were analyzed by 2 × 2 factorial designs. Data from a previously published GWAS conducted by the International Consortium on the Genetics of Systemic Lupus Erythematosus were derived for comparison and validation. Results Single-marker analysis validated the association of BLK rs2736340 (P = 4.25 × 10–6) as well as TNFSF4 rs2205960 (P = 2.82 × 10–5) and TNFAIP3 rs5029939 (P = 1.92 × 10–3) with SLE susceptibility in Chinese. Multiplicative interaction analysis indicated that BLK had an interactive effect with TNFSF4 in Chinese patients with SLE (P = 6.57 × 10–4). Additive interaction analysis revealed interactions between TRAF1 and TNFAIP3 in both Chinese (P = 2.18 × 10–3) and Caucasians (P = 2.86 × 10–4). In addition, multiple tendencies toward interactions were observed, and an additive effect was observed as the number of risk genotypes increased. Conclusion The results of this study provide evidence of the possible gene–gene interactions of BLK, TNFSF4, TRAF1, TNFAIP3, and REL in SLE, which may represent a synergic effect of T cells and B cells through the NF-κB pathway in determining immunologic aberration.

No abstract

Objectives Recent genome-wide association studies have identified several novel susceptibility genes for systemic lupus erythematosus (SLE) and IgA nephropathy (IgAN). Since both lupus nephritis (LN) and IgAN are autoimmune kidney diseases, they may share common disease mechanisms that overlap with genetic susceptibility. To test this hypothesis, we sought to identify genetic variants associated with IgAN in LN. Methods In the first stage, 500 LN patients, 240 SLE patients without LN, and 500 healthy controls were enrolled. Fifteen reported SNPs with top association signals with IgAN were selected for further testing in LN. Three independent cohorts from Beijing, Shanghai and Hong Kong were included as replicates. We also analyzed the functional significance of identified non-coding variants on regulatory motifs and gene expression. Results Except for associations with HLA gene polymorphisms, genetic variants of MTMR3 in 22q12 showed associations with LN (rs9983A with P = 2.07×10−3; OR 1.61; 95% CI 1.19–2.19) compared to healthy controls in the first stage. In replications, associations were replicated and reinforced with northern (LN vs. non-LN patients, P = 0.01) but not southern Han Chinese, although significant genetic heterogeneity was observed. In silico analyses predicted conservative and regulatory features of rs9983. In expression analysis, we observed lower MTMR3 transcription levels in blood samples with rs9983A and renal biopsies from LN and IgAN. Conclusions Our results suggested that the MTMR3 gene was shared between IgAN and LN in the northern Chinese, further highlighting the role of autophagy in SLE. However, widespread replication of these experiments, fine mapping, and functional assays are required to establish this connection.