The human GIMAP5 gene has a common polyadenylation polymorphism increasing risk to systemic lupus erythematosus

Abstract

Background: Several members of the GIMAP gene family have been suggested as being involved in different aspects of the immune system in different species. Recently, a mutation in the GIMAP5 gene was shown to cause lymphopenia in a rat model of autoimmune insulin-dependent diabetes. Thus it was hypothesised that genetic variation in GIMAP5 may be involved in susceptibility to other autoimmune disorders where lymphopenia is a key feature, such as systemic lupus erythematosus (SLE). Material and methods: To investigate this, seven single nucleotide polymorphisms in GIMAP5 were analysed in five independent sets of family-based SLE collections, containing more than 2000 samples. Result: A significant increase in SLE risk associated with the most common GIMAP5 haplotype was found (OR 1.26, 95% CI 1.02 to 1.54, p = 0.0033). In families with probands diagnosed with trombocytopenia, the risk was increased (OR 2.11, 95% CI 1.09 to 4.09, p = 0.0153). The risk haplotype bears a polymorphic polyadenylation signal which alters the 39 part of GIMAP5 mRNA by producing an inefficient polyadenylation signal. This results in higher proportion of non-terminated mRNA for homozygous individuals (p,0.005), a mechanism shown to be causal in thalassaemias. To further assess the functional effect of the polymorphic polyadenylation signal in the risk haplotype, monocytes were treated with several cytokines affecting apoptosis. All the apoptotic cytokines induced GIMAP5 expression in two monocyte cell lines (1.5-6 times, p,0.0001 for all tests). Conclusion: Taken together, the data suggest the role of GIMAP5 in the pathogenesis of SLE.

Putative GTPase GIMAP1 is critical for the development of mature B and T lymphocytes

“…2,[6][7][8] Furthermore, autoimmunityrelated traits in humans have been associated with a GIMAP5 gene variant. 9,10 The mutation in rat GIMAP5 causes peripheral T lymphopenia (reviewed in Ramanathan and Poussier 11 ), but thymic abnormalities in the mutant animals are limited and largely confined to the mature CD4 ϩ and CD8 ϩ single-positive (SP) compartments. 12 No effect on B-lymphocyte populations has been reported in these rats.…”

Structural basis of oligomerization in septin-like GTPase of immunity-associated protein 2 (GIMAP2)

“…Conditional knockout of GIMAP1 in mouse lymphoid tissues resulted in an almost complete loss of mature B and T cells, highlighting the central function of GIMAPs in regulation of lymphocyte survival also in the B cell lineage (15). The role of GIMAPs in human diseases is underpinned by the observation that a single nucleotide polymorphism in GIMAP5 is associated with IA2 autoantibodies in type 1 diabetes (T1D) patients and systemic lupus erythematosus (16,17). The expression of almost the whole GIMAP family is turned down in regulatory T cells of patients suffering from T1D (18).…”

ENU Mutagenesis in Mice - Genetic Insight into Impaired Immunity and Disease

“…Although limited information is available with regard to genetic mutations causing a null phenotype in human GIMAP5 or HEM1, ample evidence exist that dysregulation of these genes plays an important role in human disease. A previous report suggests that SLE patients were shown to have a trend for lower GIMAP5 mRNA expression in peripheral blood mononuclear cells compared to healthy controls 16 . Moreover, a poly-adenylation mutation in the 3' region of GIMAP5, resulting in minor changes in GIMAP5 mRNA expression in peripheral blood mononuclear cells, are associated with increased predisposition to SLE and T1D 15,16,53 .…”

“…A previous report suggests that SLE patients were shown to have a trend for lower GIMAP5 mRNA expression in peripheral blood mononuclear cells compared to healthy controls 16 . Moreover, a poly-adenylation mutation in the 3' region of GIMAP5, resulting in minor changes in GIMAP5 mRNA expression in peripheral blood mononuclear cells, are associated with increased predisposition to SLE and T1D 15,16,53 . Thus far, the effect on GIMAP protein expression, specifically in lymphocytes of homozygote/heterozygote carriers for this mutation, remains elusive and warrants further research.…”

“…In humans, polyadenylation polymorphisms in GIMAP5-causing relative modest changes in GIMAP5 RNA expression-were associated with increased concentrations of IA2 autoantibodies in type 1 diabetes (T1D) patients and an increased risk of systemic lupus erythematosus (SLE) 16,17 . Studies using biobreeding (BB) rats-carrying a mutation (lyp/lyp) in Gimap5-show marked lymphopenia and predisposition to the development of T1D [18][19][20][21][22] and intestinal inflammation 23 .…”