Immunological profile in a family with nephrogenic diabetes insipidus with a novel 11 kb deletion in AVPR2 and ARHGAP4 genes

Abstract

BackgroundCongenital nephrogenic diabetes insipidus (NDI) is characterised by an inability to concentrate urine despite normal or elevated plasma levels of the antidiuretic hormone arginine vasopressin. We report a Japanese extended family with NDI caused by an 11.2-kb deletion that includes the entire AVPR2 locus and approximately half of the Rho GTPase-activating protein 4 (ARHGAP4) locus. ARHGAP4 belongs to the RhoGAP family, Rho GTPases are critical regulators of many cellular activities, such as motility and proliferation which enhances intrinsic GTPase activity.ARHGAP4 is expressed at high levels in hematopoietic cells, and it has been reported that an NDI patient lacking AVPR2 and all of ARHGAP4 showed immunodeficiency characterised by a marked reduction in the number of circulating CD3+ cells and almost complete absence of CD8+ cells.MethodsPCR and sequencing were performed to identify the deleted region in the Japanese NDI patients. Immunological profiles of the NDI patients were analysed by flow cytometry. We also investigated the gene expression profiles of peripheral blood mononuclear cells (PBMC) from NDI patients and healthy controls in microarray technique.ResultsWe evaluated subjects (one child and two adults) with 11.2-kb deletion that includes the entire AVPR2 locus and approximately half of the ARHGAP4. Hematologic tests showed a reduction of CD4+ cells in one adult patient, a reduction in CD8+ cells in the paediatric patient, and a slight reduction in the serum IgG levels in the adult patients, but none of them showed susceptibility to infection. Gene expression profiling of PBMC lacking ARHGAP4 revealed that expression of RhoGAP family genes was not influenced greatly by the lack of ARHGAP4.ConclusionThese results suggest that loss of ARHGAP4 expression is not compensated for by other family members. ARHGAP4 may play some role in lymphocyte differentiation but partial loss of ARHGAP4 does not result in clinical immunodeficiency.

A novel contiguous gene deletion of AVPR2 and ARHGAP4 genes in male dizygotic twins with nephrogenic diabetes insipidus and intellectual disability

“…Recently, there have been seven reports of the contiguous deletion of AVPR2 and ARHGAP4 genes in eight unrelated NDI patients [Schoneberg et al, 1999;Demura et al, 2002;Schulz et al, 2002;Broides et al, 2006;Dong et al, 2006;Fujimoto et al, 2008;Knops et al, 2008]. Our patients had significant ID and short stature, which distinguished them from previous reports (Table II and Fig.…”

“…Previous analysis of human ARHGAP4 revealed it to be highly expressed in hematopoietic cells [Tribioli et al, 1996], suggesting immunodeficiency to be a likely clinical sign of loss of ARHGAP4 function [Schoneberg et al, 1999;Broides et al, 2006;Fujimoto et al, 2008]. A recent study demonstrated that ARHGAP4 is more widely expressed.…”

“…Interestingly, it has recently been shown that the loss of ARH-GAP4 function is not compensated for by other RhoGAP family members [Fujimoto et al, 2008]. This suggests that the loss of ARHGAP4 itself may at least contribute to risk of ID, which may or may not present in males with various ARHGAP4 deletions.…”

“…It is adjacent to the well-characterized gene Arginine Vasopressin Receptor 2 (AVPR2; OMIM# 304800) mutations in which cause X-linked congenital nephrogenic diabetes insipidus (NDI) [Spanakis et al, 2008]. There have been seven previous reports of different patterns of contiguous deletions involving the AVPR2 and ARHGAP4 genes [Schoneberg et al, 1999;Demura et al, 2002;Schulz et al, 2002;Broides et al, 2006;Dong et al, 2006;Fujimoto et al, 2008;Knops et al, 2008]. We report the clinical and genetic characterization of NDI and ID in two male dizygotic twins with a novel contiguous gene deletion of the AVPR2 and ARHGAP4 genes at Xq28 and review the reported deletions encompassing ARHGAP4 to identify the putative clinical signs of ARHGAP4 deletions.…”

Hereditary nephrogenic diabetes insipidus in Japanese patients: analysis of 78 families and report of 22 new mutations in AVPR2 and AQP2

“…Some earlier cases were analyzed in Daniel Bichet's laboratory in Montreal and reported previously [11]. Also, several cases have been reported separately before [12][13][14][15][16]. The AVPR2 and AQP2 genes are relatively small and all exons and intron-exon boundaries were sequenced with usual sequencing methods [12,17,18].…”