title: Immunological profile in a family with nephrogenic diabetes insipidus with a novel 11 kb deletion in AVPR2 and ARHGAP4 genes.
abstract: BACKGROUND
  Congenital 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.
  
  
  METHODS
  PCR 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.
  
  
  RESULTS
  We 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.
  
  
  CONCLUSIONS
  These 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.
authors.affiliation: Department of Medical Genetics, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, Japan. m0620547@md.tsukuba.ac.jp
authors.forename: Masaya
authors.initials: M
authors.lastname: Fujimoto
authors.forename: Kohsuke
authors.initials: K
authors.lastname: Imai
authors.forename: Kenji
authors.initials: K
authors.lastname: Hirata
authors.forename: Reiichi
authors.initials: R
authors.lastname: Kashiwagi
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Morinishi
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Kitazawa
authors.forename: Sei
authors.initials: S
authors.lastname: Sasaki
authors.forename: Tadao
authors.initials: T
authors.lastname: Arinami
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Nonoyama
authors.forename: Emiko
authors.initials: E
authors.lastname: Noguchi
mesh_terms: D000328:Adult; D018791:CD4 Lymphocyte Count; D018500:Diabetes Insipidus, Nephrogenic / Q000235:genetics* / Q000276:immunology; D005260:Female; D020690:GTPase-Activating Proteins / Q000235:genetics*; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D010375:Pedigree; D020161:Physical Chromosome Mapping; D016133:Polymerase Chain Reaction; D017483:Receptors, Vasopressin / Q000235:genetics*; D017384:Sequence Deletion
chemical_list: C446101:ARHGAP4 protein, human; D020690:GTPase-Activating Proteins; D007074:Immunoglobulin G; D017483:Receptors, Vasopressin