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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-act...
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Context 1
... patients (IV-2 and IV-4 in Figure 1) were admitted to the hospital at the age of 2 months with fever of unknown origin. NDI was diagnosed on the basis of clinical symp- toms and laboratory findings (dehydration, hyper- natremia, and hypotonic urine) and failure to increase urine osmolarity in response to 1-2esamino-8-D-arginine vasopressin (dDAVP) ( Table 1). The sister (IV-1) had no history of dehydration, but polyuria and polydipsia were noticed by her family members, and NDI was diagnosed on the basis of laboratory findings at the age of 2 years. ...
Citations
... In addition to the entire AVPR2, the 7.5 kb deletion encompassed the last exon (exon 22) of the adjacent ARHGAP4 gene. This is consistent with previous results where all but one [20] of the previously published large deletions causing X-linked NDIs included a part or all of the ARHGAP4 gene [6,[8][9][10][21][22][23][24][25][26][27][28][29][30]. Despite lacking the part of ARHGAP4, both patients in this family had no symptoms other than those associated with NDI [1] which supports the results of the majority of previous studies [6,8,[21][22][23][24][26][27][28][29]showing that, in such cases, disruptions of ARHGAP4 do not lead to a different clinical phenotype. ...
... This is consistent with previous results where all but one [20] of the previously published large deletions causing X-linked NDIs included a part or all of the ARHGAP4 gene [6,[8][9][10][21][22][23][24][25][26][27][28][29][30]. Despite lacking the part of ARHGAP4, both patients in this family had no symptoms other than those associated with NDI [1] which supports the results of the majority of previous studies [6,8,[21][22][23][24][26][27][28][29]showing that, in such cases, disruptions of ARHGAP4 do not lead to a different clinical phenotype. ...
Background
X-linked nephrogenic diabetes insipidus (NDI) is a rare genetic renal disease caused by pathogenic variants in the AVPR2 gene. Single nucleotide variants and small insertions/deletions in AVPR2 are reliably detected by routine clinical sequencing. Nevertheless, structural variants involving AVPR2 are challenging to identify accurately by conventional genetic testing. Here, we report a novel deletion of AVPR2 in a Czech family identified for the first time by targeted long-read sequencing (T-LRS).
Methods
A male proband with X-linked NDI underwent clinical sequencing of the AVPR2 gene that failed and thus indicated possible whole-gene deletion. Therefore, PCR mapping and subsequent targeted long-read sequencing (T-LRS) using a Pacific Biosciences sequencer were applied to search for the suspected deletion. To validate the deletion breakpoints and prove variant segregation in the family with X-linked NDI, Sanger sequencing of the deletion junction was performed. Quantitative real-time PCR was further carried out to confirm the carrier status of heterozygous females.
Results
By T-LRS, a novel 7.5 kb deletion of AVPR2 causing X-linked NDI in the proband was precisely identified. Sanger sequencing of the deletion junction confirmed the variant breakpoints and detected the deletion in the probands´ mother, maternal aunt, and maternal cousin with X-linked NDI. The carrier status in heterozygous females was further validated by quantitative real-time PCR.
Conclusions
Identifying the 7.5 kb deletion gave a precise molecular diagnosis for the proband, enabled genetic counselling and genetic testing for the family, and further expanded the spectrum of structural variants causing X-linked NDI. Our results also show that T-LRS has significant potential for accurately identifying putative structural variants.
... ARHGAP4 encodes a protein with a proline-rich structure amenable to cellular scaffold formation and the maintenance of normal intracellular vesicle transport and endocytosis. [14,15] Mutations in ARHGAP4 result in the inhibition of its binding with proline structural proteins, potentially interfering with its ability to participate in cytoskeleton formation. ARHGAP4 is expressed at significant levels in multiple specific tissues in both the developing and adult nervous systems, suggesting it to play an important role in this setting. ...
Background:
Progressive hemifacial atrophy (PHA) is a rare and progressive condition of unknown etiology that is characterized by chronic progressive atrophy of the skin, subcutaneous tissue, muscle, and bone on 1 side of the face. However, its precise pathogenesis remains poorly understood.
Case presentation:
Here, we report a case of PHA, which manifested as left-sided facial atrophy. Whole-exome sequencing of peripheral blood samples from the patient and his parents, together with bioinformatics analyses, led to the identification of mutations in ARHGAP4 and CFAP47.
Conclusion:
This report is the first to describe ARHGAP4 and CFAP47 mutations in a patient with PHA. These mutations may be related to the occurrence of hemifacial atrophy, although further studies are needed to clarify the role of ARHGAP4 and CFAP47 in the context of PHA pathogenesis.
... ARHGAP4 is a member of the Rho-GTPase activating proteins (Rho-GAPs) family and has an SH3 structure that interacts with proline-rich domains of many proteins. It is involved in cell scaffold formation, intracellular vesicle transport and endocytosis (21), and cell motility (22). ARHGAP4 has been reported to increase the expression of matrix metalloproteinase 2 and 9, resulting in the stimulation of the invasion and migration activity of pancreatic (23) and breast cancer cells (24). ...
Background/aim:
Scirrhous-type gastric cancer (SGC), one of the most intractable cancer subtypes, is characterized by rapid cancer cell proliferation and infiltration accompanied by extensive stromal fibrosis. One of the reasons for its poor prognosis may be the lack of molecular target drugs for SGC, because of the unknown driver genes. Exploration of somatic mutations in the human samples of SGC using next-generation sequencing (NGS) has been hampered by abundant fibrous tissues in these samples. Therefore, this study aimed to determine a novel oncogene by RNA-sequencing using SGC cell lines, avoiding contamination with fibrosis.
Materials and methods:
In silico analysis of RNA-sequencing public data of the gastric cancer cell line, and RNA- sequencing using five of our unique SGC cell lines, OCUM1, OCUM2MLN, OCUM8, OCUM12, and OCUM14 were performed.
Results:
We found three differentially expressed genes, ARHGAP4, NOS3, and OR51B5 that are significantly over-expressed in SGC cells. Immunohistochemical analysis indicated that the protein expression levels of these three genes were significantly higher in SGC than in other types of gastric cancer. The prognosis of patients with positive expression of these three genes was significantly poorer than those with negative expression. In particular, ARHGAP4 expression was an independent predictor of poor prognosis and recurrence.
Conclusion:
ARHGAP4, NOS3, and OR51B5 may be candidate driver genes for SGC. ARHGAP4 may be a promising molecular target for SGC.
... AVPR2 mutations usually lead to dysregulated receptors, leading to X-linked NDI and impaired urine concentration ability [16]. Approximately 90% of familial NDI is caused by X-linked mutations in AVPR2 and thereby affects males [12], whereas heterozygous females show various degrees of preference [17,18]. The genetic result of our patient is AVPR2 gene duplication, which leads to a frameshift mutation in the seventh transmembrane domain of exon 3 next to proline 306. ...
Background
Diabetes insipidus (DI) can be a common cause of polydipsia and polyuria. Here, we present a case of congenital nephrogenic diabetes insipidus (CNDI) accompanied with central diabetes insipidus (CDI) secondary to pituitary surgery.
Case presentation
A 24-year-old Chinese woman came to our hospital with the complaints of polydipsia and polyuria for 6 months. Six months ago, she was detected with pituitary apoplexy, and thereby getting pituitary surgery. However, the water deprivation test demonstrated no significant changes in urine volume and urine gravity in response to fluid depression or AVP administration. In addition, the genetic results confirmed a heterozygous mutation in arginine vasopressin receptor type 2 (AVPR2) genes.
Conclusions
She was considered with CNDI as well as acquired CDI secondary to pituitary surgery. She was given with hydrochlorothiazide (HCTZ) 25 mg twice a day as well as desmopressin (DDAVP, Minirin) 0.1 mg three times a day. There is no recurrence of polyuria or polydipsia observed for more than 6 months. It can be hard to consider AVPR2 mutation in female carriers, especially in those with subtle clinical presentation. Hence, direct detection of DNA sequencing with AVPR2 is a convenient and accurate method in CNDI diagnosis.
... ARHGAP4 is a member of the RhoGAP family and has an SH3 structure at the C-terminal that interacts with proline-rich domains of many proteins, involving in cell scaffold formation, intracellular vesicle transport and endocytosis (27). ARHGAP4 mutation was found in patients with systemic lupus erythematosus (28). ...
β-catenin is a subunit of the cadherin protein complex and acts as an intracellular signal transducer in the Wnt signaling pathway that mediates multiple cellular processes, such as cell migration and invasion. HDAC2 (histone deacetylase 2), a deacetylase that maintains histone H3 in a deacetylated state in the promoter region of Wnt-targeted genes where β-catenin is bound, negatively regulating β-catenin activation. However, the regulation of HDAC2/β-catenin pathway remains unclear. Here, we report ARHGAP4 as a new regulator of the β-catenin pathway that regulates cell invasion and migration of pancreatic cancer as well as the downstream effector MMP2 and MMP9 expression in vitro. Mechanistically, ARHGAP4 interacts with and ubiquitinates HDAC2, which in turn inhibits β-catenin activation. Furthermore, treatment of CAY10683, an HDAC2 inhibitor, and XAV939, a Wnt/β-catenin pathway inhibitor, attenuated the effects of ARHGAP4 silencing on pancreatic cancer cells. Overall, our findings establish ARHGAP4 as a novel regulator of HDAC2/β-catenin pathway with a critical role in tumorigenesis.
... The remaining 10% of the NDI cases are mainly related to AQP2 gene mutations [2], which is autosomally inherited. For X-linked NDI, males with pathogenic mutations in AVPR2 are affected, while heterozygous females show various degrees of penetrance [3]. Furthermore, skewed X inactivation, which is preferential methylation of the normal allele of the AVPR2 gene, can cause NDI in female heterozygotes [4]. ...
... To date, more than 277 AVPR2 putative disease-causing mutations have been reported (http://www.hgmd.cf.ac.uk/ ac/index.php). Large deletions that lead to complete loss of AVPR2 and parts of the neighboring genes ARHGAP4 or L1 cell adhesion molecule (L1CAM) have also been reported [3,[5][6][7][8][9][10][11][12]. However, very few X-linked NDI cases caused by gross AVPR2 deletion have been reported in China. ...
... It is particularly noteworthy that X-ray bone age was smaller than the actual age of the proband. To our knowledge, short stature is one common feature in some severe NDI cases, compared with twelve other NDI cases previously reported [3,[5][6][7][8][9][10][11]15]. It is consistent with the hypothesis that AVPR2 is expressed in osteoblasts and osteoclasts and loss of AVPR2 function would affect bone remodeling [16]. ...
Background:
It has been reported that mutations in arginine vasopressin type 2 receptor (AVPR2) cause congenital X-linked nephrogenic diabetes insipidus (NDI). However, only a few cases of AVPR2 deletion have been documented in China.
Methods:
An NDI pedigree was included in this study, including the proband and his mother. All NDI patients had polyuria, polydipsia, and growth retardation. PCR mapping, long range PCR and sanger sequencing were used to identify genetic causes of NDI.
Results:
A novel 22,110 bp deletion comprising AVPR2 and ARH4GAP4 genes was identified by PCR mapping, long range PCR and sanger sequencing. The deletion happened perhaps due to the 4-bp homologous sequence (TTTT) at the junctions of both 5' and 3' breakpoints. The gross deletion co-segregates with NDI. After analyzing available data of putative clinical signs of AVPR2 and ARH4GAP4 deletion, we reconsider the potential role of AVPR2 deletion in short stature.
Conclusions:
We identified a novel 22.1-kb deletion leading to X-linked NDI in a Chinese pedigree, which would increase the current knowledge in AVPR2 mutation.
... 22 It is not known whether DOCK8-associated lymphopenia is caused by defects in cell migration. Other immunodeficiencies affecting proteins involved in vesicle transport, such as the LPS-responsive beige-like anchor protein (LRBA), 3,24 or in the RhoGTPase activating proteins (RhoGAPs) regulating cell motility (eg, ARHGAP4) 25,26 might impair S1P receptor signaling. Mutations in LRBA cause severe, early-onset humoral immunodeficiency and autoimmunity. ...
... 25 ARHGAP4 deficiency results in primary immunodeficiency that is characterized by low numbers of circulating T cells and almost complete absence of CD8 1 T cells. 26 Studying primary B lymphocytes and EBV-immortalized B cells, we report that differentially expressed S1P receptors regulate human B-cell migration. Analyzing cells of different primary immunodeficiencies, we show that the signaling cascade induced by S1P1 ranges from b-arrestin 2 through LRBA and DOCK8 to WASp. ...
Five different G protein-coupled sphingosine-1-phosphate (S1P) receptors (S1P1-S1P5) regulate a variety of physiologic and pathophysiologic processes, including lymphocyte circulation, multiple sclerosis (MS), and cancer. Although B-lymphocyte circulation plays an important role in these processes and is essential for normal immune responses, little is known about S1P receptors in human B cells.
To explore their function and signaling, we studied B-cell lines and primary B cells from control subjects, patients with leukemia, patients with S1P receptor inhibitor-treated MS, and patients with primary immunodeficiencies.
S1P receptor expression was analyzed by using multicolor immunofluorescence microscopy and quantitative PCR. Transwell assays were used to study cell migration. S1P receptor internalization was visualized by means of time-lapse imaging with fluorescent S1P receptor fusion proteins expressed by using lentiviral gene transfer. B-lymphocyte subsets were characterized by means of flow cytometry and immunofluorescence microscopy.
Showing that different B-cell populations express different combinations of S1P receptors, we found that S1P1 promotes migration, whereas S1P4 modulates and S1P2 inhibits S1P1 signals. Expression of CD69 in activated B lymphocytes and B cells from patients with chronic lymphocytic leukemia inhibited S1P-induced migration. Studying B-cell lines, normal B lymphocytes, and B cells from patients with primary immunodeficiencies, we identified Bruton tyrosine kinase, β-arrestin 2, LPS-responsive beige-like anchor protein, dedicator of cytokinesis 8, and Wiskott-Aldrich syndrome protein as critical signaling components downstream of S1P1.
Thus S1P receptor signaling regulates human B-cell circulation and might be a factor contributing to the pathology of MS, chronic lymphocytic leukemia, and primary immunodeficiencies.
... 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]. ...
Background:
Familial form of nephrogenic diabetes insipidus (NDI) is a rare hereditary disease caused by arginine vasopressin type 2 receptor (AVPR2) or water channel aquaporin 2 (AQP2) gene mutations. It is speculated that 90% of NDI families carry disease-causing mutations in AVPR2 and 10% carry the mutations in AQP2; however, these percentages have not been supported by actual data. It is also unknown whether these percentages vary in different ethnic groups.
Methods:
Gene mutation analyses were performed for 78 Japanese NDI families. All exons and intron-exon boundaries of the AVPR2 and AQP2 genes were directly sequenced.
Results:
A total of 62 families (79%) carried disease-causing mutations in AVPR2, while nine families (12%) carried mutations in AQP2. We identified 22 novel putatively disease-causing mutations (19 in AVPR2 and 3 in AQP2). Regarding AVPR2, 52 disease-causing mutations were identified. Among them, missense mutations were most common (54%), followed by deletion mutations. In the 64 women who had monoallelic disease-causing AVPR2 mutations, 16 (25%) had NDI symptoms, including 4 complete NDI subjects. Regarding AQP2, 9 disease-causing mutations were identified in nine families. Two missense mutations and one deletion mutation showed a recessive inheritance, while one missense mutation and five small deletion mutations in the C-terminus of AQP2 showed a dominant inheritance.
Conclusions:
Most Japanese NDI families carry disease-causing mutations in AVPR2 and 12% carry mutations in AQP2. A total of 22 novel putatively disease-causing mutations were identified. The relatively high occurrence of symptomatic carriers of AVPR2 mutations needs attention.
... 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. ...
... In this report, we describe a novel 17.9 kb deletion in male dizygotic twins with X-linked NDI and ID at Xq28 affecting the AVPR2 and ARHGAP4 genes. 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. 3A,B). ...
... 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. ...
The clinical features of loss of ARHGAP4 function remain unclear despite several reports of different patterns of deletions inactivating different functional regions of the protein. The protein encoded by ARHGAP4 is thought to function as a Rho GTPase activating protein. Characterization of the genetic defect causing X-linked nephrogenic diabetes insipidus (NDI) and intellectual disability in two dizygotic twin brothers revealed a novel contiguous deletion of 17,905 bp encompassing the entire AVPR2 gene and extending into intron 7 of the ARHGAP4 gene. Examination of their mother showed that she was a carrier of this deletion. An attempt was made to distinguish the putative clinical signs of an ARHGAP4 deletion from the well-defined phenotype of X-linked NDI caused by an AVPR2 gene deletion. By reviewing all characterized deletions encompassing ARHGAP4, we reconsider the potential role of ARHGAP4 in cognition. © 2012 Wiley Periodicals, Inc.
... We analysed two patients with NDI with large deletions encompassing the entire AVPR2 gene and part of the ARHGAP4 gene, and we obtained the fine mapping of the deletion breakpoints in both cases. To our knowledge, 16 additional large deletions involving the AVPR2 gene have been described as causing X-linked NDI [4][5][6][7][8][9][10][11][12][13][14][15][16]. ...
... We analysed two patients with NDI with large deletions encompassing the entire AVPR2 gene and part of the ARHGAP4 gene, and we obtained the fine mapping of the deletion breakpoints in both cases. To our knowledge, 16 additional large deletions involving the AVPR2 gene have been described as causing X-linked NDI [4][5][6][7][8][9][10][11][12][13][14][15][16]. ...
Background
In this paper, we report two new original deletions and present an extended review of the previously characterized AVPR2 gene deletions to better understand the underlying deletion mechanisms.Methods
The two novel deletions were defined using polymerase chain reaction mapping and junction fragment sequencing. Bioinformatic analysis was performed on both the previously mapped deletions and the novel ones through several web tools.ResultsIn our two patients with nephrogenic diabetes insipidus, we found a 23 755 bp deletion and a 9264 bp deletion both comprising the entire AVPR2 gene and part of the ARHGAP4 gene. Through bioinformatic studies, the smallest overlapping region as well as several motifs and repeats that are known to promote rearrangements were confirmed.Conclusions
Through this study, it was determined that the deletion mechanisms in the AVPR2 region do not follow the rules of non-allelic homologous recombination. Two of the 13 deletions can be attributed to the fork stalling and template switching (FoSTeS) mechanism, whereas the remaining 11 deletions could be caused either by non-homologous end joining or by the FoSTeS mechanism. Although no recurrence was found, several groupings of deletion breakpoints were identified.
