Two novel types of contiguous gene deletion of the AVPR2 and ARHGAP4 genes in unrelated Japanese kindreds with nephrogenic diabetes insipidus

Abstract

Study of two families containing individuals with nephrogenic diabetes insipidus (NDI) indicated different types of 21.3 kb and 26.3 kb deletions involving the AVPR2 and ARHGAP4 (RhoGAP C1) genes. In the case of the 21.3 kb deletion, the deletion consensus motif (5'-TGAAGG-3') and polypurine runs, known as the arrest site of polymerase alpha, were detected in the vicinity of the deletion junction. Inverted repeats (7/8 matches), believed to potentiate DNA loop formation, flank the deletion breakpoint. We propose this deletion to be the result of slipped mispairing during DNA replication. In the case of the 26.3 kb deletion, the 12,945 bp inverted region with the 10,003 bp internal deletion was accompanied with the 2,509 bp deletion in the 5'-side and the 13,785 bp deletion in the 3'-side. We defined three deletion junctions in this rearrangement (DJ1, DJ2, and DJ3) from the 5'-side. The surrounding sequence of DJ1 (5'-CCC-3') closely resembled that of DJ3 (5'-AGGG-3') (DJ1; 5'-cCCCgaggg-3', DJ3; 5'-ccccAGGG-3'), and DJ1 was located in the 5'-side of DJ3 without any overlapping in sequence. The immunoglobulin class switch (ICS) motif (5'-TGGGG-3') was found around the complementary sequence of DJ3. There was a 10-base palindrome (5'-aGACAtgtct-3') in the alignment of the DJ2 (5'-GACA-3') region. From these findings, we propose a novel mutation process with the rearrangement probably resulting from stem-loop induced non-homologous recombination in an ICS-like fashion. Both patients, despite lacking ARHGAP4, had no morphological, clinical, or laboratory abnormalities except for those usually found in patients with NDI.

Novel mutations underlying nephrogenic diabetes insipidus in Arab families

“…similar mutation process involving the ICS motif was proposed for a previously reported contiguous gene deletion involving AVPR2 and ARHGAP4. 25 In addition an extrachromosomal substrate assay for ICS recombination also highlights the central role of the ICS motif in recombination that involves excision of an intervening sequence. 26 Interestingly, no symptoms specific to the ARHGAP4 gene were identified in our patients.…”

“…Contiguous deletions involving AVPR2 and ARH-GAP4 have been reported on two previous occasions, with the NDI phenotype not being compounded in either instance. 25,27 ARHGAP4 encodes a cytoplasmic protein of 115 kD that is preferentially expressed in hematopoietic cells. One patient with a contiguous deletion of ARHGAP4 and AVPR2 was followed over a 16-year period and included extensive analysis of blood chemical, enzyme and hormone values and showed no deviations from normal ranges other than those related to the CNDI phenotype.…”

Treatment of Congenital Nephrogenic Diabetes insipidus with Hydrochlorothiazide and Amiloride in an Adult Patient

“…Molecular analysis for each individual case is indispensable for contemporary medicine [15]. Our case was revealed to have a contiguous deletion of AVPR2 and ARHGAP4 (RhoGAP C1) genes [14]. As, except for a possibly milder phenotype in patients with a G185C mutation, no clear relationship between clinical and genetic data could be found [15], our patient is not thought to be a special case for evaluation of treatment.…”

“…The diagnosis of NDI was confirmed by a lack of response of the urinary osmolality to fluid restriction and 1-deamino-8- D -AVP administration. Later, molecular examination revealed a contiguous deletion of AVPR2 and ARHGAP4 (RhoGAP C1) genes [14](patient No. 1 in this report).…”

Ectopic Production of Parathyroid Hormone in a Patient with Sporadic Medullary Thyroid Cancer

“…Prehybridization, hybridization and probe labeling were performed using alkPhos Direct (ge healthcare uk Ltd., Buckinghamshire, england), as reported previously [8]. The probes comprised the PCr products, using the following forward and reverse primers for the PTh promoter region (2986 bp): 5'-aag Cag TTC aCa CTC aaa Tga CCa aCa-3' and 5'-TCC aaa agC TTC TCa Tga aaa CCa aCC-3'.…”