title: 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.
authors.affiliation: Second Department of Internal Medicine, School of Medicine, Kanazawa University, Kanazawa, Japan. fu21i8n3@sr.incl.ne.jp
authors.forename: Masashi
authors.initials: M
authors.lastname: Demura
authors.forename: Yoshiyu
authors.initials: Y
authors.lastname: Takeda
authors.forename: Takashi
authors.initials: T
authors.lastname: Yoneda
authors.forename: Kenji
authors.initials: K
authors.lastname: Furukawa
authors.forename: Mikiya
authors.initials: M
authors.lastname: Usukura
authors.forename: Yuji
authors.initials: Y
authors.lastname: Itoh
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mabuchi
mesh_terms: D000328:Adult; D044466:Asian People / Q000235:genetics*; D001482:Base Composition / Q000235:genetics; D001483:Base Sequence / Q000235:genetics; D018500:Diabetes Insipidus, Nephrogenic / Q000235:genetics*; D005260:Female; D019204:GTP-Binding Proteins / Q000235:genetics; D020690:GTPase-Activating Proteins / Q000235:genetics*; D017353:Gene Deletion; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000235:genetics; D007564:Japan; D008297:Male; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D010375:Pedigree; D017483:Receptors, Vasopressin / Q000235:genetics*; D020741:rho GTP-Binding Proteins / Q000235:genetics*
chemical_list: C446101:ARHGAP4 protein, human; D020690:GTPase-Activating Proteins; D017483:Receptors, Vasopressin; C080681:TRIM23 protein, human; D019204:GTP-Binding Proteins; D020741:rho GTP-Binding Proteins