2002 Global Researcher Conference Proceeding
April 26 - 28, 2002
| Conference: | 2002 Global Researcher Conference |
|---|---|
| Title: | Thirteen Large Deletions/Rearrangements of the AVPR2 Gene Causing X-linked Nephrogenic Diabetes Insipidus |
| Authors: | Arthus, Marie-Francoise; Lonergan, Michele; Robertson, Gary; Goodyer, Paul; Morgan, Kenneth; Fujiwara, T. Mary; Bichet, Daniel G. |
| Institutions: | Hopital du Sacre-Coeur de Montreal, Northwestern University Medical School, McGill University, Montreal General Hospital |
To date we have identified AVPR2 mutations and assembled data on a worldwide collection of 169 X-linked nephrogenic diabetes insipidus (NDI) families referred to our laboratory. Genotyping of four loci (DXS52, DXS15, G6PD, and F8) that flank the AVPR2 gene in chromosome region Xq28 was done to follow the segregation of the NDI allele in each family and to confirm X-linked inheritance (Arthus M-F, Lonergan M, Crumley MJ, Naumova AK, Morin D, De Marco L, Kaplan BS, Robertson GL, Sasaki S, Morgan K, Bichet DG, Fujiwara TM. 2000 Report of 33 novel AVPR2 mutations and analysis of 117 families with X-linked nephrogenic diabetes insipidus. J Am Soc Nephrol 11:1044-1054). Among 169 families, there were 119 different putative disease-causing mutations (56 missenses, 13 nonsenses, 26 small deletions, 9 insertions, 1 splice-site mutation and 14 large deletions). Deletions were identified in 43 families (25% of the 169 families). Deletions larger than 500 bp, arbitrarily defined as large deletions, were found in 14 families (1/3). The affected patients had no additional phenotypic features. In these patients, amplification of the full length AVPR2 with our usual primers did not yield any product. We systematically used 15 different sets of primers (4 intragenic, 11 extragenic) covering a 45 kb region encompassing the AVPR2 gene (19 kb upstream, 24 kb downstream: the nucleotide positions refer to numbering of original sequence submission of the Xq28-L1CAM locus, GenBank accession number U52112, revised October 2001). Complete breakpoints were identified in 10 families with the following length of deletions (in kb): 17.8; 13.7; 11.0; 10.9; 5.9; 4.2; 3.13; 2.27; 1.4; 0.9. Four slipped mispairing events were likely involved. Deletions with complex rearrangements occurred in four cases possibly favored by Alu repeat elements. In three families, only one breakpoint has been identified so far. Perinatal diagnosis was done in two cases. Different contiguous gene deletions of the AVPR2 and C1 genes have also been reported in three other families (Schoneberg T, Pasel K, von Baehr V, Schulz A, Volk HD, Gudermann T, Filler G. Compound deletion of the rhoGAP C1 and V2 vasopressin receptor genes in a patient with nephrogenic diabetes insipidus. Hum Mutat 14:163-74, 1999; Demura M, Takeda Y, Yoneda T, Furukawa K, Usukura M, Itoh Y, Mabuchi H. Two novel types of contiguous gene deletion of the AVPR2 and ARHGAP4 genes in unrelated Japanese kindreds with nephrogenic diabetes insipidus. Hum Mutat 19:23-9, 2002). Taken together these results indicate the diversity of large deletions and the absence of a contiguous gene syndrome (C1).
Arthus, et al., have assembled data on 169 X-linked NDI families. There were 119 different NDI causing mutations among these families. There are different types of mutations. One type is called a deletion mutation, which means that the gene is missing some of its base pairs. Arthus, et al., analyzed the NDI causing gene with large deletions (which occurred in 14 families). They found that there was a wider variety among these deletions. That is, though they were all large deletions, the constituent parts of the genes that were deleted varied widely.