Abstract
Autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI) is caused by postnatal arginine vasopressin (AVP) deficiency resulting from mutations in the AVP gene encoding the AVP pre-prohormone. To advance the understanding of adFNDI further, we have searched for mutations in the AVP gene in 15 unrelated kindreds in which diabetes insipidus appeared to be segregating. In nine kindreds, seven different previously described mutations were identified. In each of the other six kindreds, unique novel mutations were identified. Two of these (225A>G and 227G>A) change a nucleotide in the translation initiation codon of the signal peptide, whereas the other four (1797T>C, 1884G>A, 1907T>G, and 2112C>G) predict amino-acid substitutions in the neurophysin II moiety of the AVP prohormone, namely V67A (NP36), G96D (NP65), C104G (NP73), and C116W (NP85). Among these, the mutation predicting the V67A (NP36) substitution is remarkable. It affects a region of the neurophysin II not affected by any other mutations, produces only a minor change, and its inheritance suggests an incomplete penetrance. Our findings both confirm and further extend the mutation pattern that has emerged in adFNDI, suggesting that the mutations affect amino-acid residues known or reasonably presumed to be important for the proper folding and/or dimerization of the neurophysin II moiety of the AVP prohormone.
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Acknowledgements
We thank the following persons sincerely for their contribution to the study: Norbert Albers, Zentrum für Kinderheilkunde der Universität Bonn, Bonn; Michael Croxson, Auckland Hospital, Auckland; Cordula Gamm, Altonaer Kinderkrankenhaus, Hamburg; Václav Hána, Charles University, Prague; Gert Matthijs, Katholieke Universiteit Leuven, Leuven; Patrizia Matarazzo, University of Torino, Torino; K Sinko-Sanz, Universitätsklinik für Kinder- und Jugendheilkunde, Vienna; Dag Veimo, Nordland Sentralsykehus, Bodø; Franz Waldhauser, Universitätsklinik für Kinder- und Jugendheilkunde, Vienna; and Otto Westphal, Barn och Ungdoms Sjukhus, Göteborg. Last but not the least, we also thank Jane Hagelskjær Knudsen for her skilled laboratory assistance. This work was supported by grants from the Novo Nordic Foundation and the University of Aarhus, Denmark.
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Christensen, J., Siggaard, C., Corydon, T. et al. Six novel mutations in the arginine vasopressin gene in 15 kindreds with autosomal dominant familial neurohypophyseal diabetes insipidus give further insight into the pathogenesis. Eur J Hum Genet 12, 44–51 (2004). https://doi.org/10.1038/sj.ejhg.5201086
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DOI: https://doi.org/10.1038/sj.ejhg.5201086
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