Recurring dominant-negative mutations in the AVP-NPII gene cause neurohypophyseal diabetes insipidus
Journal Article
·
· American Journal of Human Genetics
OSTI ID:134305
- Children`s Hospital Medical Center, Cincinnati, OH (United States)
- Vanderbilt Univ. School of Medicine, Nashville, TN (United States); and others
Autosomal dominant neurohypophyseal diabetes insipidus (ADNDI) is a familial form of arginine vasopressin (or antidiuretic hormone) deficiency that is usually manifest in early childhood with polyuria, polydipsia and an antidiuretic response to exogenous vasopressin or its analogs. The phenotype is postulated to arise from gliosis and depletion of the magnocellular neurons that produce vasopressin in the supraoptic and paraventricular nuclei of the hypothalamus. ADNDI is caused by heterozygosity for a variety of mutations in the AVP-NPII gene which encodes vasopressin, its carrier protein (NPII) and a glycoprotein (copeptin) of unknown function. These mutations include: (1) Ala 19{r_arrow}Thr (G279A) in AVP`s signal peptide, (2) Gly 17{r_arrow}Val (G1740T), (3) Pro 24{r_arrow}Leu (C1761T), (4) Gly 57{r_arrow}Ser (G1859A) and (5) del Glu 47({delta}AGG 1824-26), all of which occur in NPII. In characterizing the AVP-NPII mutations in five non-related ADNDI kindreds, we have detected two kindreds having mutation 1 (G279A), two having mutation 3 (C1761T) and one having mutation 4 (G1859A) without any other allelic changes being detected. Two of these recurring mutations (G279A and G1859A) are transitions that occur at CpG dinucleotides while the third (C1761T) does not. Interestingly, families with the same mutations differed in their ethnicity or in their affected AVP-NPII allele`s associated haplotype of closely linked DNA polymorphisms. Our data indicated that at least three of five known AVP-NPII mutations causing ADNDI tend to recur but the mechanisms by which these dominant-negative mutations cause variable or progressive expression of the ADNDI phenotype remain unclear.
- OSTI ID:
- 134305
- Report Number(s):
- CONF-941009--
- Journal Information:
- American Journal of Human Genetics, Journal Name: American Journal of Human Genetics Journal Issue: Suppl.3 Vol. 55; ISSN AJHGAG; ISSN 0002-9297
- Country of Publication:
- United States
- Language:
- English
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