A missense mutation encoding cys(67) --> gly in neurophysin ii is associated with early onset autosomal dominant neurohypophyseal diabetes insipidus.
Autosomal dominant neurohypophyseal diabetes insipidus (ADNDI) is an inherited disorder in which progressive degeneration of magnocellular neurons of the hypothalamus impairs production of arginine vasopressin (AVP). ADNDI is caused by mutations in the arginine vasopressin-neurophysin II (AVP-NPII) gene. These mutations are hypothesized to trigger neurodegeneration via disruption of preproAVP-NPII processing. Affected individuals usually develop diabetes insipidus between 1 and 6 years of age. Here we report a novel mutation of the AVP-NPII gene in a family with unusually early presentation of ADNDI. The index case developed symptoms of diabetes insipidus at 1 month of age, her mother at 9 months of age, and the maternal grandfather in early childhood. Each was found to be heterozygous for the missense mutation 1665T > G encoding the amino acid substitution C67G within NPII. This mutation helps to define two homologous regions of the AVP-NPII precursor bounded by disulfide bridges between C13 and C27 and between C61 and C73 that have structural homology and contain the majority of amino acid substitutions associated with ADNDI. The early onset of symptomatic diabetes insipidus in this family suggests that the C67G substitution may be particularly deleterious to magnocellular neurons and may provide a valuable model for study of dominantly inherited neurodegeneration.
DiMeglio
L A
LA
Department of Pediatrics, J.W. Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Gagliardi
P C
PC
Browning
J E
JE
Quigley
C A
CA
Repaske
D R
DR
D000596:Amino Acids / Q000737:chemistry; D002648:Child; D002675:Child, Preschool; D003545:Cysteine / Q000737:chemistry*; D004262:DNA Restriction Enzymes / Q000378:metabolism; D020790:Diabetes Insipidus, Neurogenic / Q000235:genetics*; D004220:Disulfides; D005091:Exons; D005192:Family Health; D005260:Female; D005799:Genes, Dominant; D005998:Glycine / Q000737:chemistry*; D006801:Humans; D007031:Hypothalamus / Q000473:pathology; D007223:Infant; D007231:Infant, Newborn; D008279:Magnetic Resonance Imaging; D008297:Male; D008957:Models, Genetic; D009154:Mutation; D020125:Mutation, Missense; D009481:Neurophysins / Q000737:chemistry* / Q000235:genetics; D010375:Pedigree; D010902:Pituitary Gland / Q000473:pathology; D017422:Sequence Analysis, DNA
D000596:Amino Acids; D004220:Disulfides; D009481:Neurophysins; D004262:DNA Restriction Enzymes; D003545:Cysteine; D005998:Glycine