Association of an orexin 1 receptor 408Val variant with polydipsia-hyponatremia in schizophrenic subjects.
BACKGROUND
Primary polydipsia is a common complication in patients with chronic psychoses, particularly schizophrenia. Disease pathogenesis is poorly understood, but one contributory factor is thought to be dopamine dysregulation caused by prolonged treatment with neuroleptics. Both angiotensin-converting enzyme (ACE) and orexin (hypocretin) signaling can modulate drinking behavior through interactions with the dopaminergic system.


METHODS
We performed association studies on the insertion/deletion (I/D) sequence polymorphism of ACE and single nucleotide polymorphisms within the prepro-orexin (HCRT), orexin receptor 1 (HCRTR1), and orexin receptor 2 (HCRTR2) genes. Genotypes were determined by polymerase chain reaction amplification, followed by either electrophoretic separation or direct sequencing.


RESULTS
The ACE I/D polymorphism showed no association with polydipsic schizophrenia. Screening of the orexin signaling system detected a 408 isoleucine to valine mutation in HCRTR1 that showed significant genotypic association with polydipsic-hyponatremic schizophrenia (p = .012). The accumulation of this mutation was most pronounced in polydipsic versus nonpolydipsic schizophrenia (p = .0002 and p = .008, for the respective genotypic and allelic associations). The calcium mobilization properties and the protein localization of mutant HCRTR1 seem to be unaltered.


CONCLUSIONS
Our preliminary data suggest that mutation carriers might have an increased susceptibility to polydipsia through an undetermined mechanism.
Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-city, Saitama 351-0198, Japan.
Joanne
J
Meerabux
Yoshimi
Y
Iwayama
Takeshi
T
Sakurai
Hisako
H
Ohba
Tomoko
T
Toyota
Kazuo
K
Yamada
Ruby
R
Nagata
Yoko
Y
Irukayama-Tomobe
Hiromitsu
H
Shimizu
Kiyoshi
K
Yoshitsugu
Katsuya
K
Ohta
Takeo
T
Yoshikawa
D000328:Adult; D002118:Calcium / Q000378:metabolism; D004327:Drinking Behavior / Q000502:physiology*; D005110:Extracellular Space / Q000378:metabolism; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007010:Hyponatremia / Q000150:complications / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D064446:Orexin Receptors; D007703:Peptidyl-Dipeptidase A / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012559:Schizophrenia / Q000150:complications / Q000235:genetics*; D014633:Valine / Q000235:genetics*
C578630:HCRTR1 protein, human; D064446:Orexin Receptors; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D007703:Peptidyl-Dipeptidase A; D014633:Valine; D002118:Calcium