The gene encoding proline dehydrogenase modulates sensorimotor gating in mice.
Hemizygous cryptic deletions of the q11 band of human chromosome 22 have been associated with a number of psychiatric and behavioural phenotypes, including schizophrenia. Here we report the isolation and characterization of PRODH, a human homologue of Drosophila melanogaster sluggish-A (slgA), which encodes proline dehydrogenase responsible for the behavioural phenotype of the slgA mutant. PRODH is localized at chromosome 22q11 in a region deleted in some psychiatric patients. We also isolated the mouse homologue of slgA (Prodh), identified a mutation in this gene in the Pro/Re hyperprolinaemic mouse strain and found that these mice have a deficit in sensorimotor gating accompanied by regional neurochemical alterations in the brain. Sensorimotor gating is a neural filtering process that allows attention to be focused on a given stimulus, and is affected in patients with neuropsychiatric disorders. Furthermore, several lines of evidence suggest that proline may serve as a modulator of synaptic transmission in the mammalian brain. Our observations, in conjunction with the chromosomal location of PRODH, suggest a potential involvement of this gene in the 22q11-associated psychiatric and behavioural phenotypes.
Gogos
J A
JA
The Rockefeller University, New York, New York 10021, USA.
Santha
M
M
Takacs
Z
Z
Beck
K D
KD
Luine
V
V
Lucas
L R
LR
Nadler
J V
JV
Karayiorgou
M
M
D000161:Acoustic Stimulation; D000592:Amino Acid Metabolism, Inborn Errors / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D015152:Blotting, Northern; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism; D002892:Chromosomes, Human, Pair 22; D005260:Female; D006801:Humans; D019476:Insect Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009154:Mutation; D018377:Neurotransmitter Agents / Q000032:analysis / Q000378:metabolism; D011392:Proline / Q000032:analysis / Q000097:blood / Q000378:metabolism; D011394:Proline Oxidase / Q000235:genetics* / Q000378:metabolism*; D013216:Reflex, Startle / Q000502:physiology*; D017386:Sequence Homology, Amino Acid
D019476:Insect Proteins; D018377:Neurotransmitter Agents; D011392:Proline; D011394:Proline Oxidase