1Proc. Natl. Acad. Sci. U.S.A. 2002 Apr 99: 4755-6
TitleA compelling genetic hypothesis for a complex disease: PRODH2/DGCR6 variation leads to schizophrenia susceptibility.
SCZ Keywordsschizophrenia, schizophrenic
2Proc. Natl. Acad. Sci. U.S.A. 2002 Mar 99: 3717-22
TitleGenetic variation at the 22q11 PRODH2/DGCR6 locus presents an unusual pattern and increases susceptibility to schizophrenia.
AbstractThe location of a schizophrenia susceptibility locus at chromosome 22q11 has been suggested by genome-wide linkage studies. Additional support was provided by the observation of a higher-than-expected frequency of 22q11 microdeletions in patients with schizophrenia and the demonstration that approximately 20-30% of individuals with 22q11 microdeletions develop schizophrenia or schizoaffective disorder in adolescence and adulthood. Analysis of the extent of these microdeletions by using polymorphic markers afforded further refinement of this locus to a region of approximately 1.5 Mb. Recently, a high rate of 22q11 microdeletions was also reported for a cohort of 47 patients with Childhood Onset schizophrenia, a rare and severe form of schizophrenia with onset by age 13. It is therefore likely that this 1.5-Mb region contains one or more genes that predispose to schizophrenia. In three independent samples, we provide evidence for a contribution of the PRODH2/DGCR6 locus in 22q11-associated schizophrenia. We also uncover an unusual pattern of PRODH2 gene variation that mimics the sequence of a linked pseudogene. Several of the pseudogene-like variants we identified result in missense changes at conserved residues and may prevent synthesis of a fully functional enzyme. Our results have implications for understanding the genetic basis of the 22q11-associated psychiatric phenotypes and provide further insights into the genomic instability of this region.
SCZ Keywordsschizophrenia, schizophrenic
3Proc. Natl. Acad. Sci. U.S.A. 2003 Nov 100: 14433-8
TitleA comprehensive analysis of 22q11 gene expression in the developing and adult brain.
AbstractDeletions at 22q11.2 are linked to DiGeorge or velocardiofacial syndrome (VCFS), whose hallmarks include heart, limb, and craniofacial anomalies, as well as learning disabilities and increased incidence of schizophrenia. To assess the potential contribution of 22q11 genes to cognitive and psychiatric phenotypes, we determined the CNS expression of 32 mouse orthologs of 22q11 genes, primarily in the 1.5-Mb minimal critical region consistently deleted in VCFS. None are uniquely expressed in the developing or adult mouse brain. Instead, 27 are localized in the embryonic forebrain as well as aortic arches, branchial arches, and limb buds. Each continues to be expressed at apparently constant levels in the fetal, postnatal, and adult brain, except for Tbx1, PRODH2, and T10, which increase in adolescence and decline in maturity. At least six 22q11 proteins are seen primarily in subsets of neurons, including some in forebrain regions thought to be altered in schizophrenia. Thus, 22q11 deletion may disrupt expression of multiple genes during development and maturation of neurons and circuits compromised by cognitive and psychiatric disorders associated with VCFS.
SCZ Keywordsschizophrenia, schizophrenic
4Biochemistry 2004 Oct 43: 12539-48
TitleStructures of the Escherichia coli PutA proline dehydrogenase domain in complex with competitive inhibitors.
AbstractProline dehydrogenase (PRODH) catalyzes the first step of proline catabolism, the flavin-dependent oxidation of proline to Delta(1)-pyrroline-5-carboxylate. Here we present a structure-based study of the PRODH active site of the multifunctional Escherichia coli proline utilization A (PutA) protein using X-ray crystallography, enzyme kinetic measurements, and site-directed mutagenesis. Structures of the PutA PRODH domain complexed with competitive inhibitors acetate (K(i) = 30 mM), L-lactate (K(i) = 1 mM), and L-tetrahydro-2-furoic acid (L-THFA, K(i) = 0.2 mM) have been determined to high-resolution limits of 2.1-2.0 A. The discovery of acetate as a competitive inhibitor suggests that the carboxyl is the minimum functional group recognized by the active site, and the structures show how the enzyme exploits hydrogen-bonding and nonpolar interactions to optimize affinity for the substrate. The PRODH/L-THFA complex is the first structure of PRODH with a five-membered ring proline analogue bound in the active site and thus provides new insights into substrate recognition and the catalytic mechanism. The ring of L-THFA is nearly parallel to the middle ring of the FAD isoalloxazine, with the inhibitor C5 atom 3.3 A from the FAD N5. This geometry suggests direct hydride transfer as a plausible mechanism. Mutation of conserved active site residue Leu432 to Pro caused a 5-fold decrease in k(cat) and a severe loss in thermostability. These changes are consistent with the location of Leu432 in the hydrophobic core near residues that directly contact FAD. Our results suggest that the molecular basis for increased plasma proline levels in schizophrenic subjects carrying the missense mutation L441P is due to decreased stability of human PRODH2.
SCZ Keywordsschizophrenia, schizophrenic
5Psychiatr Hung 2006 -1 21: 404-12
Title[Gene polymorphism and gene expression in schizophrenia].
AbstractThe author reviews relevant data on the neuropathology and molecular genetics of schizophrenia. Anatomical alterations are localized mainly in the hippocampus, dorsal thalamus and dorsolateral prefrontal cortex, and involve the morphology and molecular structure of the neurons and synapses. Several susceptibility genes [including COMT, dysbindin, neuregulin, DISCI, RGS4, GRM3, G72, PPP3CC, CHRNA7, PRODH2, Aktl, 5qGABA(A)] having physiological function in the brain have been identified and this supports the view of schizophrenia as a disorder of cerebral synaptic function. NMDA receptor-mediated glutamate transmission may be particularly involved, but disturbances of dopamine and GABA signalling seem to be linked as well. Based on recent data, an agreement is emerging between the roles of the genes on the molecular and synaptic levels and the understanding of the disorder at the neural systems level.
SCZ Keywordsschizophrenia, schizophrenic