Genetic variation at the 22q11 PRODH2/DGCR6 locus presents an unusual pattern and increases susceptibility to schizophrenia

The 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 ≈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 ≈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.

[1]  B. Roe,et al.  Chromosome 22-specific low copy repeats and the 22q11.2 deletion syndrome: genomic organization and deletion endpoint analysis. , 2000, Human molecular genetics.

[2]  Melanie E. Goward,et al.  The DNA sequence of human chromosome 22 , 1999, Nature.

[3]  Jay N. Giedd,et al.  Premorbid speech and language impairments in childhood-onset schizophrenia: Association with risk factors , 2000, Schizophrenia Research.

[4]  J. Rapoport,et al.  Velocardiofacial syndrome in childhood-onset schizophrenia. , 1999, Journal of the American Academy of Child and Adolescent Psychiatry.

[5]  William,et al.  The Metabolic and Molecular Bases of Inherited Disease (Scriver, C. R., Beaudet, A. L., Sly, W. S., Valle, D., Childs, B., Kinzler, K. W., and Vogelstein, B., eds., 8th ed., McGraw-Hill, New-York, 2001, 7012 p., $550.00) , 2004, Biochemistry (Moscow).

[6]  M. Karayiorgou,et al.  The gene encoding proline dehydrogenase modulates sensorimotor gating in mice , 1999, Nature Genetics.

[7]  R. Shprintzen,et al.  Schizophrenia susceptibility associated with interstitial deletions of chromosome 22q11. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[8]  M. Karayiorgou,et al.  Early, non-psychotic deviant behavior in schizophrenia: a possible endophenotypic marker for genetic studies , 2001, Psychiatry Research.

[9]  J. Nurnberger,et al.  Diagnostic interview for genetic studies. Rationale, unique features, and training. NIMH Genetics Initiative. , 1994, Archives of general psychiatry.

[10]  P. Kwok,et al.  Fluorescence polarization in homogeneous nucleic acid analysis. , 1999, Genome research.

[11]  Streichenwein Sm,et al.  Am J Psychiatry , 1996 .

[12]  P. Scambler.  The 22q11 deletion syndromes. , 2000, Human molecular genetics.

[13]  High Rates of Schizophrenia in Adults With Velo-Cardio-Facial Syndrome , 1999 .

[14]  V. Pickel,et al.  The Mammalian Brain High-Affinity l-Proline Transporter Is Enriched Preferentially in Synaptic Vesicles in a Subpopulation of Excitatory Nerve Terminals in Rat Forebrain , 1999, The Journal of Neuroscience.

[15]  R. Shprintzen,et al.  A common molecular basis for rearrangement disorders on chromosome 22q11. , 1999, Human molecular genetics.

[16]  R. Weksberg,et al.  22q11 deletion syndrome in adults with schizophrenia. , 1998, American journal of medical genetics.

[17]  S. Maxwell,et al.  Differential gene expression in p53-mediated apoptosis-resistant vs. apoptosis-sensitive tumor cell lines. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[18]  A. Aurias,et al.  Isolation of a novel gene from the DiGeorge syndrome critical region with homology to Drosophila gdl and to human LAMC1 genes. , 1996, Human molecular genetics.

[19]  M. Tassabehji,et al.  A de novo pathological point mutation at the 21–hydroxylase locus: implications for gene conversion in the human genome , 1993, Nature Genetics.

[20]  M. Baron,et al.  Genetics of schizophrenia and the new millennium: progress and pitfalls. , 2001, American journal of human genetics.

[21]  P. Holzman.  Annual review of the schizophrenic syndrome. , 1974 .

[22]  R. Matsuoka,et al.  Psychiatric inpatients and chromosome deletions within 22q11.2 , 1999, Journal of neurology, neurosurgery, and psychiatry.

[23]  R. W. Davis,et al.  Detection of numerous Y chromosome biallelic polymorphisms by denaturing high-performance liquid chromatography. , 1997, Genome research.

[24]  D. Housman,et al.  Psychotic illness in patients diagnosed with velo-cardio-facial syndrome and their relatives. , 1994, The Journal of nervous and mental disease.

[25]  W. Ewens,et al.  Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). , 1993, American journal of human genetics.