Elsevier

Molecular Brain Research

Volume 132, Issue 2, 20 December 2004, Pages 95-104
Molecular Brain Research

Research report
The molecular genetics of the 22q11-associated schizophrenia

https://doi.org/10.1016/j.molbrainres.2004.09.029Get rights and content

Abstract

Schizophrenia has a strong genetic component but the mode of inheritance of the disease is complex and in all likelihood involves interaction among multiple genes and also possibly environmental or stochastic factors. A number of studies have shown that the 22q11 deletion syndrome (22q11DS) is a true genetic subtype of schizophrenia and as such may play an extremely important role in deciphering the genetic basis of schizophrenia. Microdeletions of the 22q11 locus are associated with a staggering increased risk to develop schizophrenia. The same locus has also been implicated by some linkage studies. Systematic examination of individual genes from the 1.5 Mb critical region has identified so far the PRODH and ZDHHC8 as strong candidate schizophrenia susceptibility genes from this locus. Discovery of these genes implicates neuromodulatory aminoacids and protein palmitoylation as important for disease development. Other genes, including the gene encoding for COMT, have been implicated by candidate gene approaches. It therefore appears that the 22q11-associated schizophrenia may have the characteristics of a contiguous gene syndrome, where deficiency in more than one gene contributes to the strikingly increased disease risk. Mouse models for individual candidate genes will provide the investigators with the opportunity to start understanding the function of these genes and how they may impact on schizophrenia. Mouse models that carry long-range deletions will likely capture the interactions among the culprit genes and help explain the genetic contribution of this locus to the high risk for schizophrenia. In-depth human and animal model studies of 22q11DS promise to answer critical questions relating to the devastating illness of schizophrenia, whose causes remain largely unknown.

Introduction

Schizophrenia is a severe mental illness, which affects a staggering 1% of the world's population and typically causes severe functional decline, tremendous suffering, and lifelong disability [27]. In the absence of reliable biological markers, schizophrenia is defined as a clinical syndrome. A number of relatively precise operational definitions of the syndrome exist, such as the editions of the Diagnostic and Statistical Manual of Mental Disorders (DSM) [2] that, when used in conjunction with standardized research interviews, can lead to a reliable, valid, and “heritable” diagnosis of the disease. Case identification usually begins with the observation of psychotic (“positive”) symptoms (delusional ideas, hallucinations, and disordered thinking) and bizarre behavior, often with a later emergence of “negative” symptoms, including low levels of emotional arousal, mental activity, and social drive. Furthermore, there is increasing recognition of prominent cognitive impairments, particularly in attention, memory, and executive functions, which perhaps equally contribute to schizophrenia's disability. The age of onset of the full set of diagnostic symptoms of schizophrenia is around 20 years, but there is substantial evidence to suggest that the negative symptoms and neurocognitive impairments are very often present in childhood, predate the full phenotypic expression of schizophrenia, and persist even after the resolution of the florid psychotic symptoms with traditional pharmacological treatment.

Section snippets

The genetic component of schizophrenia

A large number of family, twin, and adoption studies of the last 50 years have demonstrated conclusively that the genetic constitution of an individual plays a large role in determining whether he or she will become schizophrenic [35]. Family studies, for example, have demonstrated that an individual's lifetime risk of developing schizophrenia increases exponentially with the degree of relatedness to an affected individual. Specifically, compared with the ∼1% risk of the general population,

22q11 microdeletions and schizophrenia

The chromosome 22q11 deletion syndrome (22q11DS) occurs in one of every 6000 births [7]. 22q11DS presents a variable phenotype that can include specific congenital heart defects, thymic hypoplasia, hypocalcemia, velopharyngeal defects, neurodevelopmental delays, cognitive deficits, and/or behavioral abnormalities, coupled with facial dysmorphologies. Frequently occurring subclusters of these symptoms were previously considered to constitute distinct “syndromes” including the DiGeorge syndrome

Molecular genetic analysis of the 22q11 schizophrenia susceptibility locus

The overwhelming majority of the 22q11 deletions (∼87%) are 3 Mb in size, while a smaller percentage of them (∼8%) involve the same proximal breakpoint but a different distal breakpoint resulting in a smaller 1.5-Mb deletion (Fig. 1a). All deletions are mediated by low copy repeat sequences [20], [61]. At least one schizophrenic patient has been described to carry the smaller 22q11 microdeletion [33]; therefore, the “schizophrenia critical region” has been defined as 1.5 Mb (Fig. 1a). The

PRODH as a schizophrenia susceptibility gene

Two independent systematic screenings to examine all individual genes in the 22q11 locus in an unbiased manner have taken place [29], [40], [41]. Two different methodologies were employed: the first screen used a mutational survey of 27 genes in combination with linkage disequilibrium (LD) studies in family samples (triads) that test for preferential transmission of single nucleotide polymorphisms (SNPs) and multi-SNP haplotypes from parents to affected individuals. A total of 242 schizophrenia

ZDHHC8 as a schizophrenia susceptibility gene

The second segment of association with schizophrenia in the study of Liu et al. [40] lies at the distal part of the 22q11 locus and includes five neighboring SNPs distributed within a haplotypic block of 80 kb and having alleles with nominally significant association results [40]. In the absence of a clear causative variant, LD studies alone could not exclude any of the six genes residing in this haplotypic block. The preponderance of statistical evidence, however, strongly implicated the ZDHHC8

Mouse models

Mouse models for schizophrenia susceptibility genes are likely to help us understand how these genes contribute to the pathophysiology of schizophrenia. Furthermore, mouse models may help us address potential interactions between these genes. One has to express reasonable skepticism as to how accurately mouse models can capture such a complex human disorder as schizophrenia. It is impossible to model in mice disease manifestations such as auditory and visual hallucinations, paranoia, or

Long-range deletion models

The syntenic region of the human 22q11 locus lies on mouse chromosome 16. All human genes (except for one) are represented in the mouse, although the order of the genes is different (Fig. 1a and c; Ref. [54]). We and others (Ref. [51]; Stark et al., unpublished) have modeled the 22q11 deletion in the mouse using gene targeting and chromosomal engineering approaches [46]. Initial ascertainment of the deleted mice assessed different domains of central nervous system functioning using tests such

Individual candidate gene models

Mouse models for individual candidate genes from this region are also likely to facilitate understanding of the function of these genes and how they may impact on schizophrenia. A mutation introducing a premature termination (E453X) and reducing enzymatic activity in the mouse orthologue of the human PRODH gene in the Pro/Re hyperprolinemic mouse strain has been previously described [24]. Measurements of serum and brain proline levels revealed an increase in l-proline levels in mice homozygous

Conclusion

In all, both genetic association and animal model studies imply that the 22q11-associated schizophrenia may have the characteristics of a contiguous gene syndrome: deficiency in more than one gene contributes both by impairing synaptic function and by failing to compensate for such impairment. Such synergistic interaction among two physically linked genes, which disrupts neuronal homeostatic plasticity, could in principle lead to the high disease risk associated with this locus and/or modulate

References (72)

  • M. Karayiorgou et al.

    A turning point in schizophrenia genetics

    Neuron

    (1997)
  • S. Lobo et al.

    Identification of a Ras palmitoyltransferase in Saccharomyces cerevisiae

    J. Biol. Chem.

    (2002)
  • A.A. Mills et al.

    From mouse to man: generating megabase chromosome rearrangements

    Trends Genet.

    (2001)
  • S. Shifman et al.

    A highly significant association between a COMT haplotype and schizophrenia

    Am. J. Hum. Genet.

    (2002)
  • S.I. Usiskin et al.

    Velocardiofacial syndrome in childhood-onset schizophrenia

    J. Am. Acad. Child Adolesc. Psych.

    (1999)
  • N.M. Williams et al.

    A systematic genomewide linkage study in 353 sib pairs with schizophrenia

    Am. J. Hum. Genet.

    (2003)
  • M. Woodin et al.

    Neuropsychological profile of children and adolescents with the 22q11.2 microdeletion

    Genet. Med.

    (2001)
  • American Psychiatric Association

    Diagnostic and Statistical Manual of Mental Disorders

    (1994)
  • A.S. Bassett et al.

    22q11 deletion syndrome in adults with schizophrenia

    Am. J. Med. Genet.

    (1998)
  • C.E. Bearden et al.

    The neurocognitive phenotype of the 22q11.2 deletion syndrome: selective deficit in visual–spatial memory

    J. Clin. Exp. Neuropsychol.

    (2001)
  • J.L. Blouin et al.

    Schizophrenia susceptibility loci on chromosomes 13q32 and 8p21

    Nat. Genet.

    (1998)
  • L.D. Botto et al.

    A population-based study of the 22q11.2 deletion: phenotype, incidence, and contribution to major birth defects in the population

    Pediatrics

    (2003)
  • D.L. Braff

    Information processing and attention dysfunctions in schizophrenia

    Schizophr. Bull.

    (1993)
  • D.L. Braff et al.

    Human studies of prepulse inhibition of startle: normal subjects, patient groups, and pharmacological studies

    Psychopharmacology

    (2001)
  • T.D. Cannon et al.

    Neuropsychological functioning in siblings discordant for schizophrenia and healthy volunteers

    Arch. Gen. Psychiatry

    (1994)
  • M. Chee et al.

    Accessing genetic information with high-density DNA arrays

    Science

    (1996)
  • X. Chen et al.

    Variants in the catechol-O-methyltransferase (COMT) gene are associated with schizophrenia in Irish high-density families

    Mol. Psychiatry

    (2004)
  • I. Chumakov et al.

    Genetic and physiological data implicating the new human gene G72 and the gene for d-amino acid oxidase in schizophrenia

    Proc. Natl. Acad. Sci. U. S. A.

    (2002)
  • S.P. Donald et al.

    Proline oxidase, encoded by p53-induced gene-6, catalyzes the generation of proline-dependent reactive oxygen species

    Cancer Res.

    (2001)
  • A.E.D. El-Husseini et al.

    Protein palmitoylation: a regulator of neuronal development and function

    Nat. Rev. Neurosci.

    (2002)
  • B. Elvevag et al.

    Cognitive impairment in schizophrenia is the core of the disorder

    Crit. Rev. Neurobiol.

    (2000)
  • J.A. Gogos et al.

    The gene encoding proline dehydrogenase modulates sensorimotor gating in mice

    Nat. Genet.

    (1999)
  • K.J. Golding-Kushner et al.

    Velo-cardio-facial syndrome: language and psychological profiles

    J. Craniofac. Genet. Dev. Biol.

    (1985)
  • I.I. Gottesman et al.

    Schizophrenia: The Epigenetic Puzzle

    (1982)
  • V.D.B. Henzi et al.

    l-proline activates glutamate and glycine receptors in cultured rat dorsal horn neurons

    Mol. Pharmacol.

    (1992)
  • H. Jacquet et al.

    PRODH mutations and hyperprolinemia in a subset of schizophrenic patients

    Hum. Mol. Genet.

    (2002)
  • Cited by (122)

    • Translational medicine in psychiatry: challenges and imaging biomarkers

      2021, Principles of Translational Science in Medicine: From Bench to Bedside, Third Edition
    • Neurobehavioral changes arising from early life dopamine signaling perturbations

      2020, Neurochemistry International
      Citation Excerpt :

      Treatment of mice with the D2 DA receptor directed antipsychotic drug haloperidol has been found to induce transcriptional changes enriched for genes located at schizophrenia risk loci in genome wide association studies (Kim et al., 2018). With respect to rare, but highly penetrant gene variation and schizophrenia risk, subjects with 22q11 deletion syndrome (22q11DS) exhibit 25–30 times increased risk of developing schizophrenia relative to the general population, and the contribution of 22q11DS to cases of severe early-onset schizophrenia is even higher (Karayiorgou and Gogos, 2004; Usiskin et al., 1999). This chromosomal abnormality disrupts, among others, the gene encoding catechol-O-methyltransferase (COMT), an enzyme involved in the metabolism of catecholamines, including DA.

    • Mouse Models of Schizophrenia: Risk Genes

      2016, Handbook of Behavioral Neuroscience
    View all citing articles on Scopus
    View full text