Research reportThe molecular genetics of the 22q11-associated schizophrenia
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)
- et al.
Genetic demonstration of a role for PKA in the late phase of LTP and in hippocampus-based long-term memory
Cell
(1997) - et al.
Screening for 22q11 deletions in a schizophrenia population
Schizophr. Res.
(2001) - et al.
A haplotype implicated in schizophrenia susceptibility is associated with reduced COMT expression in human brain
Am. J. Hum. Genet.
(2003) - et al.
The inheritance of neuropsychological dysfunction in twins discordant for schizophrenia
Am. J. Hum. Genet.
(2000) - et al.
Qualitative MRI findings in adults with 22q11 deletion syndrome and schizophrenia
Biol. Psychiatry
(1999) - et al.
Structural brain abnormalities in patients with schizophrenia and 22q11 deletion syndrome
Biol. Psychiatry
(2002) - et al.
Proline-induced potentiation of glutamate transmission
Brain Res.
(1997) - et al.
Low-copy repeats mediate the common 3-Mb deletion in patients with velo-cardio-facial syndrome
Am. J. Hum. Genet.
(1999) - et al.
Molecular cloning and expression of a high-affinity l-proline transporter expressed in putative glutamatergic pathways of rat brain
Neuron
(1992) The physiological approach: functional architecture of working memory and disordered cognition in schizophrenia
Biol. Psychiatry
(1999)
A turning point in schizophrenia genetics
Neuron
Identification of a Ras palmitoyltransferase in Saccharomyces cerevisiae
J. Biol. Chem.
From mouse to man: generating megabase chromosome rearrangements
Trends Genet.
A highly significant association between a COMT haplotype and schizophrenia
Am. J. Hum. Genet.
Velocardiofacial syndrome in childhood-onset schizophrenia
J. Am. Acad. Child Adolesc. Psych.
A systematic genomewide linkage study in 353 sib pairs with schizophrenia
Am. J. Hum. Genet.
Neuropsychological profile of children and adolescents with the 22q11.2 microdeletion
Genet. Med.
Diagnostic and Statistical Manual of Mental Disorders
22q11 deletion syndrome in adults with schizophrenia
Am. J. Med. Genet.
The neurocognitive phenotype of the 22q11.2 deletion syndrome: selective deficit in visual–spatial memory
J. Clin. Exp. Neuropsychol.
Schizophrenia susceptibility loci on chromosomes 13q32 and 8p21
Nat. Genet.
A population-based study of the 22q11.2 deletion: phenotype, incidence, and contribution to major birth defects in the population
Pediatrics
Information processing and attention dysfunctions in schizophrenia
Schizophr. Bull.
Human studies of prepulse inhibition of startle: normal subjects, patient groups, and pharmacological studies
Psychopharmacology
Neuropsychological functioning in siblings discordant for schizophrenia and healthy volunteers
Arch. Gen. Psychiatry
Accessing genetic information with high-density DNA arrays
Science
Variants in the catechol-O-methyltransferase (COMT) gene are associated with schizophrenia in Irish high-density families
Mol. Psychiatry
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.
Proline oxidase, encoded by p53-induced gene-6, catalyzes the generation of proline-dependent reactive oxygen species
Cancer Res.
Protein palmitoylation: a regulator of neuronal development and function
Nat. Rev. Neurosci.
Cognitive impairment in schizophrenia is the core of the disorder
Crit. Rev. Neurobiol.
The gene encoding proline dehydrogenase modulates sensorimotor gating in mice
Nat. Genet.
Velo-cardio-facial syndrome: language and psychological profiles
J. Craniofac. Genet. Dev. Biol.
Schizophrenia: The Epigenetic Puzzle
l-proline activates glutamate and glycine receptors in cultured rat dorsal horn neurons
Mol. Pharmacol.
PRODH mutations and hyperprolinemia in a subset of schizophrenic patients
Hum. Mol. Genet.
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2020, Neurochemistry InternationalCitation 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.
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