Retinoic acid inducible-1 gene (RAI1) and clinical subtypes of schizophrenia.

MICROBIOLOGY RESEARCH ADVANCES

RETINOIC ACID INDUCIBLE-1

GENE (RAI1) AND CLINICAL

SUBTYPES OF SCHIZOPHRENIA

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MICROBIOLOGY RESEARCH ADVANCES

RETINOIC ACID INDUCIBLE-1

GENE (RAI1) AND CLINICAL

SUBTYPES OF SCHIZOPHRENIA

DUŠANKA SAVIĆ PAVIĆEVIĆ

MAJA IVKOVIĆ

JELENA KARANOVIĆ

GORAN BRAJUŠKOVIĆ

AND

STANKA ROMAC

———————————————

Nova Science Publishers, Inc.

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CONTENTS

Preface vii

Chapter 1 Introduction 1

Chapter 2 Methods 7

Chapter 3 Results 11

Chapter 4 Discussion 13

Acknowledgments 17

References 19

Index 27

PREFACE

Schizophrenia is a common neuropsychiatric disorder affecting

approximately 1% of the general population and displaying considerable

heterogeneity of symptoms, course and outcomes. It is generally

considered to be a neurodevelopmental disorder that ultimately affects

forebrain neurons and circuits. Retinoid signaling is involved in fetal

brain development, affecting patterning and neuronal differentiation, and

in the maintenance and regulation of neuronal plasticity in different areas

of the adult forebrain. Therefore, there may be a relationship between

retinoid signaling and perturbation involved in brain development and

neuronal plasticity in schizophrenia. Studies of the genes coding proteins

participating in retinoid metabolism and transport, retinoid signaling

pathway, as well as retinoic acid-responsive genes, are needed to

elucidate this relationship. To make contribution to this understudied

area, we present here our recent findings of a potential associations

between the retinoic acid inducible-1 (RAI1) gene and schizophrenic

patients of European descent.

RAI1 is retinoic acid-responsive gene expressed at high levels in the

neuronal and heart structures, and acts as transcription regulator with role

in neuronal development and differentiation, and neurobehavioral

regulation. It contains polymorphic CAG repeats coding for glutamine-

rich activation domain, involved in protein-protein interaction that can be

modulated by the number of repeats.

Our population-based case-control study showed that the number of

CAG repeats in the RAI1 gene ranged from 8 to 19 in the group of 115

unrelated patients, with the most frequent allele with 13 repeats, and

Dušanka Savić Pavićević, Maja Ivković, Jelena Karanović et al. viii

from 10 to 19 in the group of 100 controls, with the most frequent allele

with 14 repeats. When alleles were divided as ≤13 and >13 repeats,

alleles ≤13 repeats appeared significantly more often in patient group

(57.6% patients vs. 47% controls; χ2=13813.0; p=.015).

Paranoid, disorganized, undifferentiated, and residual subtypes of

schizophrenia displayed similar allelic distributions (p=.208, Pearson‘s

chi-square test), which might be misleading as stratification of sample

reduced number of patients in each subgroup. When PANSS (Positive

and Negative Syndrome Scale) scores based stratification was analyzed,

significant association between alleles ≤13 repeats and positive forms of

schizophrenia was obtained (χ2=7.675; p=.021).

As patients with prominent delusions, hallucinations and/or

disorganized speech and behavior displayed significantly shorter CAG

repeat size compared to patients with predominant negative symptoms,

our finding suggests that polyglutamine polymorphism in RAI1 gene may

underlie processes at certain brain structures related to productive

symptomatology. Polyglutamine polymorphism may affect RAI1

interaction with partner proteins, modulating its function and thus

altering developmental and neuroplastic retinoid signaling in the brain.

Chapter 1

INTRODUCTION

Schizophrenia (MIM#181500) is a common neuropsychiatric

disorder displaying considerable heterogeneity in symptomatology,

etiopathology, neurobiology, treatment response, course, and outcomes.

The annual incidence of schizophrenia averages 15 per 100,000, the

point prevalence averages 4.5 per population of 1,000, and the risk of

developing the illness over one's lifetime averages 0.7% (Tandon et al.,

2008). Schizophrenia is characterized by an admixture of positive,

negative, cognitive, disorganization, psychomotor, and mood symptoms,

whose severity varies across patients and through the course of the illness

(Tandon et al., 2009). Positive symptoms are delusions, hallucinations

and other reality distortions, while negative ones includes impairments in

emotional experience and expression, loss of motivation, poverty of

speech, inability to experience pleasure, lack of initiative, lack of interest

and reduced social drive. Varying degrees of negative and cognitive

symptomatology often precede positive symptoms that usually begin in

adolescence or early adulthood. The illness is frequently a chronic and

relapsing with generally incomplete remissions, variable degrees of

functional impairment and social disability, frequent comorbid substance

abuse, and decreased longevity (Tandon et al., 2009).

The etiology of schizophrenia is heterogeneous and includes

complex interactions of many genetic and environmental risk factors

(Tienari et al., 2004; Tsuang et al., 2004). Schizophrenia is highly

heritable and genetic factors and gene-environmental interactions

contribute over 80% of the liability for developing illness (Tandon et al.,

Dušanka Savić Pavićević, Maja Ivković, Jelena Karanović et al. 2

2008). Despite the high degree of heritability, there is not a consensus

about genetic model for schizophrenia. According to the predominantly

accepted ―common disease‖ model, schizophrenia is a heterogeneous

polygenic/multifactorial disease with multiple common genetic

polymorphisms, each of which contributes a small effect to disease

susceptibility (Risch, 1990; Lichtermann et al., 2000). According another

model, schizophrenia is a highly heterogeneous genetic entity caused by

multiple, highly penetrant and individually very rare mutations that may

be specific to single cases or individual families (McClellan et al., 2007).

The third model postulates that epigenetic factors, heritable changes in

gene expression without DNA sequence variations, represent genetic

base of schizophrenia (Crow, 2007). The main epigenetic mechanisms

are DNA methylation and histone remodeling of chromatin structure.

Many environmental risk factors are linked to liability to develop

schizophrenia. They include both biological and psychosocial risk

factors: maternal infections and nutritional deficiency during the first and

early second trimester, obstetric and perinatal complications, older

paternal ages at conception, birth during late winter or early spring,

urbanicity and migration during the childhood period, cannabis use

during adolescence, social adversity and stressful life (Tandon et al.,

2008).

How genetic and environmental risk factors might interact to cause

schizophrenia and what neurobiological processes might mediate such

gene-gene, gene-environment, and environment-environment interactive

effects is not yet understood. There is a considerable body of evidence

for the "neurodevelopmental" model of schizophrenia, according which

illness represents the behavioral outcome of an aberration in

neurodevelopmental processes that ultimately affects forebrain neurons

and circuits, and begins long before the onset of clinical symptoms

(Murray and Lewis, 1987; Lewis and Levitt, 2002; Rapoport et al.,

2005). Reported abnormalities in neuronal migration and organization in

postmortem magnetic resonance imaging studies (Jakob and Beckmann,

1986) indicated early (pre- or perinatal) brain lesions involved in

schizophrenia, while reduced neuronal size and arborization (Selemon

and Goldman-Rakic, 1999) indicated extended time period of abnormal

neurodevelopment in schizophrenia. The later is supported by

longitudinal brain imaging studies that showed gray matter volume loss

was particularly striking in adolescence period of patients (Shenton et al.,

Introduction 3

2001) and appeared to be an exaggeration of the normal developmental

pattern (Giedd et al., 1996).

Retinoic acid, a derivate of vitamin A (retinol) that acts in the cells,

is involved in neurodevelopmental processes, affecting anteroposterior

patterning of the posterior hindbrain and the anterior spinal cord, and

neuronal differentiation (Maden, 2002). Certain aspects of forebrain

morphogenesis are also under control of retinoic acid (Schneider et al.,

2001). It has became evident that this molecular signal continues to play

a role in the adult, mediating neuronal plasticity in different areas of the

brain (e.g., hippocampus and components of the limbic system), normal

nigrostriatal functioning, nerve regeneration, and neuronal stem cell

production (Haskall et al., 2002; Madden, 2007).

The pathway of the retinoic acid synthesis and mechanism of its

action are referred as retinoid signaling or retinoid cascade (Maden,

2002: Maden 2007). Retinoic acid and other retinoids are obtained from

the diet in the form of retinyl esters or β-carotene. Lipoprotein lipase is

involved in reversible catalysis of retinyl esters to retinol. Circulating

retinol, bound to retinol-binding protein, is taken up by target cells.

Inside the cells retinol is converted to retinal by alcohol dehydrogenses,

and then to retinoic acid by retinealdehyde dehydrogenases. Synthesized

retinoic acid enters to nucleus and binds to nuclear retinoid receptors:

retinoic acid receptor (RARα, RARβ and RARγ) and retinoid X receptor

(RXRα, RXRβ and RXRγ) . Nuclear retinoid receptors are ligand-

activated transcription factors, which, as heterodimers, bind to retinoic

acid-responsive elements within the promoter/enhancer region of many

target genes, influencing their expression. The presence of a retinoic

acid-responsive elements has been identified, at least, in 27 genes, but it

is estimated that more than 500 genes are retinoic-acid responsive. Once

retinoic acid has activated nuclear retinoid receptors, it exits the nucleus

and is catabolized by one class of cytochrome P450 enzymes.

Accepting the "neurodevelopmental" model of schizophrenia and the

role of retinoic acid in neurodevelopment, maintenance and regulation of

neuronal plasticity in the adult brain, there may be a relationship between

retinoid signaling and disrupted neurodevelopment and neuronal

plasticity in some patients with schizophrenia. According to Goodman

(1998) there is three lines of evidence suggesting a close causal

relationship between deregulated retinoid pathway and pathophysiology

of schizophrenia. 1) Congenital anomalies similar to those caused by


retinoid dysfunction are found to schizophrenic patients and their

relatives (mental deficit, enlarged ventricles, agenesis of the corpus

callosum, microcephaly, and a variety of major and minor congenital

malformations, among which craniofacial and digital anomalies are

prominent) (Goodman, 1996). 2) Some of the genes coding proteins for

retinoid signaling are convergent loci to loci suggestively linked to

schizophrenia by genome-wide linkage studies (Moises et al, 1995;

Pulver et al., 1995; Ng et al., 2009). Potential relationship of retinoid

signaling genes and schizophrenia is supported by microarray analyses

and genome-wide association studies. Microarray analyses showed

decreased expression of retinaldehyde dehydrogenase 1A1 (ALDH1A1)

and albumin in schizophrenic patients (Goodman, 2005). Retinaldehyde

dehydrogenase 1A1 is normally strongly expressed in dopaminergic

neurons, while albumin is a ubiquitous serum transporter of retinoic acid

and some other free fatty acids. Genome-wide association studies

showed potential association of the genes for lipoprotein lipase (LPL)

and retinoic acid receptor β (RARB) with schizophrenia (GWAS, NIH).

3) Many retinoic acid-responsive genes can be connected to

neurotransmitter abnormalities in schizophrenia (Goodman, 1998) . For

example, retinoic acid may control the function of the dopaminergic

mesolimbic pathway, as there is a retinoic acid-response element within

the promoter of the D2 dopamine receptor gene (DRD2) (Samad et al.,

1997).

Retinoic acid inducible – 1 gene (RAI1) (ID#10743, MIM#607642)

is one of the retinoic acid-responsive genes, with the highest expression

in various brain regions and muscle heart (Tolouse et al., 2003;

GATExplorer). It is located on chromosome 17p11.2, contains six exons

and its promoter has binding sites for several regulatory proteins,

including a retinoic acid-responsive element, just upstream of exon 1

(Tolouse et al., 2003). RAI1 pre-mRNA undergoes alternative splicing,

giving 8 splice variants: 6 protein-coding transcripts and 2 processed

transcripts without protein coding potential (Ensembl). The RAI1 cDNA

characterized by Tolouse et al. (2003) was 7661 base pair long with an

open reading frame coding a 1906 amino-acid protein, with 79% identity

with its mouse ortholog Rai1 (ID#19377) (Imai et al., 1995).

Bioinformatics and comparative genomic analysis between human and

mouse orthologs revealed a zinc finger-like plant homeodomain at the C-

terminus that is conserved in the trithorax group of chromatin-based

Introduction 5

transcription regulators (Bi et al., 2004). This prediction suggested that

the RAI1 protein might be involved in transcription control as a part of a

multiprotein complex.

Mouse Rai1 gene is induced during neuronal differentiation of P19

embryonal carcinoma cells by retinoic acid, and is mainly expressed in

neuronal brain structures during development and adult life (Imai et al.,

1995). The deletion in 17p11.2 region and intragenic mutations in the

RAI1 gene is associated with Smith-Magenis syndrome (SMS,

MIM#182290), a mental retardation syndrome associated with various

congenital malformations, such as distinct craniofacial and skeletal

anomalies, and disrupted behavior including self-injurious behaviors and

sleep disturbance (Seranski et al., 2001; Edelman et al., 2007). All these

findings strongly suggest that retinoid signaling through RAI1 gene could

be involved in neurodevelopment, and its alternation may be related to

neurodevelopmental diseases.

RAI1 gene contains a polymorphic CAG repeats that code N-

terminal glutamine-rich activation domain (Seranski et al., 2001), an

important class of protein-protein interacting motifs (Tanese and Tjian,

1993; Gerber et al., 1994). Comparative genomic study of human, mouse

and rat showed that the RAI1 CAG repeats is one of the four rapidly

evolving coding triplet repeats in the human genome that are mainly

expressed in the brain (Huang et al., 2004). The number of the RAI1

CAG repeats varied up to 18 in humans, and is only 4 in the mouse

ortholog (Toulouse et al., 2003). Polyglutamine repeats are mainly found

in transcription regulators, suggesting they may be one of the main cause

for modulation of their activity, and thus result in subtle or overt genomic

effects (Gerber et al., 1994). CAG repeat polymorphism in the RAI1 gene

has been associated with the severity of schizophrenia and patient

response to neuroleptic medication (Jobber et al., 1999).

To make contribution to understudied relationship between retinoid

pathway and schizophrenia, we present here our recent findings of a

potential associations between the retinoic acid-responsive gene, RAI1

gene, and schizophrenic patients of European descent. We did

population-based case-control study with the aims to investigate a

potential association between the polymorphic CAG repeats in the RAI1

gene and schizophrenia, taking into account its clinical heterogeneity.

Chapter 2

METHODS

SUBJECTS

The clinical sample included 115 unrelated patients with

schizophrenia, 55 females and 60 males, treated at Institute for

Psychiatry, Clinical Centre of Serbia, Belgrade. All subjects were

inpatients, consecutively admitted to Institute from 2006 to 2008, due to

psychotic exacerbation. The patients were directly interviewed using the

Diagnostic Interview for Genetic Studies (DIGS) (Nurnberger et al.,

1994) and their medical records were comprehensively reviewed by a

research psychiatrist. Diagnosis was based on all available data,

according to DSM-IV criteria (American Psychiatry Association, 1994).

These criteria require the presence of psychotic symptoms for a

minimum period of one month and the exclusion of mood disorder,

substance use or other recognizable ―organic‖ etiological explanation for

psychotic symptomatology. Additionally, DSM-IV requires social

dysfunction and decline for a period of more than six months and the

exclusion of pervasive developmental disorder as an explanation for the

condition.

As schizophrenia displays considerably heterogeneity in clinical

manifestation, patients were stratified according the clinical features

defined by DSM-IV criteria (American Psychiatry Association, 1994)

and according the Positive and Negative Syndrome Scale (PANSS) (Kay

et al., 1988) .


In respect to clinical features defined by DSM-IV criteria, patients

were divided into 4 clinical subtypes: paranoid (n=37), disorganized

(n=25), undifferentiated (n=23), and residual (n=29). Paranoid type is

characterized by preoccupation with one or more systematized delusions

or presence of frequent hallucinations related to a single theme.

Disorganized type is associated with marked loosening of associations,

incoherence, grossly disorganized behavior, and flat or grossly

inappropriate affect. Undifferentiated type is considered when a patient

presents with psychotic symptoms that meet criteria for schizophrenia

but not for any specific subtype. Residual type is diagnosed by the

occurrence of at least one prior episode of florid phase of schizophrenia

(such as delusions, hallucinations, and disorganized thinking) with a

current clinical picture free from prominent psychotic symptoms, but

with minimal ‗residual‘ symptoms of the illness (principally cognitive

and negative symptoms).

Another stratification of patients included differentiation between the

patients with a predominantly positive (n=63) and a predominantly

negative (n=52) syndrome of schizophrenia by using the Positive and

Negative Syndrome Scale (PANSS) (Kay et al., 1988). PANSS is

designed to measure prevalence of positive, negative and general

psychopathology symptoms. Positive scale) includes delusions,

conceptual disorganization, hallucinatory behavior, excitement,

grandiosity and suspiciousness hostility, while negative scale) includes

blunted affect (lack of emotional reactivity), emotional withdrawal, poor

rapport, passive-pathetic social withdrawal, difficulty in abstract

thinking, lack of spontaneity and flow of conversation, and stereotyped

thinking (Kay et al., 1988). Patients who scored moderate or higher on at

least 3 of 7 positive items are considered as positive-type

schizophrenics), and those with the reverse pattern ("moderate" on at

least 3 negative items) as negative type). The ratings were performed in

the acute exacerbation phase, immediately after admission to hospital

treatment). Patients scored as a positive-type schizophrenics generally

showed prominent delusions, hallucinations and disorganized speech and

behavior

Controls were 100 unrelated healthy age-matched individuals, 50

males and 50 females, screened for DSM-IV axis 1 mental disorders

using the DIGS. All participating subjects were Caucasian from Serbia.

Informed consent was obtained from all participants, including the legal

Methods 9

guardians for incompetent patients. The study was approved by Ethic

Board of Clinical Center of Serbia.

DNA ANALYSES

Genomic DNA was extracted from peripheral blood samples using

Qiagen mini kit (QIAGEN, Germany), according to the manufacturer‘s

procedure. Polymerase chain reaction (PCR) was carried out using the

following primers RAI1/1: 5'- GCA GCG GGT CCA GAA TCT TC -3'

(forward) and RAI1/2: 5'- CAG TAG CCC TGG CCT TGC -3' (reverse)

in a total reaction volume of 12,5 µl. PCR reaction mix contained 100 ng

of genomic DNA, 1xTaq buffer +KCl -MgCl2 (pH 8.8) (Fermentas,

Germany), 1.5 mM MgCl2, 200 µM dNTPs, 0.5 µM of each primer, 0.6

µg/µl BSA and 0,03 U/µl of Taq polymerase (Fermentas, Germany).

PCR conditions consisted of a denaturation step at 96oC for 3 min,

followed by 30 cycles of denaturation at 94oC for 1 min, annealing at

60oC for 1 min and extension at 72

oC for 1 min, and a final extension at

72oC for 20 min.

The absolute number of the RAI1 CAG repeats for each sample was

identified on a silver stained 6% denaturing polyacrylamide gel. Samples

were compared with the alleles that were sequenced using BDT v.1.1. kit

(Applied Biosystems, CA, USA), and analyzed on an ABI 3100 Genetic

Analyzer (Applied Biosystems, CA, USA) with the instrument‘s

Sequencing Analysis Programs. To improve the possibility of detecting

possible expansions of the RAI1 CAG repeats we performed Southern

blot hybridization at 65 oC using a 3‘DIG-ddUTP-end labeled (CAG)12

probe.

STATISTICAL ANALYSIS

Differences in the RAI1 CAG repeat size between the patients and

controls were analyzed using Pearson‘s chi-square test.

Chapter 3

RESULTS

Patients with schizophrenia and healthy controls did not differ

according to age (p=0.23) and gender distribution (p=0.64). The mean

age of patients was 42.6±7.9, while the mean age of controls was

38.7±12.4. In patients‘ group, mean age at first psychiatric evaluation

was 21.8±2.8. Slightly over half of patients were assessed as having a

predominantly positive syndrome of schizophrenia according to PANSS

score.

RAI1 CAG repeats allele distributions in patients with schizophrenia

and control groups are shown in Figure 1. The number of CAG repeats in

the RAI1 gene ranged from 8 to 19 in the patients with schizophrenia

(mean 12.86±1.41), with the most frequent one with 13 CAG repeats. In

control group, the number of CAG repeats ranged from 10 to 19 (mean

13.51±1.16), and the most frequent one was allele with 14 CAG repeats.

Alleles shorter than 10 repeats were observed only in the group of

patients with schizophrenia. Allele frequency distribution and

frequencies of individual alleles were not statistically significantly

different between patients and controls.

In order to see whether there is difference in an allele size interval

between patients and controls, data were dichotomized in intervals "less

or equal than" and "greater than" in respect to each allele size. When

alleles were divided as ≤13 and >13 repeats, it was shown that alleles

containing ≤13 repeats appeared significantly more often in patients

(57.6% patients vs. 47% controls; χ2=13813.0; p=.015) . There was no

association between the CAG repeat number and 4 different clinical


subtypes of schizophrenia: paranoid (n=37), disorganized (n=25),

undifferentiated (n=23), and residual (n=29) (χ2=4.552, df 3, p=.208),

which might be misleading, because stratification of sample reduced the

number of patients in each subgroup. When PANSS scores based

stratification of patients was applied, our results showed significant

association between alleles containing ≤13 repeats and patients with a

predominantly positive syndrome of schizophrenia, displaying prominent

delusions, hallucinations and disorganized speech and behavior

(χ2=7.675, p=.021) .

Figure 1. Allelic distribution of CAG repeats in RAI1 gene in patients with

schizophrenia and healthy controls.

Chapter 4

DISCUSSION

One of the theories of pathogenesis proposes a neurodevelopmental

model for schizophrenia, with an early disruption in neuronal migration

or proliferation and late developmental derailments of peri-adolescent

process of synaptic pruning (Murray and Lewis, 1987; Lewis and Levitt,

2002; Rapoport et al., 2005). The model is supported by the occurrence

of specific neuronal loss and abnormal architecture in several brain

structures of schizophrenic patients. Retinoid signaling is involved in the

normal development of neuronal structures, including forebrain (Maden,

2002), and in the neuronal plasticity, maintenance and nerve regeneration

in the adult (Maden, 2007) . Deregulation of the retinoid signaling may

be an etiological factor of schizophrenia (Goodman, 1998), and studies

of the genes coding proteins participating in retinoid pathway, as well as

retinoid acid-responsive genes, are further needed to elucidate

relationship between retinoid signaling and schizophrenia. The

inducibility of RAI1 gene by retinoic-acid, its expression pattern with

highest level in a different brain structures, and its proposed role in the

neurodevelopmental and neurobehavioral processes, make this gene a

potential candidate for schizophrenia.

In our population-based case-control study we were interested in a

potential relationship between the polymorphic CAG repeats in the RAI1

gene and heterogeneous clinical manifestation of schizophrenia. Study

included 215 unrelated subjects of European descent (115 patients and

100 healthy controls) and showed significant association between shorter

alleles (≤13 CAG repeats) in RAI1 gene and schizophrenia. Different


subtypes of schizophrenia (paranoid, disorganized, undifferentiated, and

residual) displayed a similar allelic distributions, which might be

misleading, because stratification of sample reduced the number of

patients in each subgroup. Indeed, when patients were divided into larger

subgroups with a predominantly positive and predominantly negative

syndrome of schizophrenia, according to PANSS score, significant

difference was observed. Patients with prominent delusions,

hallucinations and disorganized speech and behavior displayed

significantly shorter alleles (≤13 CAG repeats) compared to patients with

a predominant negative syndrome of schizophrenia. According to our

study design, all patients were assessed in acute psychotic exacerbation.

This could be a limitation to our results, since PANSS score is not

constant parameter, and clinical manifestation could vary in same patient

through time. Nevertheless, studies repeatedly show negative symptoms

and cognitive deficit to be stable over time (Andreasen and Olson, 1982).

Considering the sample size and possible population stratification

bias, the obtained results should be taken with caution. However, our

findings could be important in terms of treatment and outcome, since a

positive syndrome of schizophrenia is generally better handled with

medication, and usually have more favorable prognosis than a negative

syndrome. Antipsychotic drugs are very effective mainly against positive

and disorganization symptoms (Mazure et al., 1992; Leucht et al., 2009;

Tandon et al., 2010), while are less successful in reducing negative

symptoms. They improve negative symptoms linked with positive ones,

and can worsen those negative symptoms associated with extrapyramidal

side effects (Stahl and Buckley, 2007). Additionally, response over the

first 2 to 4 weeks of antipsychotic therapy is highly predictive of long-

term response (Lambert et al., 2009; Kinon et al., 2010). The

responsiveness of a positive symptoms to antipsychotic drugs is linked to

a proposed underlying hyperactivity of the mesolimbic dopamine system

(Crow, 1980; Weinberger, 1987; Davis et al., 1991) as neuroleptics tend

to block D2 receptors in the brain's dopamine pathways (Snyder, 1989).

Previous study reported an association of the RAI1 CAG repeat

polymorphism with both the response to medication in schizophrenic

patients and the severity of the phenotype (Joober et al., 1999) .

Significantly shorter RAI1 CAG alleles were found in patients that

responded well to neuroleptic treatment, compared to non-responder and

controls. The group of neuroleptic responder had a later age of onset, and

Discussion 15

a better long-term outcome, as they were able to function autonomously

with only occasional supervision in domains of social and vocational

activities, compared to non-responder (Joober et al., 1999). To some

extent, our and Jobber and coworkers (1998) findings are in concordance

as disturbed dopamine neurotransmission is more frequently reported in

neuroleptic responder compared to non-responder (Mazure et al., 1991)

and, as mentioned above, a dopaminergic mesolimbic hyperactivity)

appears to underlie positive symptoms of schizophrenia (Crow, 1980;

Weinberger, 1987; Davis et al., 1991).

Our findings suggest that varying number of glutamine repeats in the

RAI1 gene may represent functional polymorphism related to a positive

syndrome of schizophrenia and, possibly, to underlying etiological

processes at certain brain structures). As it was suggested for some other

transcriptional regulators with homopolymeric stretches (Mitchell and

Tjian 1989; Perutz et al. 1994; Gerber et al., 1994), glutamine repeats can

mediate interaction of RAI1 protein with its partner protein and

variations in their number may alter the strength of that interactions. This

may slightly modulate RAI1 activity and transcriptional regulatory

network during the normal neurodevelopment, and thus contribute to a

positive syndrome of schizophrenia.

The relationship between RAI1 gene and disrupted forebrain

development is confirmed in patients suffering from Smith-Magensis

syndrome (Seranski et al., 2001). Comparison of the clinical

manifestation in patients with 17p11.2 deletion and intragenic mutations

in the RAI1 gene showed that haploinsufficiency of the RAI1 gene is

associated with craniofacial, behavioral, and neurologic signs and

symptoms of Smith-Magenis syndrome (Girirajan et al., 2005).

Moreover, experiments on animal models support RAI1 protein as a

transcriptional regulator involved in embryonic and postnatal

development, including neurologic and behavioral functions, in dose-

dependent manner. Most Rai1-/- mice died during gastrulation or

organogenesis, and survivors were growth retarded and displayed

malformations in both the craniofacial and the axial skeleton (Bi et al.,

2005). Obesity and craniofacial abnormalities were observed in Rai1+/-

mice (Bi et al., 2005). Transgenic mice with 4 and 6 copies of the Rai1

gene showed a dose-dependent exacerbation of the phenotype in mice

with higher Rai1 expression (Girirajan et al., 2008), The phenotype of

Rai1 transgenic mice included growth retardation, increased locomotor


activity, and severe neurologic deficits (impaired sensorimotor activity,

and abnormal anxiety-related behavior). According to a dose-dependent

effect of RAI1 gene on embryonic and postnatal development, it may be

speculated that polyglutamine polymorphism in RAI1 gene might be

related to more subtle functional alterations during development. Thus,

the varying number of coding CAG repeats in the RAI1 gene may

represent functional polymorphisam, which could slightly modify its

function in the normal neurodevelopment, and combined with other

genetic and/or environmental factors may predispose to a positive

syndrome of schizophrenia.

Although limited due to sample size and possible stratification bias,

our report, together with Jobber and coworkers' (1998) study, suggest

that short RAI1 CAG alleles might be related to clinical presentation,

treatment response, course and outcome in some schizophrenic patients.

Polyglutamine polymorphism in the RAI1 gene may affect interaction

between RAI1 and its partner proteins, modulating its activity as

transcription regulator to some extent. This may change retinoic-acid

response during neurodevelopment and neuronal plasticity, which may,

combined with other genetic and/or environmental factors, contribute to

a positive syndrome of schizophrenia. Further studies are needed to

elucidate possible relationship between retinoid signaling and

perturbation involved in brain development and neuronal plasticity in

schizophrenia. They may also reveal a new strategy for the treatment of

schizophrenia, as some retinoids has shown pharmacological successes in

dermatology and cancer (Thacher et al., 2000), and very recently a

beneficial effect in the antipsychotic treatment of schizophrenia patients

(Lerner et al., 2008). Study investigated the efficacy of augmentation of

bexarotene to ongoing antipsychotic treatment and showed significant

improvement on total PANSS score in chronic schizophrenia patients

who were stabilized on regular antipsychotic treatment (Lerner et al.,

2008).

ACKNOWLEDGEMENTS

This work was supported by grant #173016 funded by Serbian

Ministry of Education and Science.

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Database

GWAS, NIH: http://gwas.nih.gov/

Ensembl: www.ensembl.org/

GATExplorer: http://bioinfow.dep.usal.es/xgate/

OMIM: www.ncbi.nlm.nih.gov/omim

Gene: www.ncbi.nlm.nih.gov/gene

INDEX

A

antipsychotic drugs, 14

responsiveness of a positive

symptoms, 14

D

DNA analyses

determination of RAI1 CAG

repets number, 9

isolation of DNA, 9

PCR for RAI1 CAG repeats, 9

dopaminergic mesolimbic

hyperactivity, 14, 15

DSM-IV criteria, 7

G

glutamine rich activated domen, 5

N

nuclear retionid receptors, 3

P

polyglutamine repeats, 5, 15

population-based case-control study

of RAI1 and schizophrenia, 5, 13

association between positive and

negative type of schizophrenia,

12, 14

treatment and outcome

imortance, 14

association with clinical subtypes

of schizophrenia, 12, 14

association with schizophrenia, 11,

13

controls, 8

patients, 7

stratification, 7

positive and negative syndrome scale

(PANSS), 8

negative scale, 8

negative type patients, 8

positive scale, 8

positive type patients, 8

ratings of patients, 8

Index 28

R

Rai1 animal models

Rai1-/- mice, 15

Rai1+/- mice, 15

transgenic Rai1 mice, 15

RAI1 protein, 4

role in transcription, 5

relationship with schizophrenia,

15, 16

retinoic acid, 3

biological role, 3, 13

catabolism, 3

causal relationship with

schizophrenia, 3, 13

mechanism of action, 3

synthesis, 3

retinoic acid inducible 1 gene

(RAI1), 4

expression, 4

mRNA, 4

polyglutamine repeats, 5

polymorphic CAG repeats, 5

allele distribution, 11, 12

association with schizophrenia,

5, 14, 15, 16

potential candidate gene for

schizophreania, 13

retinoic acid responsive elements, 3

retinoic acid responsive genes, 3

in schizophrenia, 4

retinoid signaling, 3

retinoids, 3

bexarotene, 16

potentail antipsychotic treatment,

16

S

schizophrenia, 1

annual incidence, 1

clinical subtypes, 8

disorganized, 8

paranoid, 8

residual, 8

undifferentiated, 8

cognitive symptoms, 1

environmental risk factors, 2

etiology, 1

genetic models, 2

heritability, 1

negative symptoms, 1

neurodevelopmental model, 2, 13

positive and negative syndrome

scale (PANSS), 8

positive symptoms, 1

prevalence, 1

risk for illness, 1

Smith-Magenis syndrome, 5, 15

Retinoic acid inducible-1 gene (RAI1) and clinical subtypes of schizophrenia.

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