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Genetic basis of schizophrenia: trinucleotide repeats an update
Bug. Newo-pSycho~hamam1.
& ISid. Psychid. 2001, Vol. 25, pp. 1187-1201 Copyright 0 2001 Elsnner Science Inc. mnted
in the USA.
0278-5846/01/$-see
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TRII’IUCLEOTIDE REPEATS GENETIC BASIS OF SCHIZOPHREBW AN UPDATE MEERA VASWANI and SUMAN KAPLJR* Department of Psychiatry, All India Institute of Medical Sciences, New Delhi, India. and *JRD Tata Foundation for Research in Ayurveda and Allied Sciences, Deen Dayal Research Institute, Chitrakoot, M. P, India.
(Final form, May 2001) Contents
1. 2. 3. 4. 5. 5.1 51.1 5.1.2 5.1.3 6.
Abstract Introduction Genetic Basis of Schizophrenia Role of Epidemiology DNA Instability: Expanded Repeats or Dynamic Mutations Expanded Trinucleotide Repeats and Affective Disorders TRE’s Associated with Specific Genes The SEFZ-1 and SEF-2 Genes Calcium Activated Potassium Channel Gene, KCNN3 or hSKCa3 Other Genes Conclusion References
Abstract Vaswani Meera and Suman Kapur: Genetic Basis of Schizophrenia: Trinucleotide Repeats An Update. Prog. Neuro-psychopharmacol. & Biol. Psychiat. 2~1,25, PP. 1187-1201. 0200 1 Elsevier Science Inc. Recent developments in technologies permit systematic screening of the entire human genome as a strategy for identification of susceptibility genes of small effect that influence risk to complex traits, like schizophrenia (S&z), inflammatory bowel disease, bipolar affective disorder (BPAD) etc. Schizophrenia is known to have a high heritability and a complex inheritance pattern. Several studies provide evidence that both genes and environment play a role in the etiology of schizophrenia. Linkage studies have observed racial and sex bias in the genetic constitution of schizophrenia. Schizophrenia also manifests clinical anticipation and genomic imprinting. “Dynamic mutations” or “tandem repeat expansions” in DNA, explain a number of observations associated with clinical anticipation and genomic imprinting. In patient populations, the repeat
1187
M. Vaswani and S. Kapur
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expands well beyond the normal range, altering the biological function of the gene. These sequence are unstable and increase in size between family members in successive generations, giving rise to greater severity of disease. 4. Several workers have reported an association of trinucleotide repeat length with adult- and childonset schizophrenia. One such expanded allele has been found at the CTGl8.1 locus on the 18th chromosome. Other genes known to have similar mutation are SEFZ-1, which codes for a helixloop-helix protein, hSKCa3 gene, which codes for a calcium- activated potassium channel and the transthyretin gene. In schizophrenic patients, significant difference in allele frequency distribution of these genes has been reported. 5. Population based genetic research would not only help identify different subgroups of this of schizophrenia. Kevwords: dynamic mutations, expanded repeats, schizophrenia, trinucleotide repeats.
Abbreviations: adult onset/childhood onset schizophrenia (AOS/COS), bipolar affective disorder (BPAD), dentatorubular pallidoluysian atrophy (DRPLA), fragile X syndrome (FRAXA), fragile XE mental retardation (FRAXE), Huntington’s disease (HD), mytonic dystrophy (DM polyglutamine expansion (PGE), schizophrenia (Schz), spinal and bulbal muscular dystrophy (SBMA), spinocerebellar ataxia type1 (SCAl), transcription factors (TFs), trinuceotide repeat expansions (TREs).
1. Introduction The etiological basis of psychotic disorders remains largely un-understood, even though genetic, neuro-developmental
and environmental
causative factors have been proposed (Alda, 1997).
Representative syndromes in this category include schizophrenia (Schz), brief psychosis and delusional disorders. thinking
Idiopathic psychoses characterized mainly by chronically
and emotional
withdrawal
hallucinations are called schizophrenia.
and often associated
with delusions
disordered
and auditory
Over 2 million adults are aMicted with schz in USA
alone causing an estimated economic burden of nearly $70 billion annually (Wyatt et al., 1995). Safe and effective treatment of this group of patients depends on early and correct diagnosis. Inappropriate treatment runs the risk of worsening agitation and/or inducing mania.
Specific
genetic marker, if identified, would not only help in counseling, but also contribute towards an early diagnosis of these diseases. Ever-evolving genetic methods and technologies now permit systematic screening of the entire human genome as a strategy for the identification
of
susceptibility genes of small effect that influence risk to complex traits, such as coronary artery disease, obesity, schizophrenia, diabetes, inflammatory bowel disease and multiple sclerosis. Schizophrenia is a severe disorder in which the sufferer is no longer in touch with reality. It is characterized by the presence of two or more of the following on the basis of DSM-IV (American Psychiatric Association, 1992) criteria: delusions, hallucinations, disorganized speech, grossly
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Genetic basis of schizophrenia
disorganized or catatonic behavior and negative symptoms.
Twin and adoptive studies provide
convincing evidence of a major genetic contribution in the etiology of functional psychoses (Goodwin and Jamison, 1990; Freimer and Reus, 1993; Bertelsen et al., 1977; Pauls et al., 1995; Spence et al., 1995). Schizophrenia has a complex inheritance pattern. It falls into the category of complex genetic disorders which may be explicable in terms of the interaction of a small number of major genes (oligogenic model) or require minor involvement (polygenic model) and may also require additional environmental
of many genes
co-factors (multifactorial
model). In such disorders a threshold of liability is observed, beyond which the illness occurs (Gottesman and Shields, 1967).
2. Genetic Basis of SchizoDhrenia Recent investigations have made important advances in identifying specific susceptibility genes for several psychiatric and neuro-degenerative diseases. Family, twin and adoption studies over the past three decades have provided very strong evidence that both genes and environment play a role in the complex etiology of affective disorders (Gottesman, 1991; Kendler and Diehl, 1995; Ross, 1999). As already stated the evidence for a significant genetic contribution to functional psychosis (s&z and BPAD) is now well established.
Heritability, which is a measure of the
proportion of the etiology (at the population level) that is attributable to genetic factors, is estimated at 60-70% for schz, after influences of a common environment are taken into account (Rao et al., 1981; Mcgue et al., 1983; Grierson et al., 1999).
Rapidly evolving genetic
technologies have been applied in the genetic analysis of schz and several genomic regions have been posited as harboring susceptibility genes. Linkage studies, conducted predominantly in the developed western world, have observed a strong racial and sex bias in the genetic constitution of patients. Modem genetics has revealed several mechanisms that may give rise to complex patterns of inheritance and phenotypic variability. Two phenomena, namely, “imprinting” and “anticipation” may provide more insights into the genetic etiology of inherited diseases. Genomic imprinting refers to the differential expression of genes depending on whether the genetic material accrues from the paternal or maternal chromosome.
This has also been referred to as parent-of-origin
effect and is believed to depend upon and involve methylation of DNA. The term anticipation refers to the decrease in age of onset and/or increase in disease severity in successive generations. Schizophrenia displays both clinical “imprinting” and “anticipation” (McGuffln and Katz, 1989; McInnis et al., 1993; Imamura et al., 1998 and Heiden et al., 1999). Based on recent studies the phenomenon of anticipation has been related to expansions of GC-enriched trinucleotide repeat sequence mutations (Nylender et al., 1994 and Zivanovic and Borisev, 1999). These so-called
M. Vaswani and S. Kapur
1190
“dynamic mutations” explain a number of clinical epidemiological observations that cannot be accounted for by classical Mendelian genetics.
The term dynamic mutation has been introduced
to distinguish differences in the number of copies of DNA repeat sequences from other type of mutations (Hummerich and Lehrach, 1995). Repeats are either composites of perfect, with no variation in the base composition of the repeat motif, or imperfect repeats where there are some copies that vary from the canonical repeat motif (Richards and Sutherland, 1992).
3. Role of Molecular EDidemiology Several interrelated developments over the past three decades have influenced the field of human genetics. Advances in human genetic map, in genetic analysis linkage and association in complex inheritable traits, have led to increased understanding of role of genetics in several diseases. Testing
of every gene in the human genome for association with illness has been proposed by
Risch and Merikangas (1996). However, majority of the estimated 100,000 genes in the human genome are as yet not identified. Therefore, several investigators have attempted to identify the chromosomal location/s rather than individual genes. Incidence
of candidate genes and/or loci
are studied to identify susceptibility genes for various inheritable traits/diseases. through the identification
of “anonymous” genetic polymorphism
It is effected
(genetic markers) which
segregate along with the disease in question. The function of such genetic markers need not be known; it is only necessary that their chromosomal location be available. The identification of a marker that segregates with the disease in a family or in the population can thus provide key information about the likely location of the disease gene. Detection of an association implies that the marker gene itself is the disease gene or that an allele of the marker gene is in linkage disequilibrium with the disease gene mutation (Suraz and Hampe, 1994). Indeed for polygenic diseases, diseases which do not follow simple Mendelian pattern of inheritance, this seems to be the only available approach.
As molecular investigation methods advance, identification
of
disease susceptibility mutations and delineation of their roles may be expected.
4. DNA Instabilitv : ExDanded ReDeats or Dvnamic Mutations Until recently, DNA was thought to be a relatively stable molecule with new mutations arising infrequently and being inherited upon further transmission.
However, the last few years have
forced us to re-evaluate our ideas on the stability of DNA and association of de novo mutations and illness in an individual’s life time.
In recent years, a new mode of molecular mutation
responsible for inherited human diseases has come to light.
These have been referred to as
“dynamic mutations” and are constituted by repeat DNA sequences. At each dynamic-mutation
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Genetic basis of schizophrenia
locus there is a normal range of copy numbers above which the repeat becomes unstable, that is, copy number can be increased to a point where the repeat manifests in a disease and/or a fragile site.
Thus, the premutation alleles cause little or no disease in individuals, but give rise to
significantly amplified repeats in affected progeny.
When located within or near transcribed
sequences the expansion can have an effect on either the gene transcript or the gene product, which may manifest in disease (Richards and Sutherland, 1997). The expansion of trinucleotide repeat DNA sequences within the transcribed regions of genes has been demonstrated to be the underlying
genetic defect in several inherited neuro-degenerative
diseases viz: Fragile X
syndrome (FRAXA), Spinal and bulbal muscular dystrophy (SBMA), Myotonic dystrophy (DM), Huntington’s disease (HD), Spinocerbellar ataxia type I (SCA l), Fragile X E mental retardation (FRAXE), Familial
spastic paraparesis and Dentatorubral pallidoluysian
atrophy (DRPLA),
(Kremer et al., 1991; LaSpada et al., 1991; Campuzano et al., 1996; Yu et al., 1997; Lalioti et al., 1997; Zhuchenko et al., 1997; Richards and Sutherland, 1996; Benson et al., 1998; Margolis et al., 1999).
In all cases, a single trinucleotide, tandemly repeated DNA sequence exists in the
transcribed region of the gene.
These sequences are unstable and show an increase in size
between family members in successive generations, giving rise to a greater severity of the disorder. population.
The triplet repeat shows moderate levels of length variation within the normal However, in patient populations, the repeat expands well beyond the normal range,
altering the biological tunctioning of the gene. The unusual properties of triplet repeat DNA sequences account for the wide-ranging disease severity and complex non-mendelian inheritance pattern is observed.
At the time of writing the present review this number had already grown
from seven to sixteen (Richaards and Sutherland, 1997). It may also be noted that not all TRE’s are disease related.
Schalling et al., (1993) reported the occurrence of an expanded repeat on
chromosome 18 in unaffected individuals.
5. ExDanded Trinucleotide ReDeat. and Affective Disorders Several studies conducted in last few years have reported a correlation between trinucleotide repeat lengths and clinical observation of anticipation seen in different familial psychiatric disorders(Fischer,1998).
As already stated both schz and BPAD manifest clinical anticipation.
Indeed, expanded trinucleotide repeat sequences have emerged as a major risk factors in affective disorders.
The identification of TEES represents a preliminary step in an emerging pathway.
These are small effect genes, best detected with affected-relative-pair linkage methods. In a study conducted in Belgium, eighty-seven two-generation pairs of patients were analyzed for expanded trinucleotide repeats (Mendlewicz et al., 1997). Significant
changes in the age at onset and
M. Vaswani and S. Kapur
1192
episode frequency in successive generations were observed by the authors.
They report an
increase in the mean CAG repeat length between parental and offspring generations when the phenotype increased in severity of disease. In these subjects the phenotype changed from major depression, single episode or unipolar recurrent depression to BPAD.
A parent-of-origin effect
was also observed in the median length CAG between Gl and G2 with maternal inheritance. The female offspring seemed to be more affected suggesting a higher penetration of this trait in females.
Lindblad et al., (1995) also reported an association between CAG repeat length and
BPAD in Swedish and Belgian patients. Similar CTG/CAG expansion has also been reported by Sirugo et al., (1997) in Danish schizophrenia kindred. Knowles et al., (1998) in his study reviewed 1013 genotyped individuals in 53 unilineal multiplex pedigrees, but did not find any evidence for linkage between BPAD and chromosome 18 pericentromeric markers. In this study the authors did not report any parent to offspring effect either. Another report based on a Europeon-American sample collected from The Genetics Initiative of National Institute of Mental Health (NIMH) also found no region showing evidence of linkage.
However, they reported that two markers on
chromosome lop did show statistical evidence suggestive of linkage in cases of schizophrenia (Faraone et al., 1998). No TRE’s were reported in a study of Spanish families by Martorell et al. (1999). Similar results have also been reported in Chinese families (Li et al., 1998a), in monozygotic twins ( Vincent et al., 1998) and in French families (Laurent et al., 1998). However, studies on TREs
have shown an association of repeat length and adult-onset schizophrenia
(AOS). Childhood-onset schizophrenia (COS) is a severe variant of schizophrenia with onset of symptoms before age 12 years. Burgess et al., (1998) reported a significant association between CAG/CTG repeat length in male Caucasian samples. Some of these expanded alleles were found to correlate with CTG18.1 locus on chromosome 18. Vincent et al. (1999a) also concluded that the occurrence of an expanded trinucleotide repeat may contribute to the genetic risk of COS, in combination with other factors. The expanded CAG repeats lead to Polyglutamine expansion (PGE) in proteins. Recently,
Moriniere et al(1999) and Joober et al.( 1999a) identified PGE
affected protein in COS and in Schizophrenic patients.
These observations put together merit
large sample population and pedigree studies for the role played by TRE’s in Schizophrenia and BPAD patients.
5.1 TRE’s Associated with Saecitic Genes 5.1.1 The SEFZ1 gene and SEFZlB
genes: Breschel et al., (1997) recently reported a very
large, 800-2100 TRE of CTG in second intron of the SEFZ1 gene to be associated with BPAD affected individuals. tripartite distribution
The CTGn repeat at 18q21 .l is highly polymorphic. They further reported of CTG18.1 alleles with stable alleles (CTGlO-CTG37),
moderately
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Genetic basis of schizophrenia
enlarged and unstable alleles (CTG53-CTG250) and very enlarged unstable alleles (CTGIOOCTG2100).
Moderately enlarged alleles were not associated with an abnormal phenotype. It is
noteworthy that SEFZ1 gene has been reported to code for a helix-loop-helix protein. loop-helix proteins are known to be involved in transcriptional regulation.
Helix-
This motif of protein
structure, along with two other motifs, viz., leucine zipper and zinc finger, is often encountered in a class of DNA binding proteins named Transcription Factors (IFS).
Several cellular oncogenes
and suppressor genes function as TFs. TFs show a binding domain which binds the DNA, and several TFs are known to bind closely in a gene region, regulating in a positive or negative manner the expression of the gene. After binding of TF to DNA, the transcription rate of a gene can be increased. The binding of TF depends on several signals. Gene Expression is, thus, tightly regulated by TFs.
SEFZ-1 gene product, by virtue of having a helix-loop-helix motif, could
Rtnction as a TF.
Other examples of this class of proteins are c-myc, N-myc, L-myc, A4jvDJ , etc
which are all known to function as TFs. N-myc forms a heterodimer with Max protein, and together they bind to DNA.
Myo-D 1, the gene involved in rhabdomyo sarcoma, also codes for a
helix-loop-helix transcription factor and is predicted to play a role in the control of cell growth and differentiation.
Activation of TFs by gene mutation, deletion and amplification can lead to
the loss of control of TFs, resulting in a deregulation of cell growth and/or function. The reported expansion mutation in the SEFZ1 gene may alter the function of this gene product, However, as yet, almost nothing is known about the role and function of this protein in the normal brain and other tissues. Recently, Vincent et al., (1999b) reported no association of expanded CAG/CTG repeats at 18q21.1 (SEFZlB) with Schizophrenia. 5.1.2 Calcium Activated Potassium Channel Gene. KCNN3 OR hSKCa3: Another gene of interest is hSKCa3 gene (now known as KCNN3), which codes for a calcium-activated potassium channel.
Calcium-activated
potassium
channels
are fundamental
regulators
of neuronal
excitability, participating in inter-spike interval and spike-frequency adaptation. In a recent study on patients of BPAD and s&z, a significant difference in allele frequency distribution of this gene has been reported (Chandy et al., 1998). They found that the hSKCa3 gene contains two arrays of CAG trinucleotide repeats. The second CAG repeat in hSKCa3 is highly polymorphic in control individuals, with alleles rang~mg in size from 12-28 repeats. Strober et al. (1998) also reported similar findings.
Upon comparing the allelic frequency distribution between Schizophrenic
patients and ethnically matched controls, a significant excess of longer CAG repeats was observed in Schizophrenic patients in the caucasian population both from Europe and USA. Similar findings have been reported by Bowen et al., (1996 and 1998) in white population from UK and by Dror et al., (1999) in Israeli Ashkenazi jews. On the other hand, a study on 97 Chinese family trios with schizophrenia found no evidence for an excess of longer CAG repeats in the patients (Li et al., 1998b). The authors did report a deficit of transmission of the CAGZO repeat allele to affected offspring. Further in a study of 54 multiplex families, Antonarakis et al., (1999) found no differences in the distribution of (CAG)n alleles between
affected and normal individuals.
Several other studies have also reported no association and involvement of hSKCa3 gene in
M. Vaswani and S. Kapur
1194
schizophrenia (Meissner et al., 1999; Tsai et al., 1999; Wittekindt et al., 1999; Austin et al., 1999; and Joober et al., 1999b). However, recently Cardno et a1.,(1999) reported correlation of negative symptoms of schizophrenia with hSKCa3 gene and concluded that negative symptoms in schizophrenia may be partly mediated through the hSKCa3 gene. This gene needs to be further evaluated in other patient populations of BPAD and Schizophrenia. Sirugo et al., (1997) identified an expansion of a triplet repeat at
5.1.3 Other Genes:
chromosome1 8q2 1 in a Danish Schz kindred. This locus seems to be adjacent to the locus of the Transthyretin gene (TTR) which spans bands 18q12-q21, identified by TTR’s flanking markers D18S456-18S472 (Goodman, 1998). These markers have also been positively linked to a common locus for Schz in large kindreds from Quebec (Merette et al., 1997). Further studies on the role of TTR gene might prove productive in disclosing a mechanism involved in increasing vulnerability to schz. The gene for spino-cerebellar ataxia type1 (SCAI) is a potential candidate gene for schz due to positive linkage findings in this region(6p22-24). SCAl onset is also positively correlated with TRE-(CAG)n. Joo et al.,( 1999) reported increased frequency in one out of 13 alleles in patients of schizophrenia as compared to control subjects. Similarly, Breen et a1.,(1999) studied the expansion in a coding 3’ CAG repeat causing spino-cerbellar ataxia , but found no association with schz susceptibility. MAP2 expression has been reported to be altered in Schz and other neurological disorders. MAP2 gene also contains a region of trinucleotide repeat located in exon 1 of the 5’ untranslated region. However, analysis of this region by Kalcheva et al., (1999) showed no evidence of expansion in this gene in schizophrenic patients. Further studies are clearly warranted to delineate the role of TRE?s in the molecular etiology and pathophysiology of schizophrenia and bipolar affective disorders, 6. Conclusions As
an
outcome
polymorphism/s,
of
molecular
epidemiological
studies
targeting
it can be expected that a better understanding
physiology of human diseases will emerge.
population
of the underlying
genetic patho-
Results from studies done on neuro-psychiatric
patient population will throw more light on ascertaining the number of susceptibility loci, disease risk conferred by each locus and also help in developing new and safer mood altering agents. More importantly, a positive genetic marker can be envisaged to provide an immediate diagnostic tool for those select individuals, with known familial history and comprising the high risk group. Available diagnostic criteria for affective disorders are subjective clinical validity criteria. Genetically determined characterization of validity would no doubt be more precise, if specific
Genetic basis of schizophrenia genetic
1195
factors/targets could be identified. Population based genetic research would not only help
identify different subgroups of these diseases, but would also delineate ethnic differences and/or similarities in the genetic etiology.
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Genetic basis of schizophrenia
GOODMAN, A.B. (1998) Is transthyretin (TTR) disrupted by a trinucleotide in a schizophrenia kindered? Am. J. Med. Genet. &l: 347.
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repeat expansion
GOODWIN, F.K. and JAMISON, K.R. (1990) Manic Depressive Illness, Oxford University Press, New York. pp 373-401. GOTTESMAN,I.I. and SHIELDS, J. (1967) A polygenic theory of schizophrenia. Proc. of Natl. Acad. Sci USA. 3: 199-205. GOTTESMAN,I.I. (1991) Schizophrenia Genesis, In: The origin of madness. WI-I Freeman k company, New York. GRIERSON, A.J. VAN-GROENIGEN, M. GROOT, N.P. LINDBLAD, K. HOOVERS, J.M. SCHALLING, M. De-BELLEROCHE, J. and BAAS, F. (1999) An integrated map of chromosome 18 CAG trinucleotide repeat loci. Eur.J.Hum.Genet. 2111: 12-19. HEIDEN, A. WILLINGER, U. SCHARFETTER, J. MESZAROS, K. KASPER, S. and ASCHAUER, H.N. (1999) Anticipation in schizophrenia. Schizophr. Res. m: 25-32. HUMMERICH, H. and LEHRACH, H. (1995) Trinucleotide repeat expansion and human disease. Electrophoresis. m: 1698-1704. IMAMURA, A. HONDA, S. NAKANE, Y. and OKAZAKI, Y. (1998) Anticipation in Japanese families with schizophrenia. J.Hum.Genet. Q@: 217-223. JOO, E.J. LEE, J.H. CANNON, T.D. and PRICE, R.A. (1999) Possible association between schizophrenia and a CAG repeat polymorphism in the spinocerbellar ataxia typel(SCA1) gene on human chromosome 6~23. Psychiatr. Genet. m: 7-l 1. JOOBER, R. BENKELFAT, C. JANNATIPOUR, M. TURECKI, G. LAL, S. MANDEL, J.L. BLOOM, D. LALONDE, P. LOPES-CENDES, I. FORTIN, D. and ROULEAU, G. (1999a) Polyglutamine containing proteins in schizophrenia (see comments). Mol. Psychiatry. 4&I: 53-57. JOOBER, R. BENKELFAT, C. BRISEBOIS, K. TOULOUSE, A. LAFRENIERE, R.G. TURECKI, G. LAL, S. BLOOM, D. LABELLE, A. LALONDE. P. FORTIN, D. ALDA, M. PALMOUR, R. and ROULEAU, G.A. (1999b) Lack of association between the hSKCa3 channel gene CAG polymorphism and schizophrenia. Am.J.Med.Genet. m: 154 -157. KALCHEVA, N. LACHMAN, H.M. SHAFIT-ZAGARDO, B. (1999) Survey for CAG repeat polymorphism in the human MAP-2 gene. Psychiatr. Genet. m: 43-46. KENDLER,K.S. and DIEHL, S.R. (1995) Schizophrenia Genetics, In : Comprehensive Text Book of Psychiatry, 6th ed. HLKaplan and B.J.Sadock (eds). Williams and Wilkims Company, Baltimore MD. pp 942-957
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KNOWLES, J.A. RAO, P.A. COX-MATISE, T. ELLENLOTH, J. GRACIELLE, H. ENDICOTT, J. LEVINE, L. DAS, K. PENCHASZADEH, G.K. ALEXANDER, J.R, LERER, B. ENDICOTT, J. OTT. J. GILLIAM, T.C. and BARON, M. (1998) No evidence for significant linkage between bipolar affective disorder & chromosome 18 pericentromeric markers in a large series of multiplex extended predigrees, Am. J. Hum. Genet., w: 916 924. KREMER, E.J. PRITCHARD, M. LYNCH, M. YU,S. HOLMAN, K. BAKER, E. WARREN, S.T. SCHLESSINGER, D. SUTHERLAND, G.R. and RICHARDS, R.I. (1991) Mapping of DNA instability at the fragilex to a trinucleotide repeat sequence p(CCG)n. Science. 252: 1711-1714. LALIOTI, M.D. SCOTT, H.S. BURESI, C. ROSSIER, C. BOTTANI,A. M0RRISN.A. MALAFOSSE, A. and ANTONARAKIS, S.E. (1997) Dodecamer repeat expansion in cystetin B gene in progressive myoclonus epilepsy.(Comments) Nature. 386(6627): 847-851. LA SPADA, A.R. WILSON, E.M. LUBHAN, D.B. HARDING, A.E. and FISCHBECK, K.H. (1991) Androgen receptor gene mutation X-linked spinal and bulbar muscular atrophy. Nature. 352: 77-79. LAURENT, C. ZANDER, C. THIBAUT, F. BONNET-BRILHAULT, F. CHAVAND, 0. JAY, M. SAMOLYK, D. PETIT, M. MARTINEZ, M. CAMPION, D. NERI, C. MALLET, J. and CANN, H. (1998) Anticipation in schizophrenia: no evidence of expanded CAG/CTG repeat sequences in French families and sporadic cases. Am.J.Med. Genet. &I&Q:342-346. LINDBLAD, K. NYLANDER, P.O. DEBRUYN, A. SOUREY, D. ZANDER, C. ENGSTROM, C. HOLMGREN, G. HUDSON, T. CHOTAI, J. and MENDLEWICZ, J (1995) Detection of expanded CAG repeats in bipolar affective disorder using repeat expansion detection (RED) method. Neurobiol. Dis. m: 55-62. LI, T. VALLADA, H.P. LIU, X. TANG, X. ZHAO, J. O’DONOVAN, M.C. MURRAY, R.M. SHAM, P.C. and COLLIER, D.A. (1998a) Analysis of CAG/CTG repeat size in Chinese subjects with schizophrenia & bipolar disorder using the repeat expansion method. Biol. Psychiatry. 440 1): 1160-l 165. LI,
T. HU, X. CHANDY, K.G. FANTINO, E. KALMAN, K. GUTMAN, G. GARGUS, JJ. FREEMAN, B. MURRAY, R.M. DAWSON, E. LIU, X. BRUINVELS, A.T. SHAM, P.C. and COLLIER, D.A. (1998b) Transmission disequilibrium analysis of a triplet repeat within the hKCa3 gene using family trios with schizophrenia. Biochem. Biophys. Res. Commun. 251(2): 662-665.
MARGOLIS, R.L. McINNIS, M.G. ROSENBLATT, A. and ROSS, C.A. (1999) Trinucleotide repeat expansion and neuropsychiatric disease. Arch. Gen. Psychiatry. 56(11’): 1019-103 1. MARTORELL, L. PUJANA, M.A. VALERO, J. JOVEN, J. VOLPINI, V. LABAD, A. ESTIVILL, X. and VILELLA, E. (1999) Anticipation is not associated with CAG repeat
Genetic basis of schizophrenia expansion in parent-offspring pairs of patients affected with schizophrenia. Genet. u: 50-56.
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McGUE, M. GOTTESMAN, 1.1. and RAO, DC. (1983) The transmission of schziphrenia under multifactional threshold model. Am. J. Hum. Genet. s: 161-l 178. McGUFFIN, P. and KATZ, R. (1989) The genetics of depression and manic depressive disorder. Br. J. Psychiatry. 155: 294-304. McINNIS, M.G. McMAHON,F. J. CHASE,G. A. SIMPSON, S.G. ROSS, C.A. and DEPAULO, J.R. JR (1993) Anticipation in bipolar affective disorder. Am.J.Hum.Genetics. 2: 385-390. MEISSNER, B. PURMANN, S. SCHURMANN, M. ZUHLKE, C. LENCER, R. AROLT, V. MULLER-MYHSOK, B. MORRIS-ROSENDAHL, D.J. and SCHWINGER, E. (1999) hSKCa3: a candidate gene for schizophrenia. Psychiatr. Genet. m: 91-96 MENDLEWICZ, J. LINDBLAD, K. SOUERY D, MAHIEU, B. NYLENDER, P.O. DEBRUYN, A. ZANDER, C. ENGSTROM, C. ADOLFSSON, R. and LIPP, 0. (1997) Expanded trinucleotide CAG repeats in families with bipolar affective disorder, Biol. Psychiatry. 42(12): 1115-l 122. MERETTE, C. BISSONNETTE, L. ROUILLARD,E. ROY, M.A. and MAZIADE, M. (1997) Positive linkage results for bipolar disorder on 18q in large kindreds from eastern Quebec. (Abstract) Am.J.Med.Genetics. 74: 674. MORINIERE, S. SAADA, C. HOLBERT, S. SIDRANSKY, E. GALAT, A. GINNS, E. RAPOPORT, J.L. and NERI, C. (1999) Detection of polyglutamine expansion in a new acidic protein: a candidate for childhood onset schizophrenia? (see comments). Mol. Psychiatry. a: 58-63. NYLANDER, P.O. ENGSTROM, C. CHOTAI, J. WAHLSTROM, J. and ADOLFSSON, R. (1994) A Anticiation in Swedish families with Bipolar affective disorder. J.Med.Genetics. 21 B: 686-689. PAULS, D.L. BAILEY, J.N. CARTER, A.S. ALLEN, C.R. and FGELAN, J.A.( 1995) Complex segregation analysis of older Amish families ascertained through Bipolar 1 individuals. Am. J. Med. Genetics. @: 290-297. RAO, D.C. MORTON, N.E. GOTTESMAN, 1.1.and LEW, R. (1981) Path analysis of qualitative data or pairs of relatives: application to schizophrenia. Hum.Hered. 31: 325-333. RICHARDS, R.I. and SUTHERLAND, R.G. (1992) Dynamic mutations: a new class of mutations causing human disease. Cell. 70: 709-712. RICHARDS, RI. and SUTHERLAND, G.R. (1996) Repeat Offenders: Simple repeat sequences and complex genetic problems. Hum. Mutat. 8: 1-7.
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RICHARDS, R.I. and SUTHERLAND, R.G. (1997) Dynamic mutation: possible mechanisms and significance in human disease. TIBS. 22: 432-436 RISCH, N.J. and MERIKANGES, K. (1996) Future of genetic studies of complex human diseases. Science. 273: 516-1517. ROSS, C.A. (1999) Schizophrenia genetics: expansion of knowledge? (editorial; comment) Mol. Psychiatry. m: 4 -5. SCHALLING, M. HUDSON, T.J. BUETOW, K.H. and HOUSMAN, D.E. (1993) Direct detection of nova1 expanded trinucleotide repeats in the human genome. Nat.Genet. m: 135-139. SIRUGO, G. PARNAS, CTG/CAG Genet. 3:
PAKSTIS, A.J. KIDD, K.K. MATHYSSE,S. LEVY, D.L. HOLZMAN, P.S. J. McINNIS, M. BRESCHEL, T. and ROSS, C.A. (1997) Detection of a large trinucleotide repeat expansion in a Danish schizophrenia kindered. Am.J.Med. 546-548.
SPENCE, M.A. KLADMAN, P.L. SADOVNICK, A.D. BAILEY-WILSON, J.E. AMELI, H. and REMICK, R.A. (1995) Bipolar disorder: Evidence for a major locus. Am. J. Med. Genetics. @: 370-376. STOBER, G. JATZKE, S. MEYER, J. OKLADNOVA, 0. KNAPP, M. BECKMANN, H. and LESCH, K.P. (1998) Short CAG repeats within the hSKCa3 gene associated with schizophrenia: results of a family- based study. Neuroreport. 9(16): 3595-3599. SURAEZ, B.K. and HAMPE, C.L. (1994) Linkage and association. Am. J. Hum. Genetics.3: 554-559. TSAI, M.T. SHAW, C.K. HSIAO, K.J. and CHEN, C.H. (1999) Genetic association study of a polymorphic CAG repeats array of calcium -activated potassium channel (KCNN3) gene and schizophrenia among the Chinese population from Taiwan, Mol. Psychiatry. m: 272-273 VINCENT, J.B. KALSI, G. KLEMPAN, T. TATUCH, Y. SHERRINGTON, R.P. BRESCHEL, T. McINNIS, M.G. BRYNJOLFSSON, J. PETURSSON, H. GURLING, H.M. GOTTESMAN, II. TORREY, E.F. PETRONIS, A. and KENNEDY, JL. (1998). No evidence of expansion of CAG or GAA repeats in schizophrenia families and monozygotic twins. Hum. Genet.l03(1): 41-47. VINCENT, J.B. KOVACS, M. KROL, R. BARR, C.L. and KENNEDY, J.L. (1999a) Intergenerational CAG repeat expansion at ERDA1 in a family with childhood-onset depression, schizoaffective disorder, and recurrent major depression. Am. J. Med. Genet.m: 79-82.
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VINCENT, J.B. PETRONIS, A. STRONG, E. PARIKI-IS. V. MELTZER,H.Y. LIBERMAN, J. and KENNEDY, J. (1999b) Analysis of genome- wide CAG/CTG repeats & at SEFZ-1B & ERDA1 in Schizophrenia and bipolar disorder. MolPsychiatry. m: 229-234. WITTEKINDT, 0. SCHWAB, S.G. BURGERT, E. KNAPP, M. ALBUS, M. LERER, B. HALLMAYER, J. RIETSCHEL, M. SAGMAN, R. BORRMANN, M. LICHTERMANN, D. CROCQ, M.A. MAIER, W. MORRIS-ROSENDAHL, D.J. and WILDENAUER, D.B. (1999) Association between hSKCa3 and schizophrenia not confirmed by transmission disequilibrium test in 193 offspring/ parents trios. Mol. Psychiatry.=: 267-270 WYATT, R.J. HENTER, I. LEARY, M.C. and TAYLOR, L.E. (1995) An economic evaluation of schizophrenia, Social Psychiatry & Psychiatric Epidemiology, 30: 196-205. YU, S. MANGELSDROF, M. HEWETT, D. HOBSON, L. BAKER, E. EYER, H. J. LAPSYS, N. LePASLIER, D. DOGGET, N.A. SUTHERLAND, G.R. and RICHARDS, R.I. (1997) Human chromosomal fragile site FRA16B is an amplified AT- rich mini satellite repeat. Cell. m: 367-374. ZHUCHENKO, 0. BAILEY, J. BONNEN, P. ASHIZAWA, T. STOCKTON, D.W. AMOS, C. DOBYNS, W. B. SUBRAMONY, S. H. and ZOGHBI, H.Y. (1997) Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine in the alpha 1A voltage dependent calcium channel. Nature Genetics. m: 62-69. ZIVANOVIC, 0. and BORISEV, L. (1999) Genetic factors in the onset of schizophrenia. Med. Pregl. 52(1-2) : 25-28.
Inquiries and reprint requests should be addressed to:
Dr. Meera Vaswani Additional Professor Department of Psychiatry All India Institute of Medical Sciences (A.I.I.M.S.) New Delhi---l 10029 INDIA.
& ISid. Psychid. 2001, Vol. 25, pp. 1187-1201 Copyright 0 2001 Elsnner Science Inc. mnted
in the USA.
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TRII’IUCLEOTIDE REPEATS GENETIC BASIS OF SCHIZOPHREBW AN UPDATE MEERA VASWANI and SUMAN KAPLJR* Department of Psychiatry, All India Institute of Medical Sciences, New Delhi, India. and *JRD Tata Foundation for Research in Ayurveda and Allied Sciences, Deen Dayal Research Institute, Chitrakoot, M. P, India.
(Final form, May 2001) Contents
1. 2. 3. 4. 5. 5.1 51.1 5.1.2 5.1.3 6.
Abstract Introduction Genetic Basis of Schizophrenia Role of Epidemiology DNA Instability: Expanded Repeats or Dynamic Mutations Expanded Trinucleotide Repeats and Affective Disorders TRE’s Associated with Specific Genes The SEFZ-1 and SEF-2 Genes Calcium Activated Potassium Channel Gene, KCNN3 or hSKCa3 Other Genes Conclusion References
Abstract Vaswani Meera and Suman Kapur: Genetic Basis of Schizophrenia: Trinucleotide Repeats An Update. Prog. Neuro-psychopharmacol. & Biol. Psychiat. 2~1,25, PP. 1187-1201. 0200 1 Elsevier Science Inc. Recent developments in technologies permit systematic screening of the entire human genome as a strategy for identification of susceptibility genes of small effect that influence risk to complex traits, like schizophrenia (S&z), inflammatory bowel disease, bipolar affective disorder (BPAD) etc. Schizophrenia is known to have a high heritability and a complex inheritance pattern. Several studies provide evidence that both genes and environment play a role in the etiology of schizophrenia. Linkage studies have observed racial and sex bias in the genetic constitution of schizophrenia. Schizophrenia also manifests clinical anticipation and genomic imprinting. “Dynamic mutations” or “tandem repeat expansions” in DNA, explain a number of observations associated with clinical anticipation and genomic imprinting. In patient populations, the repeat
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expands well beyond the normal range, altering the biological function of the gene. These sequence are unstable and increase in size between family members in successive generations, giving rise to greater severity of disease. 4. Several workers have reported an association of trinucleotide repeat length with adult- and childonset schizophrenia. One such expanded allele has been found at the CTGl8.1 locus on the 18th chromosome. Other genes known to have similar mutation are SEFZ-1, which codes for a helixloop-helix protein, hSKCa3 gene, which codes for a calcium- activated potassium channel and the transthyretin gene. In schizophrenic patients, significant difference in allele frequency distribution of these genes has been reported. 5. Population based genetic research would not only help identify different subgroups of this of schizophrenia. Kevwords: dynamic mutations, expanded repeats, schizophrenia, trinucleotide repeats.
Abbreviations: adult onset/childhood onset schizophrenia (AOS/COS), bipolar affective disorder (BPAD), dentatorubular pallidoluysian atrophy (DRPLA), fragile X syndrome (FRAXA), fragile XE mental retardation (FRAXE), Huntington’s disease (HD), mytonic dystrophy (DM polyglutamine expansion (PGE), schizophrenia (Schz), spinal and bulbal muscular dystrophy (SBMA), spinocerebellar ataxia type1 (SCAl), transcription factors (TFs), trinuceotide repeat expansions (TREs).
1. Introduction The etiological basis of psychotic disorders remains largely un-understood, even though genetic, neuro-developmental
and environmental
causative factors have been proposed (Alda, 1997).
Representative syndromes in this category include schizophrenia (Schz), brief psychosis and delusional disorders. thinking
Idiopathic psychoses characterized mainly by chronically
and emotional
withdrawal
hallucinations are called schizophrenia.
and often associated
with delusions
disordered
and auditory
Over 2 million adults are aMicted with schz in USA
alone causing an estimated economic burden of nearly $70 billion annually (Wyatt et al., 1995). Safe and effective treatment of this group of patients depends on early and correct diagnosis. Inappropriate treatment runs the risk of worsening agitation and/or inducing mania.
Specific
genetic marker, if identified, would not only help in counseling, but also contribute towards an early diagnosis of these diseases. Ever-evolving genetic methods and technologies now permit systematic screening of the entire human genome as a strategy for the identification
of
susceptibility genes of small effect that influence risk to complex traits, such as coronary artery disease, obesity, schizophrenia, diabetes, inflammatory bowel disease and multiple sclerosis. Schizophrenia is a severe disorder in which the sufferer is no longer in touch with reality. It is characterized by the presence of two or more of the following on the basis of DSM-IV (American Psychiatric Association, 1992) criteria: delusions, hallucinations, disorganized speech, grossly
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Genetic basis of schizophrenia
disorganized or catatonic behavior and negative symptoms.
Twin and adoptive studies provide
convincing evidence of a major genetic contribution in the etiology of functional psychoses (Goodwin and Jamison, 1990; Freimer and Reus, 1993; Bertelsen et al., 1977; Pauls et al., 1995; Spence et al., 1995). Schizophrenia has a complex inheritance pattern. It falls into the category of complex genetic disorders which may be explicable in terms of the interaction of a small number of major genes (oligogenic model) or require minor involvement (polygenic model) and may also require additional environmental
of many genes
co-factors (multifactorial
model). In such disorders a threshold of liability is observed, beyond which the illness occurs (Gottesman and Shields, 1967).
2. Genetic Basis of SchizoDhrenia Recent investigations have made important advances in identifying specific susceptibility genes for several psychiatric and neuro-degenerative diseases. Family, twin and adoption studies over the past three decades have provided very strong evidence that both genes and environment play a role in the complex etiology of affective disorders (Gottesman, 1991; Kendler and Diehl, 1995; Ross, 1999). As already stated the evidence for a significant genetic contribution to functional psychosis (s&z and BPAD) is now well established.
Heritability, which is a measure of the
proportion of the etiology (at the population level) that is attributable to genetic factors, is estimated at 60-70% for schz, after influences of a common environment are taken into account (Rao et al., 1981; Mcgue et al., 1983; Grierson et al., 1999).
Rapidly evolving genetic
technologies have been applied in the genetic analysis of schz and several genomic regions have been posited as harboring susceptibility genes. Linkage studies, conducted predominantly in the developed western world, have observed a strong racial and sex bias in the genetic constitution of patients. Modem genetics has revealed several mechanisms that may give rise to complex patterns of inheritance and phenotypic variability. Two phenomena, namely, “imprinting” and “anticipation” may provide more insights into the genetic etiology of inherited diseases. Genomic imprinting refers to the differential expression of genes depending on whether the genetic material accrues from the paternal or maternal chromosome.
This has also been referred to as parent-of-origin
effect and is believed to depend upon and involve methylation of DNA. The term anticipation refers to the decrease in age of onset and/or increase in disease severity in successive generations. Schizophrenia displays both clinical “imprinting” and “anticipation” (McGuffln and Katz, 1989; McInnis et al., 1993; Imamura et al., 1998 and Heiden et al., 1999). Based on recent studies the phenomenon of anticipation has been related to expansions of GC-enriched trinucleotide repeat sequence mutations (Nylender et al., 1994 and Zivanovic and Borisev, 1999). These so-called
M. Vaswani and S. Kapur
1190
“dynamic mutations” explain a number of clinical epidemiological observations that cannot be accounted for by classical Mendelian genetics.
The term dynamic mutation has been introduced
to distinguish differences in the number of copies of DNA repeat sequences from other type of mutations (Hummerich and Lehrach, 1995). Repeats are either composites of perfect, with no variation in the base composition of the repeat motif, or imperfect repeats where there are some copies that vary from the canonical repeat motif (Richards and Sutherland, 1992).
3. Role of Molecular EDidemiology Several interrelated developments over the past three decades have influenced the field of human genetics. Advances in human genetic map, in genetic analysis linkage and association in complex inheritable traits, have led to increased understanding of role of genetics in several diseases. Testing
of every gene in the human genome for association with illness has been proposed by
Risch and Merikangas (1996). However, majority of the estimated 100,000 genes in the human genome are as yet not identified. Therefore, several investigators have attempted to identify the chromosomal location/s rather than individual genes. Incidence
of candidate genes and/or loci
are studied to identify susceptibility genes for various inheritable traits/diseases. through the identification
of “anonymous” genetic polymorphism
It is effected
(genetic markers) which
segregate along with the disease in question. The function of such genetic markers need not be known; it is only necessary that their chromosomal location be available. The identification of a marker that segregates with the disease in a family or in the population can thus provide key information about the likely location of the disease gene. Detection of an association implies that the marker gene itself is the disease gene or that an allele of the marker gene is in linkage disequilibrium with the disease gene mutation (Suraz and Hampe, 1994). Indeed for polygenic diseases, diseases which do not follow simple Mendelian pattern of inheritance, this seems to be the only available approach.
As molecular investigation methods advance, identification
of
disease susceptibility mutations and delineation of their roles may be expected.
4. DNA Instabilitv : ExDanded ReDeats or Dvnamic Mutations Until recently, DNA was thought to be a relatively stable molecule with new mutations arising infrequently and being inherited upon further transmission.
However, the last few years have
forced us to re-evaluate our ideas on the stability of DNA and association of de novo mutations and illness in an individual’s life time.
In recent years, a new mode of molecular mutation
responsible for inherited human diseases has come to light.
These have been referred to as
“dynamic mutations” and are constituted by repeat DNA sequences. At each dynamic-mutation
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Genetic basis of schizophrenia
locus there is a normal range of copy numbers above which the repeat becomes unstable, that is, copy number can be increased to a point where the repeat manifests in a disease and/or a fragile site.
Thus, the premutation alleles cause little or no disease in individuals, but give rise to
significantly amplified repeats in affected progeny.
When located within or near transcribed
sequences the expansion can have an effect on either the gene transcript or the gene product, which may manifest in disease (Richards and Sutherland, 1997). The expansion of trinucleotide repeat DNA sequences within the transcribed regions of genes has been demonstrated to be the underlying
genetic defect in several inherited neuro-degenerative
diseases viz: Fragile X
syndrome (FRAXA), Spinal and bulbal muscular dystrophy (SBMA), Myotonic dystrophy (DM), Huntington’s disease (HD), Spinocerbellar ataxia type I (SCA l), Fragile X E mental retardation (FRAXE), Familial
spastic paraparesis and Dentatorubral pallidoluysian
atrophy (DRPLA),
(Kremer et al., 1991; LaSpada et al., 1991; Campuzano et al., 1996; Yu et al., 1997; Lalioti et al., 1997; Zhuchenko et al., 1997; Richards and Sutherland, 1996; Benson et al., 1998; Margolis et al., 1999).
In all cases, a single trinucleotide, tandemly repeated DNA sequence exists in the
transcribed region of the gene.
These sequences are unstable and show an increase in size
between family members in successive generations, giving rise to a greater severity of the disorder. population.
The triplet repeat shows moderate levels of length variation within the normal However, in patient populations, the repeat expands well beyond the normal range,
altering the biological tunctioning of the gene. The unusual properties of triplet repeat DNA sequences account for the wide-ranging disease severity and complex non-mendelian inheritance pattern is observed.
At the time of writing the present review this number had already grown
from seven to sixteen (Richaards and Sutherland, 1997). It may also be noted that not all TRE’s are disease related.
Schalling et al., (1993) reported the occurrence of an expanded repeat on
chromosome 18 in unaffected individuals.
5. ExDanded Trinucleotide ReDeat. and Affective Disorders Several studies conducted in last few years have reported a correlation between trinucleotide repeat lengths and clinical observation of anticipation seen in different familial psychiatric disorders(Fischer,1998).
As already stated both schz and BPAD manifest clinical anticipation.
Indeed, expanded trinucleotide repeat sequences have emerged as a major risk factors in affective disorders.
The identification of TEES represents a preliminary step in an emerging pathway.
These are small effect genes, best detected with affected-relative-pair linkage methods. In a study conducted in Belgium, eighty-seven two-generation pairs of patients were analyzed for expanded trinucleotide repeats (Mendlewicz et al., 1997). Significant
changes in the age at onset and
M. Vaswani and S. Kapur
1192
episode frequency in successive generations were observed by the authors.
They report an
increase in the mean CAG repeat length between parental and offspring generations when the phenotype increased in severity of disease. In these subjects the phenotype changed from major depression, single episode or unipolar recurrent depression to BPAD.
A parent-of-origin effect
was also observed in the median length CAG between Gl and G2 with maternal inheritance. The female offspring seemed to be more affected suggesting a higher penetration of this trait in females.
Lindblad et al., (1995) also reported an association between CAG repeat length and
BPAD in Swedish and Belgian patients. Similar CTG/CAG expansion has also been reported by Sirugo et al., (1997) in Danish schizophrenia kindred. Knowles et al., (1998) in his study reviewed 1013 genotyped individuals in 53 unilineal multiplex pedigrees, but did not find any evidence for linkage between BPAD and chromosome 18 pericentromeric markers. In this study the authors did not report any parent to offspring effect either. Another report based on a Europeon-American sample collected from The Genetics Initiative of National Institute of Mental Health (NIMH) also found no region showing evidence of linkage.
However, they reported that two markers on
chromosome lop did show statistical evidence suggestive of linkage in cases of schizophrenia (Faraone et al., 1998). No TRE’s were reported in a study of Spanish families by Martorell et al. (1999). Similar results have also been reported in Chinese families (Li et al., 1998a), in monozygotic twins ( Vincent et al., 1998) and in French families (Laurent et al., 1998). However, studies on TREs
have shown an association of repeat length and adult-onset schizophrenia
(AOS). Childhood-onset schizophrenia (COS) is a severe variant of schizophrenia with onset of symptoms before age 12 years. Burgess et al., (1998) reported a significant association between CAG/CTG repeat length in male Caucasian samples. Some of these expanded alleles were found to correlate with CTG18.1 locus on chromosome 18. Vincent et al. (1999a) also concluded that the occurrence of an expanded trinucleotide repeat may contribute to the genetic risk of COS, in combination with other factors. The expanded CAG repeats lead to Polyglutamine expansion (PGE) in proteins. Recently,
Moriniere et al(1999) and Joober et al.( 1999a) identified PGE
affected protein in COS and in Schizophrenic patients.
These observations put together merit
large sample population and pedigree studies for the role played by TRE’s in Schizophrenia and BPAD patients.
5.1 TRE’s Associated with Saecitic Genes 5.1.1 The SEFZ1 gene and SEFZlB
genes: Breschel et al., (1997) recently reported a very
large, 800-2100 TRE of CTG in second intron of the SEFZ1 gene to be associated with BPAD affected individuals. tripartite distribution
The CTGn repeat at 18q21 .l is highly polymorphic. They further reported of CTG18.1 alleles with stable alleles (CTGlO-CTG37),
moderately
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Genetic basis of schizophrenia
enlarged and unstable alleles (CTG53-CTG250) and very enlarged unstable alleles (CTGIOOCTG2100).
Moderately enlarged alleles were not associated with an abnormal phenotype. It is
noteworthy that SEFZ1 gene has been reported to code for a helix-loop-helix protein. loop-helix proteins are known to be involved in transcriptional regulation.
Helix-
This motif of protein
structure, along with two other motifs, viz., leucine zipper and zinc finger, is often encountered in a class of DNA binding proteins named Transcription Factors (IFS).
Several cellular oncogenes
and suppressor genes function as TFs. TFs show a binding domain which binds the DNA, and several TFs are known to bind closely in a gene region, regulating in a positive or negative manner the expression of the gene. After binding of TF to DNA, the transcription rate of a gene can be increased. The binding of TF depends on several signals. Gene Expression is, thus, tightly regulated by TFs.
SEFZ-1 gene product, by virtue of having a helix-loop-helix motif, could
Rtnction as a TF.
Other examples of this class of proteins are c-myc, N-myc, L-myc, A4jvDJ , etc
which are all known to function as TFs. N-myc forms a heterodimer with Max protein, and together they bind to DNA.
Myo-D 1, the gene involved in rhabdomyo sarcoma, also codes for a
helix-loop-helix transcription factor and is predicted to play a role in the control of cell growth and differentiation.
Activation of TFs by gene mutation, deletion and amplification can lead to
the loss of control of TFs, resulting in a deregulation of cell growth and/or function. The reported expansion mutation in the SEFZ1 gene may alter the function of this gene product, However, as yet, almost nothing is known about the role and function of this protein in the normal brain and other tissues. Recently, Vincent et al., (1999b) reported no association of expanded CAG/CTG repeats at 18q21.1 (SEFZlB) with Schizophrenia. 5.1.2 Calcium Activated Potassium Channel Gene. KCNN3 OR hSKCa3: Another gene of interest is hSKCa3 gene (now known as KCNN3), which codes for a calcium-activated potassium channel.
Calcium-activated
potassium
channels
are fundamental
regulators
of neuronal
excitability, participating in inter-spike interval and spike-frequency adaptation. In a recent study on patients of BPAD and s&z, a significant difference in allele frequency distribution of this gene has been reported (Chandy et al., 1998). They found that the hSKCa3 gene contains two arrays of CAG trinucleotide repeats. The second CAG repeat in hSKCa3 is highly polymorphic in control individuals, with alleles rang~mg in size from 12-28 repeats. Strober et al. (1998) also reported similar findings.
Upon comparing the allelic frequency distribution between Schizophrenic
patients and ethnically matched controls, a significant excess of longer CAG repeats was observed in Schizophrenic patients in the caucasian population both from Europe and USA. Similar findings have been reported by Bowen et al., (1996 and 1998) in white population from UK and by Dror et al., (1999) in Israeli Ashkenazi jews. On the other hand, a study on 97 Chinese family trios with schizophrenia found no evidence for an excess of longer CAG repeats in the patients (Li et al., 1998b). The authors did report a deficit of transmission of the CAGZO repeat allele to affected offspring. Further in a study of 54 multiplex families, Antonarakis et al., (1999) found no differences in the distribution of (CAG)n alleles between
affected and normal individuals.
Several other studies have also reported no association and involvement of hSKCa3 gene in
M. Vaswani and S. Kapur
1194
schizophrenia (Meissner et al., 1999; Tsai et al., 1999; Wittekindt et al., 1999; Austin et al., 1999; and Joober et al., 1999b). However, recently Cardno et a1.,(1999) reported correlation of negative symptoms of schizophrenia with hSKCa3 gene and concluded that negative symptoms in schizophrenia may be partly mediated through the hSKCa3 gene. This gene needs to be further evaluated in other patient populations of BPAD and Schizophrenia. Sirugo et al., (1997) identified an expansion of a triplet repeat at
5.1.3 Other Genes:
chromosome1 8q2 1 in a Danish Schz kindred. This locus seems to be adjacent to the locus of the Transthyretin gene (TTR) which spans bands 18q12-q21, identified by TTR’s flanking markers D18S456-18S472 (Goodman, 1998). These markers have also been positively linked to a common locus for Schz in large kindreds from Quebec (Merette et al., 1997). Further studies on the role of TTR gene might prove productive in disclosing a mechanism involved in increasing vulnerability to schz. The gene for spino-cerebellar ataxia type1 (SCAI) is a potential candidate gene for schz due to positive linkage findings in this region(6p22-24). SCAl onset is also positively correlated with TRE-(CAG)n. Joo et al.,( 1999) reported increased frequency in one out of 13 alleles in patients of schizophrenia as compared to control subjects. Similarly, Breen et a1.,(1999) studied the expansion in a coding 3’ CAG repeat causing spino-cerbellar ataxia , but found no association with schz susceptibility. MAP2 expression has been reported to be altered in Schz and other neurological disorders. MAP2 gene also contains a region of trinucleotide repeat located in exon 1 of the 5’ untranslated region. However, analysis of this region by Kalcheva et al., (1999) showed no evidence of expansion in this gene in schizophrenic patients. Further studies are clearly warranted to delineate the role of TRE?s in the molecular etiology and pathophysiology of schizophrenia and bipolar affective disorders, 6. Conclusions As
an
outcome
polymorphism/s,
of
molecular
epidemiological
studies
targeting
it can be expected that a better understanding
physiology of human diseases will emerge.
population
of the underlying
genetic patho-
Results from studies done on neuro-psychiatric
patient population will throw more light on ascertaining the number of susceptibility loci, disease risk conferred by each locus and also help in developing new and safer mood altering agents. More importantly, a positive genetic marker can be envisaged to provide an immediate diagnostic tool for those select individuals, with known familial history and comprising the high risk group. Available diagnostic criteria for affective disorders are subjective clinical validity criteria. Genetically determined characterization of validity would no doubt be more precise, if specific
Genetic basis of schizophrenia genetic
1195
factors/targets could be identified. Population based genetic research would not only help
identify different subgroups of these diseases, but would also delineate ethnic differences and/or similarities in the genetic etiology.
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Inquiries and reprint requests should be addressed to:
Dr. Meera Vaswani Additional Professor Department of Psychiatry All India Institute of Medical Sciences (A.I.I.M.S.) New Delhi---l 10029 INDIA.