The C/At is out of the bag: a gene for mental illness
M-L Wong
1
3
troversial due to the difficulties
encountered in replication. To compli-
cate matters, schizophrenia has vari-
able clinical presentations, natural his-
tory, and response to medication that
The C/At is out of the bag: a gene
for mental illness
M-L Wong
implies
a
pathologically hetero-
geneous group of diseases. Therefore,
the assumption that schizophrenia
could be a syndrome, thus a collection
of several nosological entities, had
been lingering in the field, though
most investigators had not examined
this concept carefully enough to sys-
tematically study the genetics of dis-
ease subtypes. Ironically, soon after
experts have ascertained that the
recurrence risks of schizophrenia have
conclusively allowed the rejection of
the possibility that schizophrenia
could be caused by a single gene dis-
order or collection of single gene dis-
orders, even when taking into account
incomplete penetrance, we are con-
fronted with the surprising findings of
Meyer et al.
Laboratory of Pharmacogenomics, UCLA Neuropsychiatric Institute, Los Angeles, CA,
USA
Has the first ‘schizophrenia’ gene been
identified? The knowledge that genes
play a considerable role in the etiology
of schizophrenia is well recognized.
However, failures of consistent repli-
cation of any of the several chromo-
somal regions implicated in schizo-
Psychotic symptoms, such as halluci-
nations and paranoid delusions, are
notable for their aberrant represen-
tations of, and relation to the external
world. A core clinical manifestation
of schizophrenia is disruption of
thought, which is a mental process
that is poorly localized in the brain
and influenced by multiple neural sys-
tems. Recent studies suggest that
schizophrenia may involve cortical,
limbic, and subcortical structures as
well as multiple neurotransmitter sys-
tems. Lesch’s group has used Leonard’s
classification of schizophrenia, which
unlike the DSM (Diagnostic and Stat-
istical Manual of the American Psychi-
atric Association) classification of
schizophrenia, catatonia type, makes a
distinction between periodic and sys-
tematic catatonia based on different
types of symptoms, longitudinal
course and outcome.
phrenia
have
left
investigators
frustrated, especially in this last dec-
ade. It seems that now, signs for an era
of new definitions of nosological enti-
ties in psychiatry are appearing on the
horizon. With the recent work by
Meyer et al from Lesch’s group that
1
appeared in Molecular Psychiatry, the
1
In this recent report, Meyer et al
first C/At is out of the bag. What we
call schizophrenia appears to actually
be a syndromal definition encom-
passing various heterogenous diseases.
One of those diseases is a type of per-
iodic catatonia, which is a subform of
catatonic schizophrenia (MIM 181500,
OMIM , Online Mendelian inherit-
ance in Man, http://www.ncbi.nlm.
nih.gov/Omin). Periodical catatonia is
a heterologous, Mendelian dominant
disease with a major-gene effect and it
were looking for a trinucleotide repeat
when they discovered a mutation in a
novel gene encoding a protein, pro-
visionally named WKL1, which is
expressed highly in the amygdala, cau-
date nucleus, thalamus and hippocam-
pus, and detected exclusively in brain.
1
In one large pedigree, Meyer et al
Several twin and adoption studies
have provided clear evidence for a
considerable genetic contribution to
schizophrenia. Though the evidence
for shared environments has not been
convincing in the familial clustering
of the disorder, environmental risk
factors could still play a role in the dis-
ease. Among these environmental risk
factors obstetric complications and
viral infections have been the most
implicated ones. Decades of genetic
studies seem to indicate that schizo-
phrenia is a complex, non-Mendelian,
polygenic disease that involves epis-
tatic interactions between loci and
environmental influences. There has
been a worldwide search for the gen-
etic markers of schizophrenia. This
search has resulted in a long list of
implicated chromosomes (1,2,4,5,6,7,
8,9,10,13,15,18,22, and the X) thus far
(see Riley and McGuffin for a recent
have demonstrated that a 1121C → A
transversion occurred in all seven
affected individuals and all unaffected
obligate carriers. This transversion
results in a Leu309Met substitution.
But this mutation was not present in
three other pedigrees of periodic cata-
tonia, which further supports the
notion that periodic catatonia is gen-
etically heterogeneous. Their strategy
started with the examination of a well-
characterized cohort of periodic cata-
tonia, a clinical subtype of schizo-
phrenia in which a major gene effect
has been already predicted. A total of
12 large pedigrees with 135 individuals
were examined with a genome-wide
linkage scan that identified two sus-
ceptibility loci, the main one in chro-
mosome 15q15 and another locus on
has loci mapped at 22q13.33 and
2
1
5q15. In the recent report in Molecu-
lar Psychiatry, the results of a restricted
genome-wide linkage scan study fol-
lowed by positional gene approach on
periodic catatonia have resulted in the
finding of an association of a gene
encoding
a novel putative cation
channel in the 22q13 locus and per-
1
iodic catatonia.
Schizophrenia is possibly the most
severe, incapacitating and devastating
psychiatric disorder, with a lifetime
risk of 1% in the general population
and a peak onset in early adulthood.
The diagnosis of schizophrenia is cur-
rently made by criterion-based sys-
tems, including positive (eg, halluci-
nations and delusions) and negative
2
chromosome 22q13. The 22q13 locus
has been mainly supported by the
family that was further characterized
3
(eg, avolition and alogia) symptoms.
review ). These results have been con-
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