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Psychiatric CNV Hotspot Harbors Head Size Gene

25 May 2012. A single gene within a chromosomal region associated with autism, schizophrenia, and other brain disorders controls head size in zebrafish, according to a study published in Nature on 17 May. Led by Nicholas Katsanis at Duke University, Durham, North Carolina, the study fingers KCTD13, a relatively unknown gene lying within the 16p11.2 region implicated in head size in humans: duplications and deletions of this region are associated with microcephaly and macrocephaly, respectively. Whether autism or schizophrenia are also linked to KCTD13 is unclear, but the findings offer up a new genetic controller of brain development, which is thought to go awry in both disorders.

The study uses zebrafish to efficiently identify the dosage-sensitive genes among the 29 genes contained in the 16p11.2 locus. This region has been associated with a variety of phenotypes by copy number variants (CNVs): deletions of the 16p11.2 locus are associated with autism, obesity, and macrocephaly, whereas duplications are associated with both autism and schizophrenia, anorexia, and microcephaly. The “mirror phenotype” of head size gave the researchers a chance to explore the effects of each gene in the region on the anatomy of the experimentally amenable zebrafish, with only KCTD13 falling out as a controller of head size (see SRF conference report). Along with a recent flurry of imaging genetics studies of brain size in humans (see SRF related news story), the findings on head size might prove to be a useful intermediate phenotype through which more complex disorders may be understood (Meyer-Lindenberg and Weinberger, 2006).

Sliding scale
First author Christelle Golzio and colleagues began by injecting human transcripts of the different 16p11.2 genes into zebrafish embryos. Zebrafish have versions of all but five of these genes, making most of these injections overexpression experiments. Four days after injections, overexpression of only one—KCTD13—affected head size, giving a significantly smaller head than controls. The researchers then knocked down expression of the zebrafish version of KCTD13, and found a corresponding increase in head size compared to controls. This kind of sliding scale was not seen for body length, which argues that KCTD13 was not simply delaying or accelerating body development.

KCTD13 encodes a protein that interacts with proliferating cell nuclear antigen (PCNA), a protein that helps with DNA replication. This suggests that KCTD13 may be involved with neurogenesis, and consistent with this, the researchers found that KCTD13 was strongly expressed in the developing brain. When the researchers stained zebrafish embryos with markers for cell birth and death, they found that the microcephaly induced by KCTD13 overexpression was accompanied by decreased neural proliferation and increased cell death relative to controls, whereas the macrocephaly induced by KCTD13 downregulation came with only increases in proliferation. These shifts in proliferation and death were apparent even before the head size differences developed, which argues that an altered balance in cell birth and/or death drove the microcephaly and macrocephaly.

Moving into mammals
In mice, KCTD13 is expressed during development in cortex, striatum, hippocampus, and the olfactory tubercle. To test whether downregulation of KCTD13 in mice could recapitulate the increased head size found in zebrafish, the researchers designed short hairpin RNAs (shRNAs) against the mouse version of KCTD13 and injected them into the ventricular space of developing brains in mouse embryos. Two days later, they found a twofold increase in newborn cells compared to controls, consistent with a similar relationship between KCTD13 expression and head size; an overexpression experiment was not reported.

As for humans, the researchers noted a report last year of a smaller than usual deletion within the 16p11.2 locus (118 kb versus the usual 600 kb) that included only five genes, including KCTD13; three members of the family carrying this deletion also had autism (Crepel et al., 2011). In the new study, Katsanis’ team screened this restricted region in 518 people with autism and 8328 controls. This turned up a KCTD13-specific deletion in an exon in one case of autism. The person also harbored another CNV nearby, however, obscuring a potential link between KCTD13 and autism.

The KCTD13 findings don’t preclude a role for other genes in head size—indeed, the researchers reported that combinations of KCTD13 and other 16p11.2 gene transcripts (either MAPK3 or MVP) enhanced microcephaly in zebrafish. Still, the study illustrates how this approach can offer a fast track to function for the many, many genes implicated by CNVs in psychiatric disorders. People carrying these CNVs often come with physical anomalies, which can seem secondary to their psychiatric diagnoses. But these anatomical features might be key clues to understanding the fine grain of a CNV, and potentially, more complex disorders like schizophrenia.—Michele Solis.

Reference:
Golzio C, Willer J, Talkowski ME, Oh EC, Taniguchi Y, Jacquemont S, Reymond A, Sun M, Sawa A, Gusella JF, Kamiya A, Beckmann JS, Katsanis N. KCTD13 is a major driver of mirrored neuroanatomical phenotypes of the 16p11.2 copy number variant. Nature. 2012 May 16;485(7398):363-7. Abstract

Comments on Related News


Related News: Altered Gene Expression Prioritizes CNVs in Autism

Comment by:  Karoly Mirnics, SRF Advisor
Submitted 16 July 2012
Posted 16 July 2012

This is another excellent genomics study from the Geschwind laboratory, challenging us to think in the context of gene networks (rather than single genes). We always knew that genome deletion, duplications, and mutations will have an effect on development and cellular function only if they ultimately affect gene expression, but rarely has this been proven so eloquently as in this study. Knowing a genetic alteration is not sufficient—the consequences are what matter—and establishing the relevance/causality of mutations and CNVs vis-à-vis a disease process is quite challenging. Combining genetics and genomics can help to achieve this, especially if the expression studies can be performed on peripheral tissues from living patients. Still, even this approach has limitations: the brain has a very different expression profile from peripheral tissues—and the real effect of altered genetic sequence cannot be evaluated if a gene is uniquely expressed in the brain. Furthermore, we know that in schizophrenia, expression events in the periphery and the CNS are only marginally overlapping, and a number of neurotransmitters and phenotype-specific functional proteins are not expressed outside of the brain. In these cases, inhibitory postsynaptic currents (IPSCs) might be very beneficial to study the cause-effect relationship and in evaluating the significance of the genetic alterations. However, the approach of the Geschwind lab is perfectly suited for evaluation of multifunctional, generic developmental gene networks, where the genes are expressed and play a similar role across various tissues. It is also important to expand these studies to many patients across a variety of human brain disorders; otherwise, due to the staggering number of genetic variations, we might not be able to recognize the common patterns that are essential for understanding mental disorders.

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Related News: Protection From Schizophrenia—Too Much 22q11.2 Is a Good Thing

Comment by:  Bernard Crespi
Submitted 27 November 2013
Posted 27 November 2013
  I recommend the Primary Papers

Reciprocal CNVs at 22q11.2: New Insights Into Protection Versus Risk for Neurodevelopmental Disorders

The discovery of factors that protect against schizophrenia has immediate and important implications for prevention and treatment of this condition, as well as providing useful insights into the relationship of schizophrenia with other disorders. The recent finding that duplications of the 22q11.2 chromosome region protect against schizophrenia (Rees et al., 2013) provides an outstanding case in point, because the reciprocal deletion of this region represents one of the most highly penetrant and well-documented causes of schizophrenia uncovered to date. Of particular interest with regard to deletions and duplications of 22q11.2 is that, whereas deletions are strongly associated with schizophrenia risk, duplications of 22q11.2 not only protect against schizophrenia, but also increase risk for autism (Crespi et al., 2010; Sanders et al., 2011; Crespi and Crofts, 2012; Rees et al., 2013).

Comparable findings have been reported for 16p11.2: Whereas a 0.6 Mb deletion in this chromosomal region is strongly associated with risk of autism (Sanders et al., 2011), the reciprocal duplication is strongly associated with risk of schizophrenia (McCarthy et al., 2009). For both of these loci, the schizophrenia-associated CNV has also been linked with ASD, but these findings remain controversial because relatively severe premorbidity to schizophrenia may present as ASD in childhood, such that these autism spectrum diagnoses could represent false positives (Eliez, 2007; Crespi et al., 2010; Crespi and Crofts, 2012; Angkustsiri et al., 2013; Karayiorgou, 2013).

Why, then, should reciprocal CNVs predispose to autism on one hand, but schizophrenia on the other? Why should an autism risk factor protect against schizophrenia? And most importantly, how can these findings help to guide future research on these conditions?

The simplest explanation for why autism and schizophrenia may be mediated by reciprocal CNVs is that they represent, in some sense, "reciprocal" or "diametric" disorders (Crespi and Badcock, 2008). The idea of diametric disorders is novel to psychiatry, but it represents a straightforward application of the concept that biological systems may generally be perturbed in two opposite directions, towards, for example, lower versus higher levels of some gene product, lower versus higher activation of some pathway, or smaller versus larger size for a given structure. Here, the "system" is neurological and social-behavioral development. In this context, autism involves, in part, underdeveloped social cognition and behavior (Lai et al., 2013). By contrast, schizophrenia, and related psychotic-affective conditions, involve, in part, "hyper-developed" social cognition and behavior, expressed in such exaggerated social phenotypes as paranoia, auditory hallucinations, mania, megalomania, high levels of guilt and shame, and dysregulated, chaotic speech and language (Frith, 2004; Crespi and Badcock, 2008).

This diametric model will remain overly simplistic, and contentious, until its neurodevelopmental basis has been better elucidated and evaluated. However, it provides a straightforward hypothesis that, on face value, provides the clearest account to date for the observed psychiatric effects of these reciprocal CNVs. Directly comparable reciprocal risk and protective factors have also been reported for X chromosome dosage effects: Klinefelter syndrome (usually XXY) involves increased risk of schizophrenia and schizotypy (DeLisi et al., 2005; van Rijn et al., 2006), but Turner syndrome (XO) involves increased risk of autism but decreased risk of schizophrenia and bipolar disorder (Mors et al., 2001; Knickmeyer and Davenport, 2011).

The primary usefulness of the diametric model for autism spectrum and psychotic-affective conditions is that it makes novel, specific, and testable predictions regarding causes, protective factors, and potential therapies for both autism and schizophrenia. Such predictions are valuable because they allow for reciprocal illumination of the causes, correlates, and treatments of both sets of disorders, whose study has proceeded virtually independently for many decades.

Consider as examples:

1. Prenatal valproate represents a well-validated model for autism (Rinaldi et al., 2007), but in adulthood valproate serves as a therapeutic treatment for some psychotic-affective conditions (Haddad et al., 2009).

2. One of the best validated factors protecting against schizophrenia is congenital blindness (Landgraf and Osterheider, 2013; Silverstein et al., 2012); by contrast, congenital blindness represents a well-studied risk factor for autism (Hobson and Bishop, 2003).

3. mGluR5 antagonists represent one of the most promising new treatments for the autistic syndrome fragile X (Gürkan and Hagerman, 2012; Pop et al., 2013); by contrast, quite independently, mGluR5 agonists are under development and trials as treatment for schizophrenia (Lindsley and Stauffer, 2013).

4. Agonists of nicotinic acetylcholine receptors, the receptors that individuals with schizophrenia self-stimulate via their extraordinarily high rates of cigarette smoking (Mobascher and Winterer, 2008), are being developed and tested for schizophrenia (Deutsch et al., 2013). Again quite independently, antagonists of the same receptor have been proposed as therapeutic agents for autism, based on a variety of evidence including low rates of smoking in autism (Lippiello, 2006).

5. Deletions of the SHANK3 gene represent a strong risk factor for autism (Betancur and Buxbaum, 2013), but duplications of this gene are associated with schizophrenia (Crespi et al., 2010), and SHANK3 overexpression causes mania-like behavior in mice (Han et al., 2013).

With regard to CNVs at 22q11.2, and protection from schizophrenia in individuals with duplications, it is of notable interest that 1) selective prefrontal overexpression of COMT, a key 22q11.2-region gene, rescues schizophrenia-like symptoms in a mouse model of deletion of 22q11.2 (Kimoto et al., 2012), and 2) an allele linked to low COMT expression is associated with psychosis among individuals with 22q11.2 deletions (Gothelf et al., 2013). If higher COMT expression protects against schizophrenia, might it also represent a risk factor for autism? In turn, might therapies that reduce COMT expression or effects help to alleviate symptoms of autism?

Testing the diametric model, in comparison to models that posit overlap between schizophrenia and autism, requires strong inference tests of alternative predictions. Such tests must also carefully take into account possible confounding of autism spectrum disorder with childhood premorbidity to schizophrenia (especially for relatively penetrant risk factors) and confounding of autistic social deficits with negative symptoms of schizophrenia that are superficially but not causally similar.

Most importantly, joint, integrated study of autism and schizophrenia should generate new insights into both sets of conditions, including factors that increase risk as well as the remarkable ones that protect.

References

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View all comments by Bernard Crespi