29 December 2008. The neurexin1 gene (NRXN1) at 2p16.3 encodes a cell adhesion receptor that plays a role in brain development and synapse formation, and deletions of the gene have been implicated in autism and mental retardation. Earlier this year, the gene showed up twice in studies looking for rare mutations in schizophrenia patients. Those initial findings have now been followed up by the SGENE consortium. The work, published online in October in Human and Molecular Genetics from David Collier of King’s College, London, and colleagues, finds that deletions involving the coding regions of NRXN1 are significantly associated with schizophrenia in a large study involving nearly 3,000 patients and 30,000 controls. Those results are buttressed by another October report, this one by Roel A. Ophof of University Medical Centre Utrecht in the Netherlands, in the American Journal of Human Genetics, of four patients with disruption of the gene.
The accumulating data add up to the suggestion that deletions in NRXN1
amount to a genetic risk factor for schizophrenia. If true, the results suggest that autism and schizophrenia might share at least in part a common etiology, possibly involving misregulated synapse formation. Alternative interpretations include the ideas that NRXN1 deficiency causes an endophenotype common to both conditions, or that the genetic lesion affects brain development in a general way that manifests as a variety of different neurological disorders. (For more on this, see SRF related news story on the effects of CNVs in the 1q21.1 region, also linked to schizophrenia.) One thing is for sure—the new year will bring with it continuing interest in the role of NRXN1 in schizophrenia.
Focusing on the exons
The new work follows two reports from earlier this year, each of which found one case of copy number variation in NRXN1 in patients with schizophrenia (Kirov et al., 2008 and Walsh et al., 2008, and see SRF related news story).
For a larger study, first author Dan Rujescu of the Ludwig-Maximilians-University in Munich, Germany, and Andres Ingason of deCODE Genetics in Reykjavik, Iceland, and Copenhagen University, Denmark, looked at the NRXN1 gene in 2,977 schizophrenia patients and 33,746 controls from European populations. They found NRXN CNVs were more prevalent in patients, although they were also present in controls, occurring in 0.47 percent of affected subjects versus 0.15 percent of controls. However the difference was not statistically significant (p = 0.13). The investigators also checked the NRXN2 and NRXN3 genes, and found no disruptions.
Reasoning that deletions that were solely intronic might not affect protein expression or association of neurexins with their counter-receptors, known as neuroligins or neurexophilins, the researchers did a secondary analysis looking only at deletions that disrupted exons. These were also more prevalent in cases than controls (0.17 percent of cases vs. 0.020 percent of controls), and in this case, were significantly associated with schizophrenia (p = 0.0027).
From these results, the authors write, “It is tempting to speculate that the disruption of NRXN1/neurexophilins interactions that are likely seen in all our observed exonic deletions may explain some of the pathology of schizophrenia.”
The study in AJHG by co-first authors Terry Vrijenhoek of Radboud University Nijmegen Medical Centre and Jacobine E. Buizer-Voskamp of University Medical Centre Utrecht, both in the Netherlands, identified 13 rare CNVs in a discovery cohort of 54 patients. Closer examination pointed to four that disrupt genes: in addition to NRXN1, the researchers report rare CNV disruption of three other genes in their patient sample: MYT1L, CTNND2, and ASTN2, all coding for proteins involved in aspects of neurodevelopment or plasticity.
In the second phase of their study, Vrijenhoek and colleagues looked at these regions in a larger cohort of 752 patients with schizophrenia and 706 unaffected controls. Of the seven CNVs identified in these candidate regions in patients (compared to one CNV identified in the controls), three were in NRXN1.
Writing in a recent review in Schizophrenia Bulletin, author David St. Clair of the University of Aberdeen, Scotland opines, “Disruption of the Neurexin1 gene now looks like a definite high-impact genetic risk factor for schizophrenia as well as for other psychiatric phenotypes.”
Figuring out just how NRXN1 deletions exert their influence will not be easy. The gene is complex, with six splice sites that can generate on the order of a thousand isoforms, whose roles in synapse formation and axonal guidance are likely just as complex. Arguing for a general developmental effect are findings that a neurexin relative, the contactin-associated protein 2 (CNTNAP2), is also found to be disrupted in schizophrenia with other complications. That study (Friedman et al., 2008) identifies three patients with CNTNAP2 haploinsufficiency with schizophrenia and epilepsy; two also have mental retardation. Previously, a mutation in CNTNAP2 was found in Old Order Amish families, where it causes a syndrome of epilepsy, mental retardation, language regression, and other problems, but the work of Friedman is the first link to schizophrenia.
Genetic pry bars
At least part of CNTNAP2’s function has to do with language, a commonly affected domain in schizophrenia and autism. Work just published in the New England Journal of Medicine (Vernes et al., 2008) indicates that polymorphisms of the CNTNAP2 gene are associated with a common and highly heritable, specific speech impairment signified by the inability to repeat nonsense words. The same variants are associated with speech delays in autism, supporting the idea that developmental speech problems in different disorders may have a common genesis. It remains to be seen how deletions, rather than polymorphisms, might affect the speech endophenotype.
Of interest, the authors discovered the role of CNTNAP2 by studying a rare disorder of speech development caused by a mutation in the transcription factor FOXP2. The investigators identified CNTNAP2 as a FOXP2 target gene using biochemical techniques, and then followed up with single nucleotide polymorphism analysis to prove the gene’s role in a common speech impairment. In the work, they write, “We provide an example of how knowledge of a genetic cause of a rare single-gene disorder provides an entry point into the causes of a more complex phenotype.” Clearly, CNVs are not the magic key, but may be more like a genetic pry bar that can open a small crack in the door to understanding complex neuropsychiatric diseases.—Pat McCaffrey and Hakon Heimer.
Rujescu D, Ingason A, Cichon S, Pietiläinen OP, Barnes MR, Toulopoulou T, Picchioni M, Vassos E, Ettinger U, Bramon E, Murray R, Ruggeri M, Tosato S, Bonetto C, Steinberg S, Sigurdsson E, Sigmundsson T, Petursson H, Gylfason A, Olason PI, Hardarsson G, Jonsdottir GA, Gustafsson O, Fossdal R, Giegling I, Möller HJ, Hartmann A, Hoffmann P, Crombie C, Fraser G, Walker N, Lonnqvist J, Suvisaari J, Tuulio-Henriksson A, Andreassen OA, Djurovic S, Hansen T, Werge T, Melle I, Kiemeney LA, Franke B, Buizer-Voskamp JE, Ophoff RA; GROUP Investigators, Rietschel M, Nöthen MM, Stefansson K, Peltonen L, St Clair D, Stefansson H, Collier DA. Disruption of the neurexin 1 gene is associated with schizophrenia. Hum Mol Genet. 2008 Oct 22. Abstract
St Clair D. Copy number variation and schizophrenia. Schizophr Bull. 2009 Jan;35(1):9-12. Epub 2008 Nov 5. Abstract
Vernes SC, Newbury DF, Abrahams BS, Winchester L, Nicod J, Groszer M, Alarcón M, Oliver PL, Davies KE, Geschwind DH, Monaco AP, Fisher SE. A functional genetic link between distinct developmental language disorders. N Engl J Med. 2008 Nov 27;359(22):2337-45. Abstract