A balanced (1;11)(q42.1;q14.3) translocation segregates with schizophrenia and related psychiatric disorders in a large Scottish family (maximum LOD = 6.0). We hypothesize that the translocation is the causative event and that it directly disrupts gene function. We previously reported a dearth of genes in the breakpoint region of chromosome 11 and it is therefore unlikely that the expression of any genes on this chromosome has been affected by the translocation. By contrast, the corresponding region on chromosome 1 is gene dense and, not one, but two novel genes are directly disrupted by the translocation. These genes have been provisionally named Disrupted-In-Schizophrenia 1 and 2 ( DISC1 and DISC2 ). DISC1 encodes a large protein with no significant sequence homology to other known proteins. It is predicted to consist of a globular N-terminal domain(s) and helical C-terminal domain which has the potential to form a coiled-coil by interaction with another, as yet, unidentified protein(s). Similar structures are thought to be present in a variety of unrelated proteins that are known to function in the nervous system. The putative structure of the protein encoded by DISC1 is therefore compatible with a role in the nervous system. DISC2 apparently specifies a non-coding RNA molecule that is antisense to DISC1, an arrangement that has been observed at other loci where it is thought that the antisense RNA is involved in regulating expression of the sense gene. Altogether, these observations indicate that DISC1 and DISC2 should be considered formal candidate genes for susceptibility to psychiatric illness.

Amyotrophic lateral sclerosis 2 (ALS2) is an autosomal recessive form of juvenile ALS and has been mapped to human chromosome 2q33. Here we report the identification of two independent deletion mutations linked to ALS2 in the coding exons of the new gene ALS2. These deletion mutations result in frameshifts that generate premature stop codons. ALS2 is expressed in various tissues and cells, including neurons throughout the brain and spinal cord, and encodes a protein containing multiple domains that have homology to RanGEF as well as RhoGEF. Deletion mutations are predicted to cause a loss of protein function, providing strong evidence that ALS2 is the causative gene underlying this form of ALS.

We have serendipitously established a mouse that expresses an N-terminal human huntingtin (htt) fragment with an expanded polyglutamine repeat (Ϸ120) under the control of the endogenous human promoter (shortstop). Frequent and widespread htt inclusions occur early in shortstop mice. Despite these inclusions, shortstop mice display no clinical evidence of neuronal dysfunction and no neuronal degeneration as determined by brain weight, striatal volume, and striatal neuronal count. These results indicate that htt inclusions are not pathogenic in vivo. In contrast, the full-length yeast artificial chromosome (YAC) 128 model with the identical polyglutamine length and same level of transgenic protein expression as the shortstop demonstrates significant neuronal dysfunction and loss. In contrast to the YAC128 mouse, which demonstrates enhanced susceptibility to excitotoxic death, the shortstop mouse is protected from excitotoxicity, providing in vivo evidence suggesting that neurodegeneration in Huntington disease is mediated by excitotoxic mechanisms.Huntington disease ͉ mouse models ͉ excitotoxicity ͉ aggregates ͉ fragment H untingtin (htt), the protein product encoded by the gene mutated in Huntington disease (HD), forms aggregates and inclusion bodies in the presence of a pathogenic expanded polyglutamine (polyQ) repeat. Htt protein inclusions are a hallmark of HD and are present in brains of human patients (1), in HD mouse models (2, 3), and in cell culture models of HD (4). It is still controversial whether htt inclusions are pathogenic (2), benign biomarkers (5), or neuroprotective (4, 6). The distinction between these hypotheses is clinically relevant, because much therapeutic research has focused on screening compounds for their ability to inhibit inclusion formation (7,8). A decrease in inclusion formation has been interpreted as a positive outcome in preclinical therapeutic trials with mouse models (9, 10).Increasing evidence in vitro in cell culture models supports the hypothesis that htt inclusions are not pathogenic (5, 11). In a recent study, Arrasate et al. (4) discovered that in their cell culture system, neurons with inclusions had an increased likelihood of survival compared with neurons without inclusions. However, because these results were obtained in a cell culture system, the question of whether htt inclusions are toxic in vivo during the lifespan of an organism and therefore clinically relevant for patients with HD remains unanswered.Examinations of inclusions in brains from HD patients are limited due to the inability to sample inclusions over the natural history of the disease, and, therefore, studies of mouse models of HD can be useful in determining the role of htt inclusions in vivo. The yeast artificial chromosome (YAC) 128 model of HD, which expresses full-length mutant htt, forms intranuclear inclusions 12 months after the onset of behavioral changes measured by rotarod and 6 months after striatal neuronal degeneration (3).During the development of the full-length YAC mouse models, a m...