We wished to determine the specificity of smooth-pursuit eye tracking dysfunction to schizophrenia and the prevalences of dysfunction among functionally psychotic and normal individuals. Therefore, we investigated pursuit tracking in a large sample of psychotic patients, normal subjects, and first-degree relatives (N = 482). Patients were recruited as part of an epidemiological study of first-episode psychosis that used a broadly based referral network to identify all cases in a major metropolitan area over a 2'/2-year period. Patients received diagnoses of schizophrenia, schizophreniform disorder, psychotic mood disorder, and paranoid or other psychotic disorder based on the third edition of the Diagnostic and Statistical Manual of 'Mental Disorders (American Psychiatric Association, 1980). The distribution of tracking performance was bimodal for the schizophrenic patients and their relatives, perhaps reflecting major gene action. Moreover, poor tracking ran in families. Pursuit tracking dysfunction was relatively specific to schizophrenic patients and their relatives and occurred infrequently in other psychotic patients and normal subjects.In many independent investigations an association between smooth-pursuit eye tracking impairment and schizophrenia has been documented (for recent reviews, see lacono, 1988). First-degree relatives of schizophrenic individuals, including their twins, are also likely to show oculomotor dysfunction (Holzman et al, 1988;Matthysse, Holzman, & Lange, 1986). Some have speculated that deviant pursuit oculomotion is a psychophysiological marker of genetic predisposition to schizophrenia, and a genetic model has been advanced to account for some family data (Holzman et al., 1988). Holzman et al. (1988) and Matthysse et al. (1986) have posited that almost all cases of schizophrenia can be accounted for by a latent trait governed by a dominant gene. The expression of the gene is hypothesized to be pleiotropic, with carriers manifesting schizophrenia, dysfunctional pursuit tracking, or both traits.

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BackgroundThe human 90-kDa heat shock protein (HSP90) functions as a dimeric molecular chaperone. HSP90 identified on the cell surface has been found to play a crucial role in cancer invasion and metastasis, and has become a validated anti-cancer target for drug development. It has been shown to self-assemble into oligomers upon heat shock or divalent cations treatment, but the functional role of the oligomeric states in the chaperone cycle is not fully understood.Principal FindingsHere we report the crystal structure of a truncated HSP90 that contains the middle segment and the carboxy-terminal domain, termed MC-HSP90. The structure reveals an architecture with triangular bipyramid geometry, in which the building block of the hexameric assembly is a dimer. In solution, MC-HSP90 exists in three major oligomer states, namely dimer, tetramer and hexamer, which were elucidated by size exclusion chromatography and analytical ultracentrifugation. The newly discovered HSP90 isoform HSP90N that lacks the N-terminal ATPase domain also exhibited similar oligomerization states as did MC-HSP90.ConclusionsWhile lacking the ATPase domain, both MC-HSP90 and HSP90N can self-assemble into a hexameric structure, spontaneously. The crystal structure of MC-HSP90 reveals that, in addition to the C-terminal dimerization domain, the residue W320 in the M domain plays a critical role in its oligomerization. This study not only demonstrates how the human MC-HSP90 forms a hexamer, but also justifies the similar formation of HSP90N by using 3D modeling analysis.

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