Increased expression of aphidicolin-induced common fragile sites in Tourette syndrome: The key to understand the genetics of comorbid phenotypes?

Abstract

In a comparison of 80 common aphidicolin‐induced fragile sites (FS) between 26 DSM‐IV Tourette syndrome (TS) and 24 control individuals, the mean of the summed break frequencies following mild aphidicolin pre‐treatment was significantly higher in TS individuals than in controls (P <0.001). Other breakpoints encountered during this study, i.e., random breaks, breaks corresponding to rare FS, and breakpoints recorded by others but not listed as common FS according to the Chromosome Coordinating Meeting [1992] were listed as category II breakpoints. By using the most significantly different mean FS breakage figures between TS and control individuals, further stepwise discriminant analysis allowed identification of TS individuals from only a few sites in both the common FS and category II breakpoint groups. Future research needs to focus on confirmation of altered common fragile site expression in association with behavioral variation, whether expression of certain discriminatory sites concurs with specific comorbid disorder expression; the nature of the molecular alterations at these FS and the implications of a genomic instability phenotype for the mapping of a primary TS gene or genes. © 1996 Wiley‐Liss, Inc.

Characterization of a conserved aphidicolin-sensitive common fragile site at human 4q22 and mouse 6C1: possible association with an inherited disease and cancer

“…Furuya et al (1989) described a CFS that accounts for 13.4% of the total BCG scored in human bone marrow cells of healthy persons at 4q21-25 (the most expressed in these cells). Recurrent BCG were also localized at 4q21 or 4q23 in other types of cells (Murano et al, 1989;Caporossi et al, 1995;Gericke et al, 1996;Simonic et al, 1997). In the mouse genome, no CFS was described at 6C1, but one analysis localized a relatively weak site at 6B3, the band directly adjacent to 6C1 (Elder and Robinson, 1989).…”

Peek-a-boo fragile site at 16d associated with Tourette syndrome, bipolar disorder, autistic disorder, and mental retardation

“…Gericke et al [1996] reported that the fra16D was one of the most common abnormalities in patients with TS. They found aphidicolin‐induced fra16D present in a substantial number of patients with TS.…”

“…Second, because the original blood samples that demonstrated the fragile sites were drawn at a point in four of our patient's illnesses when their behaviors were at peak severity, we wonder if there is a relationship between either the fragile site and severity of illness or the possibility of a threshold of illness severity that enables the cytogenetic expression of a fragile site. In general, fragile sites may be a cytogenetic expression of vulnerability of genomic sites to physiological or other environmental disturbance [Gericke et al, 1996]. Another hypothesis presented by Shabtai et al [1983] suggests the possibility of viral induction of this fragile site.…”

A Unifying Hypothesis for the Genome Dynamics Proposed to Underlie Neuropsychiatric Phenotypes

“…In 1995, our research group at the University of Pretoria reported a small set of CFSs that could reliably distinguish between Tourette and non-Tourette individuals [34], and in a subsequent publication in 1996 [35] we speculated whether associated (variably) expressed FS could underlie endophenotypes which would explain (a genetic basis for) comorbidity in NPDs. In an evo-devo view, in 1995, Gericke proposed that an 'anthropogenetic' view of behavioral alteration may assist with the elucidation of genetic changes underlying neurobehavioral variation [36].…”