Neurobiology of Fragile X syndrome: From molecular genetics to neurobehavioral phenotype

Fragile X syndrome (FraX) is one the most common genetic disorders associated with mental retardation (Moser, 1995). Recent developments in FraX research have led to an increased interest in the neurobiology of this condition; several factors contribute to this focus on FraX: its relatively high frequency, its association with a single gene defect (the FMR1 gene), the molecular characterization of the FMR1 gene product (Fragile X Mental Retardation Protein or FMRP), an increasing knowledge about the (specific) FraX neurobehavioral phenotype, and the development of transgenic animal models of FMR1 and related genes. For all these reasons, FraX is considered as one of the best models for understanding how a genetic defect can lead to a severe behavioral and cognitive phenotype. This special issue, which includes a combination of topical reviews and original publications, intends to provide a broad perspective about how the discovery of FMR1 in 1991 (Verkerk et al., 1991) has resulted in an explosion of research on FraX that has evolved from molecular genetics to neurobiology. Although the genetics of FraX is not the subject of this issue, several important features should be noted. The mutation of the FMR1 gene occurs “in stages”; the expansion of a CGG polymorphism within the 5 untranslated region of the gene is linked to an obvious phenotype, due to the lack of FMRP, only when it reaches a certain magnitude (full mutation allele). This process of CGG expansion appears to be gradual, evolving from normal to premutation to full mutation over several generations (Kaufmann and Reiss, 1999). There is still controversy about the existence of a phenotype associated with intermediate level mutations (i.e., premutation) (Sherman, 2000; Tassone et al., 2000; Kenneson et al., 2001). Nonetheless, if all patterns of FMR1 mutation are taken into account, the condition affects as many as 1 in 25 subjects in the general population (Kenneson et al., 2001). FMR1 full mutation alleles are associated, in males, with severe reduction in FMRP levels (Kaufmann et al., 1999). This FMRP deficiency appears to be the most important factor determining the FraX phenotype. In this issue, Kaufmann and colleagues review the current knowledge about FMRP expression in human subjects, its possible molecular consequences, and provide novel data on the expression of other members of the family of RNA-binding proteins that includes FMRP. The next paper, by Feng, focuses on FMRP’s structure and function with emphasis on its potential role in neuronal development and function. As Kaufmann and collaborators point out, the existence of a phenotype secondary to FMRP deficit implies that other proteins, with similar structure and function (to FMRP), are not capable of compensating for the lack of FMRP. This issue, of critical importance for developing genetic therapeutic approaches for FraX, has led to a great interest in characterizing FMRP homologues: the Fragile X Related Proteins or FXRPs. Hoogeven and colleagues provide a comprehensive review of this group of proteins, including their molecular and functional analogies with FMRP, pattern of expression, and potential for gene therapy. In addition, the paper presents an overview of knockout and transgenic mice of relevance to FraX. The first section of this issue is completed by the paper by Churchill and collaborators, in which the role of FMRP in neuronal function is revisited with a focus on the contribution of the FMR1 knockout mouse to our understanding of the FraX neurobehavioral phenotype. The second section of this special issue includes four papers dealing with the neurologic phenotype of FraX. These papers cover major neuroanatomic, neurophysiologic, and behavioral aspects of the FraX phenotype, which in recent years have begun to be examined in light of the molecular and cell biological advances illustrated in the previous section. While our current knowledge on the neurobiology of other developmental disorders associated with mental retardation (i.e., Down syndrome) has been significantly influenced by postmortem brain studies, in the case of FraX limited data are available on the neuropathology and neurochemistry of the condition (Kaufmann and Moser, 2000). For this reason, quantitative neuroimaging in vivo studies of FraX subjects offer a unique window into the basic substrate of the FraX phenotype. Kates and colleagues summarize today’s knowledge about the neuroanatomy of FraX. In addition, this contribution includes original data on the early postnatal cerebral development of males with FraX. The results demonstrate that, despite common features with other developmental disorders, FraX is associated with unique cortical anomalies that, surprisingly, not only affect the gray matter but also the white matter. The next paper, by Hagerman and collaborators, presents novel data on the effect of stimulants on electrodermal responses in FraX subjects. This contribution represents an example of a relatively underdeveloped field of research in FraX, which includes neurophysiologic, neurochemical, and functional neuroimaging studies. The paper also enhances our understanding of pharmaco-