ReviewNeuroanatomical, molecular genetic, and behavioral correlates of fragile X syndrome
Introduction
Fragile X syndrome (FXS) is the most common form of inherited mental retardation and developmental delay. The exact prevalence figures have not been firmly established, although estimates range between 1 in 4000 males and 1 in 8000 females to 1 in 1250 males and 1 in 2500 females (Turner et al., 1996, Warren and Nelson, 1994, Oostra et al., 1993). The causative mutation is a (CGG) expansion of the 5′-untranslated region of the X-linked fmr-1 gene, as first described by Verkerk et al. (1991). The expansion mutation leads to the hypermethylation of the promoter region and ensuing silencing of the gene, leading to a reduced expression of Fragile X Mental Retardation Protein (FMRP).
Fragile X syndrome is characterized by a constellation of clinical manifestations including mild to severe mental retardation, hyperactivity, and autism (Hatton et al., in press). Although fragile X children often display autistic features, there may be a qualitative difference in autistic behavior between children with fragile X and autism (Demark et al., 2003). At a cognitive level, FXS is associated with deficits in short-term memory (Loesch et al., 2004), visuo-spatial abilities (Crowe et al., 1990), and linguistic processing (Belser and Sudhalter, 2001). The physical phenotype comprises a broad forehead, large prominent ears, mitral valve prolapse, dermatoglyphic abnormalities, and macroorchidism in postpubescent males (Meryash et al., 1984). Behavioral characteristics include poor eye contact, hand flapping, tactile defensiveness, impulsivity, and aggression (Lachiewicz et al., 1994).
Autopsy studies on fragile X brain specimens and on fmr-1 KO mice reveal neuronal abnormalities in the neocortex. Among the more striking features are dendritic spines that have an immature morphology—i.e., thin, elongated, and lack the typical “mushroom shape” found in mature neurons (Comery et al., 1997, Irwin et al., 2001, Irwin et al., 2002, Rudelli et al., 1985, Wisniewski et al., 1991). Histological studies on brains from FXS individuals have revealed higher spine density along dendrites (Irwin et al., 2001),which is typical in the developing brain before synaptic elimination. These data suggest that FXS is associated with abnormalities in developmental maturation (Irwin et al., 2000). Although the exact function of FMRP remains elusive, it is known to bear several features common to RNA-binding proteins.
Over the past decade, there has been mounting evidence that the FMRP protein represses the translation of its target mRNAs (Adinolfi et al., 2003, Laggerbauer et al., 2001, Mazroui et al., 2002, Mazroui et al., 2003, Zalfa et al., 2003). This function in conjunction with its known presence in dendrites and dendritic spines suggests that FMRP may repress the local translation of mRNAs (Churchill et al., 2002). The reduced expression of FMRP, as occurs in FXS, may therefore lead to abnormally increased translation of proteins involved in neuronal maturation. The finding that spine elongation is a translation-dependent mechanism substantiates this theory (Vanderklish and Edelman, 2002, Vanderklish and Edelman, 2005).
The current focus on the role of FMRP in neuronal maturation makes it timely to assemble the extant information on how reduced expression of the fmr-1 gene leads to neuronal dysmorpholgy. The purpose of this review is to summarize the recent genetic, neuroanatomical, and behavioral studies of fragile X syndrome and to offer potential mechanisms to account for the pleiotropic phenotype of this disorder.
Section snippets
The genetics of fragile X syndrome
Until recently, little was known about the genetic determinants of fragile X syndrome. In 1969, Lubs (1969) described a specific chromosomal variant that segregated with mental retardation over three generations. The anomaly consisted of a constriction at the end of the long arm of chromosome X noticed in metaphase spreads from mentally retarded individuals. A subsequent study enabled the localization of the X-linked anomaly to Xq27.3 (Harrison et al., 1983) and the variant was then known as
Neuroanatomy of fragile X syndrome
In the normal population, fmr-1 mRNA and its associated protein are expressed in a broad range of tissues. Of particular importance is the finding of high fmr-1 expression in neurons of fetal and adult brains (Abitbol et al., 1993, Devys et al., 1993). A significant outcome of expression analysis studies is the finding that the anatomical regions where the fmr-1 gene is highly expressed are believed to be associated with the major phenotypic abnormalities in FXS. We review the link between
Overproduction and elimination: a question of balance
It is now well established that competition occurs among developing neurons whereby some synapses are eliminated and others are strengthened (Katz and Crowley, 2002, Shatz and Stryker, 1978). This maturation process involves the transition from small synapses with thin, long dendritic spines, to more bulbous synapses associated with shorter, “mushroom-shaped” dendritic spines (Fiala et al., 1998, Greenough and Chang, 1985, Harris, 1999, Holtmaat et al., 2005). The neuronal morphology of the FXS
Neuropsychological deficits in fragile X syndrome
It is now well established that fragile X syndrome is associated with spatial deficits, i.e., impairments in the processing of visual spatial information to discriminate and manipulate figures and objects, as well as attentional and inhibitory impairment. This section provides a review of these neuropsychological deficits associated with FXS.
Heterogeneous phenotype in fragile X syndrome
An effort to determine the role of the FMRP protein in normal cells is crucial to understanding the mechanisms that lead to fragile X syndrome. A particular challenge in this regard is associated with the wide discrepancy in the FXS phenotype. A number of recurring clinical traits found in FXS have led to the establishment of a “13-item checklist” (Hagerman et al., 1991). This checklist encompasses both physical and behavioral traits that are typically found in FXS patients. However, given the
Conclusion
A major finding from neuroanatomical studies of autopsy material is dendritic spine dysgenesis that arises in FXS. This finding has been extended to more recent studies of fmr-1 knockout mice. Dendritic dysmorphology, which is characterized by abnormally long and thin spines, suggests that FXS is associated with an incomplete neuronal maturation process. Although the role of the FMRP protein in this process remains elusive, it appears to be involved in synaptic protein synthesis. Recent studies
Acknowledgments
This work was supported by a research grant to A.C. from the Natural Sciences and Engineering Research Council of Canada (NSERC). The authors would like to thank Dr. Evan Balaban for valuable comments on an earlier version of this article.
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