Understanding the biological underpinnings of fragile X syndrome Pietro Chiurazzi a , Giovanni Neri a and Ben A. Oostra b Purpose of review The purpose of this review is to present the latest findings on fragile X syndrome and to put them into perspective. Fragile X syndrome is a relatively common form of inherited mental retardation, caused by loss of function of the FMR1 gene on the long arm of the X chromosome. The molecular mechanisms underlying the syndrome are complex and continue to surprise researchers more than 12 years after the cloning of the gene. Recent findings We will specifically discuss the various aspects of the clinical phenotype, reassessed with the employment of functional imaging and electrophysiological techniques. The unexpected finding of a pathologic phenotype in premutation carriers is highlighted, as it represents a new and distinct condition with a different presentation in males and females. The third section deals briefly with the various functions of the FMRP protein, an RNA-binding protein interacting with multiple RNA molecules as well as proteins. It is important to realize that FMRP is probably changing partners several times, depending on its localization, on posttranslational modifications and on the available interacting proteins. In the following section, we present in short recent discoveries on the defective neuronal circuits in the fragile X syndrome. Most of these new data were made available by the study of animal models, mostly the Fmr1 knockout mouse, but also Drosophila. Summary We briefly discuss the alternative options for treating fragile X syndrome. Presently, a neuropharmacological approach acting on either critical receptors or aimed at reactivating the silenced FMR1 gene appears promising. Keywords fragile X syndrome, mental retardation, translational repression, synaptogenesis, neuronal plasticity Curr Opin Pediatr 15:559–566. © 2003 Lippincott Williams & Wilkins. Introduction In the past 2 years, several advances have been made in the understanding of fragile X syndrome, a heritable form of mental retardation caused by mutation of the X-linked FMR1 gene [1]. The characteristics of FMRP, the protein encoded by FMR1, and of its related FXR proteins are gradually being revealed [2,3]. FMRP inter- acts with multiple RNA molecules and proteins at the same time [4,5], while shuttling between the nucleus and the cytoplasm. In neurons, the cells in which FMR1 is expressed at the highest level, FMRP reaches post- synaptic terminations in the dendrites by active trans- portation as part of a ribonucleoprotein complex (mRNP), bound to a kinesin motor and following cyto- skeletal microtubules and actin filaments [5]. At the syn- apse, FMRP acts as a negative regulator of translation [6,7], possibly switching between active and inactive statesdependingonitsphosphorylation[8•],onitsbind- ing partners, and on the activation of specific receptors [9].TheabsenceofFMRPinfragileXpatientsaswellas in animal models causes both functional and morpho- logic changes of synapses [9,10]. In Drosophila, an indi- rect connection has been found between FMRP and Rac1 GTPase via the interacting protein CYFIP [11], linking FMRP to a molecular pathway crucial for cyto- skeleton remodeling [12]. However, the most surprising recent finding has been the discovery of a distinct phenotype in male carriers of a premutation: these intellectually normal individuals have increased FMR1 mRNA levels and may develop tremor, ataxia, and dementia with aging [13], usually ac- companied by extensive brain atrophy. In fact, this neu- rodegenerative condition, the fragile X premutation tremor/ataxia syndrome (FXTAS), is entirely distinct from fragile X syndrome, and its cause appears to be the accumulation of premutated FMR1 mRNA molecules rather than their absence. Clinical aspects, behavior, and diagnostics Fragile X syndrome is clinically characterized by a long and relatively narrow face, large protruding ears, mac- roorchidism, and joint hyperlaxity. A recent report has statistically compared physical measurements of patients and unaffected members of their families in a large set fromAustraliaandtheUnitedStates[14],confirmingthe significance of the above-mentioned anomalies and documenting also a decreased body height and limb length. The authors of this report suggest that a possible a Institute of Medical Genetics, Catholic University, Rome, Italy; and b Department of Clinical Genetics, Erasmus University, Rotterdam, The Netherlands Correspondence to Ben A. Oostra, PhD, Department of Clinical Genetics, Erasmus University, PO Box 1738, Rotterdam, 3000 DR, The Netherlands E-mail: b.oostra@erasmusmc.nl Current Opinion in Pediatrics 2003, 15:559–566 Abbreviations FXTAS fragile X premutation tremor/ataxia syndrome KO knockout POF premature ovarian failure © 2003 Lippincott Williams & Wilkins 1040-8703 559