Disease relevance of Fragile X Syndrome

• The fragile site at Xq27 (FRAXA) is associated with a common form of X-linked mental retardation (Martin-Bell syndrome) [1].
• This indicates that the behavior of the CAG repeat is similar to that observed for small premutations in the fragile X syndrome, or small abnormal alleles in myotonic dystrophy, two diseases which are caused by expansion of an unstable trinucleotide repeat [2].
• In addition, the striking similarity between findings at the DNA level in DM and those in fragile X syndrome and spinal and bulbar muscular atrophy suggests that the mechanism leading to the increase in copy number of trinucleotide repeats at particular loci may be responsible for a number of other genetic diseases [3].
• The influence of nucleotide excision repair (NER), the principal in vivo repair system for DNA damages, was investigated in Escherichia coli with uvrA, uvrB and uvrAuvrB mutants with the triplet repeat sequences (TRS) involved in myotonic dystrophy, the fragile X syndrome and Friedreich's ataxia [4].
• In Family 1, a 19-year-old male had facial features consistent with fragile X syndrome; however, his profound mental and growth retardation, small testes, and lover limb skeletal defects and contractures demonstrated a more severe phenotype, suggestive of a contiguous gene syndrome [5].

Psychiatry related information on Fragile X Syndrome

• The Fragile X syndrome, which results from the absence of functional FMRP protein, is the most common heritable form of mental retardation [6].
• As a test of this theory, McBride et al. show that in a Drosophila model for Fragile X syndrome, treatment with mGluR antagonists can rescue short-term memory, courtship, and mushroom body defects [7].
• OBJECTIVE: Over the past 3 years, reports of DNA alteration in myotonic dystrophy, fragile X syndrome (types A and E), Kennedy's disease, Huntington's disease, spinocerebellar ataxia type 1, and dentatorubral-pallidoluysian atrophy have identified a new class of human mutation, referred to as trinucleotide repeat amplification [8].
• Effects of long-acting propranolol on agonistic and stereotyped behaviors in a man with pervasive developmental disorder and fragile X syndrome: a double-blind, placebo-controlled study [9].
• Anxiety, shyness, and difficulty understanding social cues have been reported for females with Turner syndrome; whereas social withdrawal, avoidance of social interactions, and anxiety are often reported for females with fragile X syndrome [10].

High impact information on Fragile X Syndrome

• We show that Brm and MeCP2 assembly on chromatin occurs on methylated genes in cancer and the gene FMR1 in fragile X syndrome [11].
• Sequence-specific RNA binding by a Nova KH domain: implications for paraneoplastic disease and the fragile X syndrome [12].
• Acetylated histones are associated with FMR1 in normal but not fragile X-syndrome cells [13].
• Fragile X syndrome results from the expansion of the CGG repeat in the FMR1 gene [14].
• Deletions of FMR1 and flanking sequence (some of substantial size) have been reported in patients with phenotypes consistent with a diagnosis of fragile X-syndrome, however, none is strictly intragenic [15].

Chemical compound and disease context of Fragile X Syndrome

• Dilantin and the fragile X syndrome [16].
• The routine use of folic acid in patients with established mental retardation and the fragile X syndrome is not indicated [17].
• Insofar as folate content and distribution reflect a primary abnormality of folate metabolism, there appears to be no such abnormality in the fragile X syndrome [18].
• Fragile X syndrome: search for phenotypic manifestations at loci for hypoxanthine phosphoribosyltransferase and glucose-6-phosphate dehydrogenase [19].
• Cyclic AMP metabolism in fragile X syndrome [20].

Biological context of Fragile X Syndrome

• Methylation of the expanded repeats correlates with down-regulation of transcription of FMR1; thus fragile X syndrome is postulated to be due to a loss of function of the FMR1 gene product, and this has been demonstrated at the protein level [15].
• Recent advances in the identification of the mRNA ligands that are bound by FMRP, the RNA sequence and structure required for FMRP-RNA interaction, and the physiological consequences of FMRP deficiency in the brain are important steps towards understanding the molecular pathogenesis of fragile X syndrome, and learning and memory in general [21].
• An n-allele model is developed for the FMR1 locus, which causes the fragile X syndrome, where n is the number of triplet repeats in the first exon [22].
• 3. The cytogenetic expression of FRAXE is thought to be associated with mental handicap, but this is usually mild compared to that of the more common fragile X syndrome that is associated with the expression of the FRAXA fragile site [23].
• These data support the nonpenetrant status of premutation carriers of fragile X syndrome and suggest that the occasional case reports to the contrary may reflect either other causes, including low-level mosaicism for larger, methylated FMR1 alleles, or simply coincidence [24].

Anatomical context of Fragile X Syndrome

• To study the involvement of the FMR-1 gene in the fragile X syndrome, its expression was studied in lymphoblastoid cell lines and leukocytes derived from patients and normal controls [25].
• The analysis of a lymphoblastoid cell line (5106), derived from a rare individual of normal intelligence with an unmethylated full mutation of the FMR1 gene, allowed us to reconstruct the chain of molecular events leading to the FMR1 inactivation and to fragile X syndrome [26].
• The purpose of the present work is to test the effect of butyrate and of the acetylating compound acetyl-L-carnitine on the expression of fra(X)(q27.3) by treating peripheral lymphocytes of fragile X syndrome patients with these substances in vitro [27].
• Effects of Fragile X syndrome and an FMR1 knockout mouse model on forebrain neuronal cell biology [28].
• RESULTS: The cultured fragile X cells displayed many of the characteristics of neural progenitor cells, including nestin and CD133 expression, as well as the biochemical hallmarks of fragile X syndrome, including CGG repeat expansion and a lack of FMRP expression [29].

Gene context of Fragile X Syndrome

• Our data indicate that the frequency of SLC6A8 mutations in the XLMR population is close to that of CGG expansions in FMR1, the gene responsible for fragile-X syndrome [30].
• The expression of FRAXA is associated with the fragile X syndrome, the most prevalent form of inherited mental retardation whilst the expression of FRAXE is associated with a rarer and comparatively milder form of mental handicap [31].
• Sensorimotor gating abnormalities in young males with fragile X syndrome and Fmr1-knockout mice [32].
• A further two families had consistent expression of a different folate sensitive fragile site, FRAXE, close to FRAXA but not associated with fragile X syndrome and not detectable with the pfxa3 probe [33].
• Thus, a dominant negative effect of abnormal multimeric protein complexes lacking FMRP (e.g. by modification of FXR1 and FXR2 protein functions) may result in the fragile X syndrome phenotype [34].

Analytical, diagnostic and therapeutic context of Fragile X Syndrome

• Identification of the FMR1 gene and the repeat-amplification mechanism causing fragile X syndrome led to development of reliable DNA-based diagnostic methods, including Southern blot hybridization and PCR [35].
• An animal model for fragile X syndrome has been generated, which can be used to study the clinical and biochemical abnormalities caused by absence of FMR1 protein product [36].
• Evaluation of the fragile X (FRAXA) syndrome with methylation-sensitive PCR [37].
• Spatial performance in a group of young Fragile-X syndrome females with FMR-1 full mutation was compared to two control groups of mainstream schoolchildren [38].
• Accelerated prenatal diagnosis of fragile X syndrome by polymerase chain reaction restriction fragment detection [39].

References