The X chromosome and fragile X mental retardation.
Fragile X syndrome represents the most common inherited cause of mental retardation. It is caused by a stretch of CGG repeats within the fragile X gene, which increases in length as it is transmitted from generation to generation. Once the repeat exceeds a threshold length, no protein is produced, resulting in the fragile X phenotype. Both X chromosome inactivation and inactivation of the FMR1 gene are the result of methylation. X inactivation occurs earlier than inactivation of the FMR1 gene. The instability to a full mutation is dependent on the sex of the transmitting parent and occurs only from mother to child. For most X-chromosomal diseases, female carriers do not express the phenotype. A clear exception is fragile X syndrome. It is clear that more than 50% of the neurons have to express the protein to ensure a normal phenotype in females. This means that a normal phenotype in female carriers of a full mutation is accompanied by a distortion of the normal distribution of X inactivation.
Oostra
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Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands. b.oostra@erasmusmc.nl
Willemsen
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D041321:Chromosomes, Human, X / Q000235:genetics*; D051860:Fragile X Messenger Ribonucleoprotein 1; D005600:Fragile X Syndrome / Q000235:genetics* / Q000473:pathology; D006801:Humans; D038901:X-Linked Intellectual Disability / Q000235:genetics* / Q000473:pathology; D008957:Models, Genetic; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics; D016601:RNA-Binding Proteins; D019680:Trinucleotide Repeat Expansion / Q000235:genetics
D051860:Fragile X Messenger Ribonucleoprotein 1; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; C497683:FMR1 protein, human