The molecular basis for fragile X syndrome is beginning to be understood and relates to silencing of the product of the FMR1 gene, familial mental retardation protein (FMRP). The normal FMR1 gene contains CGG repeats in its 5′ untranslated region. When the number of trinucleotide repeats exceeds approximately 230, the DNA of the entire 5′ region of the gene becomes abnormally methylated. Methylation also extends upstream into the promoter region of the gene, resulting in transcriptional suppression of FMR1. The resulting absence of FMRP is believed to cause the http://ebooksmedicine.net
Fig. 7.17 FragileXpedigree.XandYchromosomesareshown.Notethatinthefirstgeneration,allsonsarenormalandallfemalesarecarriers(harborapremutation).Duringoogenesisinthecarrierfemale,premutationexpandstofullmutation;hence,inthenextgeneration,allmaleswhoinherittheXwithfullmutationareaffected.However,only50%offemaleswhoinheritthefullmutationareaffected,andoftenonlymildly.(Based on an original sketch courtesy of Dr. Nancy Schneider,Department of Pathology,University of Texas Southwestern Medical School,Dallas,Texas.) phenotypic changes. FMRP is widely expressed in normal tissues, but higher levels are found in the brain and the testis. It is an RNA-binding protein that is transported from the cytoplasm to the nucleus, where it binds specific mRNAs and transports them to the axons and dendrites (
Fig. 7.18 ). It is in the synapses that FMRP–mRNA complexes perform critical roles in regulating the translation of specific mRNAs involved in control of synaptic functions. The absence of this finely coordinated “shuttle” function seems to underlie the fragile X syndrome.
Although initially assumed to be innocuous, CGG premutations in the FMR1 gene can cause a disease that is phenotypically different from fragile X syndrome through a distinct mechanism involving a toxic “gain-offunction.” This disease was discovered when it was noted that approximately 20% of females carrying the premutation (carrier females) have mild cognitive impairment and premature ovarian failure (before the age of 40 years), and more than 50% of premutation-carrying males (transmitting males) exhibit a progressive neurodegenerative syndrome starting in their sixth decade. This syndrome, referred to as fragile X tremor/ataxia, is characterized by intention tremors and cerebellar ataxia and may progress to parkinsonism.
How do premutations cause disease? In these patients, the FMR1 gene instead of being methylated and silenced continues to be transcribed. CGG-containing FMR1 mRNAs so formed are “toxic.” They accumulate in the nucleus and form intranuclear inclusions. In this process the aggregated mRNA recruits RNA-binding proteins.
Fig. 7.18 Amodelfortheactionoffamilialmentalretardationprotein(FMRP)inneurons.FMRPplaysacriticalroleinregulatingthetranslationofaxonalproteinsfromboundRNAs.Theselocallyproducedproteins,inturn,playdiverserolesinthemicroenvironmentofthesynapse.(Adapted from Hin P, Warren ST: New insights into fragile X syndrome: from molecules to neu-robehavior, TrendsBiochemSci28:152, 2003.) FMRP Ribosomes Axonal proteins Dendritic proteins Ribosomes FMRP-mRNA complex AXON DENDRITE http://ebooksmedicine.net
Perhaps sequestration of these proteins at abnormal locations leads to events that are toxic to the cell.
As noted, earlier many other neurodegenerative diseases related to trinucleotide repeat expansions are recognized. Some general principles follow: