Dissertation > Medicine, health > Neurology and psychiatry > Neurology > Brain diseases > Paralysis agitans syndrome

Analysis of Mutations of FMR1Gene in Patients with Parkinsonism in Mainland China

Author ZhangXiong
Tutor WangNing; WuZhiYing
School Fujian Medical
Course Neurology
Keywords parkinsonism FMR1 GZ alleles eukaryotic expression plasmid
CLC R742.5
Type PhD thesis
Year 2012
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Background and ObjectivesParkinson’s disease (PD) is a neurodegenerative disorder which is more common inmiddle-aged and old people and1.7%of people over65years old get PD. Thepathogenesis of idiopathic PD remains unclear, but genetic factors are thought toconfer a risk. Expanded alleles of the fragile X mental retardation1(FMR1) gene aregenerally divided into four classes based on the abundance of unstable CGG repeatexpansions (CGGs) in its5’-untranslated region. It has recently been reported that twoof the four classes, premutation (PM) alleles (55–200CGGs) and Gray Zone (GZ)alleles (40–54CGGs), was potentially associated with parkinsonism. However, thepathogenesis of the association is unclear, and that is supposed to be caused by “toxic mRNA”.And we should pay attention to that most of the participants in those studies wereCaucasians, and no observation has been reported regarding Chinese populations(even Asian populations). Here we screened expanded FMR1alleles in parkinsonismpatients in mainland China and on the basis of the results we analyzed the clinicalcharacteristics of carriers with the expanded FMR1alleles. We also constructedeukaryotic expression plasmids of the FMR1GZ and normal alleles in further, andthen observed characteristics of them.The aim was to understand the characteristics ofthe expanded FMR1alleles and the associations between that and the clinicalmanifestations, in further to analyze the pathogenesis of idiopathic PD on a cellularlevel at last.Methods1. Patients with PD and healthy controls were included: the360patients (male,213;female,147) were from the first affiliated hospital of Fujian Medical University andWenzhou Medical College. Patients with a PD history were excluded. And in thestudy there were14atypical PD patients with some extent of parkinsomismmanifestations, of whom7have no or little response to levodopa,3have a history ofstroke with positive Babinski’s sign (however, we don’t think that the stroke canexplain the symptoms),2seemed to have ataxia, the other2are considered at the early stage of PD which didn’t meet the diagnostic criteria yet. Any other patientswere diagnosed with idiopathic PD by two associate chief physicians at least.2. Combined polymerase chain reaction (PCR) with agarose gel electrophoresis,polyacrylamide gel electrophoresis and DNA sequencing to detect the expandedFMR1alleles and the number of the CGGs.Results1. No premutation or full mutation alleles (>200CGGs) was detected among all of thesubjects.2. A total of11parkinsonism patients were identified to have GZ alleles comparedwith only1carrier among the controls. Notably,10of the11GZ alleles carriers withparkinsonism were female, which was6.8%of all147female patients compared withnone in the control females (P<0.05).3. No significant difference was detected between the male groups of patients andcontrols.4. Nine females of the11GZ allele carriers had normal age of menopause (about45to50years old) with one (43years old) had not entered menopause. No manifestationrelated with POF was detected.5. A female patient of the11GZ allele carriers was found to have slight wmh on MRIin the basis pontis.6. We succeeded in constructing the two eukaryotic expression plasmids,(CGG)44-FMR1cDNA/PEGFP/N1and FMR1cDNA/PEGFP/N1, and they had beenverified by double-enzyme cleavage and gene sequence analysis.Conclusions1. FMR1GZ alleles are potentially associated with parkinsonism in mainland China,and the association is only present in the female patients, but not in the male.2. The GZ alleles may be not linked to POF in Chinese women.3. In our study, two eukaryotic expression plasmids were constructed, but no obviousimplication had been obtained, we will observed about the neuronal cell death causedby “toxic mRNA” and α-Synuclein aggregation caused by mitochondrial disfunction,to explore the mechanism of the association between the FMR1GZ alleles and PD infurther.

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