Analysis of the Fragile X Mental Retardation 1 Premutation in Han Chinese Women Presenting with Primary Ovarian Insufficiency

Background: The aim of this study is to investigate the prevalence of the fragile X mental retardation 1(FMR1) gene premutation in Han Chinese women with primary ovarian insufficiency(POI) using a rapid and cost-effective method. Methods: A total of 153 Han Chinese women with sporadic POI were systematically analyzed for trinucleotide repeats within the FMR1 gene. We employed an improved strategy to screen for cytosine-guanine-guanine repeats in the 5’ untranslated region of the FMR1 gene. Before using the previously reported Fragil Ease polymerase chain reaction(PCR) method for premutation identification, we developed a new cost-effective PCR-based method to exclude most of the normal allele carriers during the initial screening stage. Results: In our initial screening, 62.1% of women with POI were found to carry heterozygous normal alleles of FMR1, which were recognized by our sensitive and cost-effective method. The remaining women were further screened for the presence of the FMR1 premutation. We identified a Han Chinese woman with a premutation allele of FMR1 out of 153 sporadic POI women(0.7%). Conclusions: The frequent FMR1 premutation in Caucasian individuals with POI may not be a common genetic cause of sporadic POI in the Han Chinese population.

Intranuclear inclusions in a fragile X mosaic male

Lack of the fragile X mental retardation protein leads to Fragile X syndrome(FXS)while increased levels of FMR1 mRNA,as those observed in premutation carriers can lead to Fragile X-associated tremor ataxia syndrome(FXTAS).Until recently,FXTAS had been observed only in carriers of an FMR1 premutation(55–200 CGG repeats);however the disorder has now been described in individuals carriers of an intermediate allele(45–54 CGG repeats)as well as in a subject with a full mutation with mosaicism.Here,we report on molecular and clinical data of a male FMR1 mosaic individual with full and premutation alleles.Molecular analysis of FMR1 and FMRP expression in this subject is consistent with a FXS phenotype.We observed reduced expression of FMRP in both peripheral blood and brain leading to the FXS diagnosis.In addition,a dramatic 90%depletion of both FMR1 mRNA and FMRP levels was observed in the blood,as normally observed in FXS cases,and an even greater depletion in the brain.A clinical report of this patient,at age 71,described neurodegenerative signs of parkinsonism that were likely,in retrospect,part of a FXTAS scenario as post-mortem examination shows the presence of intranuclear inclusions,the hallmark pathology of FXTAS.The findings presented in this study indicate co-morbidity for both FXS and FXTAS in this individual carrying both full and premutation FMR1 alleles.In addition,based on symptoms and pathological and molecular evidence,this report suggests the need to redefine the diagnostic criteria of FXTAS.