Molecular genetic study of the FMR1 CGG repeat configurations in the Japanese population and patients with Fragile X-Associated Tremor/Ataxia Syndrome

概要

Fragile X–Associated Tremor/Ataxia Syndrome (FXTAS) is an adult-onset neurodegenerative disorder, usually affecting individuals over 50 years of age, caused by an expansion of CGG triplet repeats between 55–200 CGG repeats (premutation) in the FMR1 gene. FMR1 Premutation may also cause another disease in women, which is Fragile X-Associated Primary Ovarian Insufficiency. While an expansion into >200 CGG repeats (full mutation) leads to Fragile X Syndrome, an inherited intellectual disability disorder. Typically, individuals possess under 45 CGG repeats (normal), and those with the range of expansion between 45-54 CGG repeats (intermediate) have not been linked to any known phenotype.

　We performed a wide population-based molecular genetic study for the FMR1 gene in Japan. We recruited 1095 Japanese patients with movement disorders (348 patients with cerebellar ataxia, 702 patients with multiple system atrophy, and 45 patients with neuronal intranuclear inclusion disease) and 384 healthy controls. We identified three male patients with FMR1 premutation. Two carriers were in a group of 76 male patients with sporadic-late cerebellar ataxia, giving an estimation of 2.7%, which is a high rate considering the low prevalence of the FMR1 premutation in the Japanese general population. Their CGG repeat lengths in FMR1 were 84 and 103 CGG repeats. And one carrier with 60 CGG repeats, among 106 male patients with multiple system atrophy-parkinsonism.

　Also, we identified two male patients and one female patient with multiple system atrophy as carriers for FMR1 intermediate, in addition to two males and three females with FMR1 intermediate in healthy controls.

　In the present study, we characterized the CGG repeats motif and AGG interruption in a group of 346 Japanese patients with cerebellar ataxia and 103 healthy controls. We found that the modal length of CGG repeats in the Japanese population was 29, followed by 30, and 36 CGG repeats, which is compatible with values in other populations, except for the 36 CGG repeats which is unique for Asian people.