Genetic epidemiology of phenotypes associated with FMR1premutation alleles 公开

Hunter, Jessica Ezzell (2008)

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Abstract Genetic epidemiology of phenotypes associated with FMR1 premutation alleles

by Jessica Ezzell Hunter The 5 untranslated region of the fragile X mental retardation gene, FMR1, contains a highly polymorphic CGG repeat. The most common alleles contain 40 repeats or less. Rare expansions of this repeat are associated with a spectrum of disorders. Repeats of 200 or more, termed full mutation alleles, are associated with hypermethylation and subsequent loss of expression of the FMR1 gene. The loss of FMR1 expression results in fragile X syndrome (FXS), the most common inherited mental retardation syndrome. Repeats of 55 to 199, termed premutation alleles, are associated with varying levels of transcript and protein product. Phenotypes known to be associated with premutation alleles include a tremor-ataxia syndrome (FXTAS), affecting roughly 30% of male carriers over the age of 50, and primary ovarian insufficiency (FXPOI), affecting roughly 20% of carrier females. Any global neuropsychological and neurobehavioral impact of carrying a premutation allele has been unclear in adult carriers under the age of 50. This dissertation presents research focused on determining phenotypes associated with premutation alleles among males and females in the largest study population to date in order to ask the question: in the absence of FXTAS or perhaps before the onset of FXTAS, what is the neuropsychological and/or neurobehavioral impact of carrying a premutation allele among younger adults? Results of these studies indicate subtle phenotypes associated with premutation alleles among males and females, including increased symptoms associated with depression and self- concept as well as increased inattention. However, these results find no evidence for an increased risk of any clinical disorder. Lastly, in order to determine the extent to which background genetics might be involved in the variable penetrance of phenotypes associated with premutation alleles, the first study analyzing familial aggregation of FXPOI was performed. Results of this study showed significant familial aggregation of age at menopause, a proxy for ovarian function, after adjustment for FMR1 genotype. In future studies, this methodology can also be applied to the other phenotype known to be associated with premutation alleles, FXTAS.

Table of Contents

Table of Contents Chapter 1.

Introduction to FMR1 and FMR1-related phenotypes. 1 - 28 Chapter 2. Is there evidence for neuropsychological and neurobehavioral phenotypes among adults without FXTAS who carry the FMR1 premutation? A review of current literature. 29 - 72 Chapter 3. Investigation of phenotypes associated with mood and anxiety among male and female fragile X premutation carriers. 73 -105 Chapter 4. No evidence for a difference in neuropsychological profile among carriers and non-carriers of the FMR1 premutation in adults under the age of 50. 106 -145 Chapter 5. Fragile X-associated primary ovarian insufficiency (FXPOI): evidence for additional genetic contributions to severity. 146 - 170 Chapter 6. Discussion. 171 - 175

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