Fragile X and Associated Diseases Being Researched at WaNPRC

Targeted gene editing in nonhuman primate research model may hold key to unlocking mysteries of Fragile X and other genetic disorders.

Fragile X Syndrome (Martin-Bell Syndrome) can result in a spectrum of mental disabilities (such as autism) and physical characteristics such as elongated face and protruding ears. Nearly half of children with Fragile X meet the criteria for autism diagnosis.

fmr1-geneFragile X and associated disorders encompass a range of genetic conditions, all of which result as a function of changes within the FMR1 gene and abnormal production and/or expression of the FMR1 gene products. FMR1 was discovered as the causative gene in Fragile X syndrome in 1991 and is a unique dominant X-linked disorder where both males and females can exhibit pathophysiology.

The normal allele consists of anywhere between 5 to 54 trinucleotide repeats (CGG) that are stably transmitted to offspring.  However, 1 in 250 women and 1 in 800 men are carriers of the FMR1 pre-mutation, where the repeat sequence has expanded to within 55 to 200 repeats.

The FMR1 pre-mutation is associated with an adult onset tremor/ataxia syndrome (FXTAS) in both sexes as well as primary ovarian insufficiency and early onset menopause in women (FXPOI). Further expansion of the CGG repeats beyond 200 leads to Fragile X syndrome, the most common heritable form of intellectual disability and the most common known cause of autism or “autistic-like” behaviors with approximately 1 in 4,000 males and 1 in 6,000 females affected.

While the inheritance of the FMR1 pre-mutation and full mutation is of clinical significance to both men and women, the expansion of the mutation within a single generation shows a sex-bias, occurring exclusively upon transmission through the maternal germline. This renders women carrying the FMR1 pre-mutation at a significant risk of conceiving a child who is affected by Fragile X syndrome.

Animal Research Models for Fragile X and Early Onset of Menopause

To date there are no known naturally occurring animal models of Fragile X and while the rodent and fly models have been beneficial for studying the cellular and molecular mechanisms of Fragile X syndrome and FXTAS there are no clinically relevant models of FXPOI.

Work in the Reproductive Biology and Stem Cell Lab at the Washington National Primate Research Center is focused on developing a nonhuman primate model of FXPOI to define the associated ovarian pathophysiology and explore the mechanism(s) of FMR1 repeat expansion in females. To achieve these goals we employ recent advances in targeted gene editing strategies to macaque pluripotent stem cells and embryos and advanced embryo manipulation techniques to produce both cellular and whole animal model systems.

As a natural extension of this work additional models that support FXTAS and Fragile X syndrome are also underway and we have successfully knocked out the FMR1 gene in macaque embryos with high rates of efficiency. Our next step in this process of model development will be to generate live born macaque infants with the FMR1 gene modifications and characterize their neurodevelopmental and behavioral phenotype through the Infant Primate Research Laboratory.

Ultimately, the aim of these models is to provide a basis for defining the pathophysiology across the range of Fragile X disorders from which therapeutic strategies for their treatment can be identified and evaluated.

Dr. Eliza Curnow | Research Scientist | Reproductive Biology and Stem Cell Core| Division of Reproductive and Developmental Sciences