Fragile X SyndromeWhat Is the Link Between Autism and Fruit Flies?
Part of the answer to the question in the subtitle above lies in our ability to use Drosophila as a model organism for human disease. For more on that, listen to Dr. Nancy Bonini from the University of Pennsylvania describe why fruit flies are a great model organism [YouTube].
Fragile X Syndrome and Autism
Fragile X syndrome in humans is characterized by a broad collection of physical and mental impairments and is the most common form of inherited mental retardation. The syndrome is accompanied by morphological changes in the facial features as well.
The gene for this disorder was discovered in 1991 and is called fragile X mental retardation 1 gene (FMR1). Scientists recently have shown that two different mutations in the FMR1 gene may lead to autism. This is one of the first links between autism and inheritance.
Autism spectrum disorders affect on average 1 in 100 children in the United States and occurs five times more often in boys than in girls. Autism is characterized by problems with social development, limited eye contact, unusual repetitive movement, and difficulty reading facial cues. Understanding the FMR1 gene’s normal function and the effect of mutations in this gene will lead the way for scientists to develop targeted treatments for autism as well as for fragile X syndrome.
What Do We Know About FMR1 in Humans?
We know that the FMR1 gene is found on the X chromosome (image at right). The X chromosome is one of the two sex-determining chromosomes in humans and many other organisms; females have two X chromosomes; males, one X and one Y.
The traits that develop in an individual with a mutant FMR1 gene do so because of a “loss of function” of the gene. Loss of expression of the FMR1 gene occurs as the result of expanded repeats of a three-base DNA sequence (CGG). The number of repeats determines the severity of the disease. The image below shows how repeats of CGG can expand to create the disease.
In normal individuals the number of repeats varies between 29 and 31 copies of CGG, but in those affected by the disease we see greater than 200 copies of the repeat. In autism, we see individuals who have inherited the full mutation but also some with an intermediate number of repeats (55-200). The FMR protein (FMRP) is an RNA binding protein involved in translational regulation of several other genes at the synapse. Two of these genes, neurolgins 3 and 4, have also been shown to be involved in autism. Loss FMRP leads to the up-regulation of many of these genes and consequently the expression of the disease.
What Do We Know About FMR1 in Drosophila?
Drosophila have a single FMR1 gene, dFMR, which is involved in many pathways related to neuronal development. The image at right shows the dFMR1 mutant phenotype in the Drosophila brain.
Drosophila with mutations in and loss of function of the dFMR1 gene show decreased locomotor activity and a change in the timing of the emergence of the adult from its pupal case. The neurons in dfmr mutants also have structural changes that can be monitored, including over-growth, over-branching, and abnormal synapses. You can see the effects of a dFMR1 mutation in the figure at right, in which the mutant brain (bottom panel) has regions with high concentrations of neurotransmitters (signalled with arrows) when compared to the normal fly brain (top panel). These phenotypic changes in the fly allow researches to study the effect of loss of dFMR function on other proteins.
What Other Things Can Drosophila Tell us About Autism?
Using Fruit Flies to Discover New Treatments for Fragile X Syndrome.
The following news announcement talks about exciting new studies being done by Dr. Stephen Warren in the Department of Human Genetics at Emory University. Dr. Warren is using Drosophila to study new drugs that have had promising success in reversing the features of Fragile X Syndrome. This is another great example of how Drosophila can be a tremendously informative animal model of human disease.
You can read Dr. Warren’s results directly in S. Chang et al., Identification of small molecules rescuing fragile X syndrome phenotypes in Drosophila, Nature Chemical Biology 4, 256-263 (2008).
- CDC Report on Autism.
- R. J. Hagerman, Lessons from fragile X regarding neurobiology, autism, and neurodegeneration, Dev. and Behavior. Ped. 27, 63-73 (2006).
- L. W. Wang et al., Fragile X: leading the way for targeted treatments in autism, Neurotherapeutics 7, 264-274 (2010).
- Stephane Jamain, et al., Mutations of the X linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism, Nat. Genet. 34, 27-29 (2003).
- T. Sekine T et al., Circadian phenotypes of Drosophila fragile x mutants in alternative genetic backgrounds, Zoolog Sci. 25, 561-571 (2008).
- L. Pan et al., The Drosophila fragile X gene negatively regulates neuronal elaboration and synaptic differentiation, Curr. Biol. 14, 1863-1870 (2004).
- Lili Wan et al., Characterization of dFMR1, a Drosophila melanogaster Homolog of the Fragile X Mental Retardation Protein, Mol. Cell Biol. 20, 8536-8547 (2000).
- Y. Q. Zhang et al., Protein expression profiling of the Drosophila fragile X mutant brain reveals up-regulation of monoamine synthesis, Mol. Cell. Proteom. 4, 278-290 (2005).
- S. Chang et al., Identification of small molecules rescuing fragile X syndrome phenotypes in Drosophila, Nat. Chem. Biol. 4, 256-263 (2008).