David L. Nelson, Ph.D.
Cullen Foundation Professor, Department of Molecular and Human Genetics
Co-Director, BCM-Michigan-Emory Fragile X Research Center
Associate Director, BCM Intellectual and Developmental Disabilities Research Center
Director, BCM Cancer and Cell Biology PhD Program
Director, BCM Integrative Molecular and Biomedical Sciences PhD Program
Past President (2018), American Society of Human Genetics
The Nelson lab has been involved in research into the causes of and therapies for Fragile X syndrome since the late 1980s, contributing to the discovery of the repeat expansion mutation that results in the disorder and the gene that is affected. For nearly 30 years, the Nelson lab has worked to define both the characteristics of the unusual repeat expansion in the disease and the function(s) of FMR1, the gene that is down regulated in the disease. The Nelson lab has also worked to understand the incompletely penetrant neurodegenerative (Fragile X-associated tremor/ataxia syndrome-FXTAS) and early onset menopause (Fragile X-associated primary ovarian insufficiency – FXPOI) disorders. Both of these disorders are caused by smaller expansions of the repeat known as premutations. Premutations predispose women to having children with to Fragile X syndrome, but do not cause intellectual disability. The Nelson lab principally employs model systems for its studies; working with mice, flies, yeast and bacteria, but it also has participated in human studies where appropriate.
The Nelson lab created and utilized mutant mice to study these disorders. Mice that lack genes related to FMR1 (FXR1 and FXR2) have been studied; this work demonstrated that these gene products are capable of compensating for some of the functions missing when FMR1 is absent. Anomalies found in these mutant animals include behavioral, electrophysiological and biochemical differences. The lab continues to characterize animals lacking FXR1 and FXR2 in combination with FMR1 knockout to understand this gene family’s range of functions and compensation by the FXRs for absence of FMR1 in Fragile X syndrome. This has uncovered a role for these genes in circadian activity and metabolism. These changes relate to human patients’ phenotypes and provide an avenue to understanding additional aspects of Fragile X symptoms.
With collaborators, the Nelson lab has developed mice that allow FMR1 and similar genes to be turned on or off in specific tissues or at specific developmental time points. The lab has completed work to determine whether the restoration of FMR1 in a late adolescent mouse can reverse abnormalities. This is especially relevant to the potential therapies for Fragile X syndrome, since it is currently unknown whether these can be expected to be effective in older patients. The lab has shown that restoration of FMR1 expression in mice at four weeks of age can restore nearly all functions such that they cannot be distinguished from non-mutant mice. Eliminating FMR1 expression at the same time point also causes these abnormalities to develop. The lab has investigated behavior and learning, biochemical, and anatomical differences. These exciting findings suggest considerable potential for treatment in Fragile X syndrome.
With collaborators at Michigan and Emory, the Nelson lab has recently received funding for one of three Fragile X Centers. The BCM center will study genetic factors that contribute to the premutation disorders, FXTAS and FXPOI. It also proposes to better understand the normal function of the FMR1 CGG repeat and to explore potential therapies for Fragile X syndrome and the premutation disorders.