The combination of our research accomplishments and an interactive group of IDDRC investigators created a clear identity for Intellectual and Developmental Disabilities research at Baylor College of Medicine. Baylor faculty have made numerous contributions towards understanding the etiology and pathogenesis of several leading causes of Mental Retardation and Developmental Disabilities and are recognized as leading experts for these disorders. The labs of David Nelson Ph.D., James Lupski M.D., Ph.D., and Huda Zoghbi M.D. are a few examples that have been highlighted to demonstrate some of the IDDRC successes.
Dr. Nelson and his collaborators discovered the dynamic nature of the Fragile X mutation, which provided an elegant explanation for the increasing severity of the disease upon transmission to another generation. Further studies on trinucleotide repeats at Baylor not only allowed the identification of numerous disease genes, such as those causing myotonic dystrophy, Friedreich’s ataxia and several spinocerebellar ataxias, but lent insight into the mechanisms contributing to triplet repeat instability and disease pathogenesis.
Another important success story is Dr. Lupski’s discovery that single gene dosage can be as important (and liable to disruption) as sequence integrity. His studies of the dosage-sensitive myelin gene PMP22 led to the discovery that duplications and deletions are caused by aberrant recombination between repeated sequences. Such a mechanism has now been shown to account for deletions in other disorders such as Williams syndrome, Smith-Magenis syndrome, velocardiofacial syndrome, and type 1 neurofibromatosis. The realization that these “genomic disorders” are a rather common source of mental retardation and disability has led to new efforts to identify additional such repeats as candidates for similar mutations.
The discovery in the Zoghbi Lab of the genetic basis of Rett syndrome made clear the importance of epigenetic modifications in brain function. Disruptions in MeCP2 turn out to be responsible not only for Rett syndrome, one of the most common causes of mental retardation, but also for a broad spectrum of phenotypes ranging from autism, non-syndromic retardation or affective disorders to neonatal encephalopathy. The IDDRC cores have allowed Baylor scientists to generate and characterize a remarkable mouse model of this disease. Work on UBE3A in the Dr. Arthur Beaudet's laboratory is probing the epigenetic pathways controlling neuronal function and integrity in Angelman Syndrome and Autism.