“Dosage and Titration in Genetic Disease: Repeat Mutations and Developmental Disorders”

About the speaker:  (From the speaker’s website, at https://www.bcm.edu/people/view/david-nelson-ph-d/genetics-research-faculty-l-n/b22602ea-ffed-11e2-be68-080027880ca6/53710726-79c4-47f0-8d58-2d590a1612dc)

One of the most exciting recent developments in human genetics has been the identification of unstable trinucleotide repeats involved in high frequency mutations leading to more than one dozen genetic disorders, including myotonic dystrophy and Huntington’s disease. With collaborators, Dr. Nelson described the first of these unstable DNA sequences, a CGG trinucleotide repeat in the FMR1 gene and responsible for the fragile X site and mental retardation found in people with Fragile X syndrome. This is the most common form of inherited mental retardation, with a frequency of ~1/2000 males in the general population. The mechanism by which this mutation leads to disease is through loss of function of the FMR1 gene product due to diminished expression resulting from aberrant methylation of the gene. Recent evidence suggests that the gene product of FMR1 interacts with complexes of RNA and ribosomes, implying a role in regulation of translation. Efforts in the Nelson group are focused on dissecting this pathway and understanding the development of DNA instability at this locus. Two additional fragile sites are found in the vicinity of the FMR1 gene on the X chromosome. The Nelson laboratory described one of these at the molecular level (FRAXF) and has identified a second gene involved in mental retardation expressed from the FRAXE fragile site (FMR2). Efforts to understand the function of FMR2 are underway.

The group has recently identified the gene defect in the X-linked disorder Incontinentia Pigmenti. This mutation is lethal in males, and leads to a spectrum of effects in females. Mutations are found in an essential modulator of NF-kB activity (NEMO), and the role of loss of function for this protein in the disease is under investigation.

The Nelson group has been involved in numerous aspects of the Human Genome Project, with key input into the mapping and sequencing of the human X chromosome, and participation in several other sequencing projects, from fly to Rhesus monkey. Dr. Nelson also has interest in the genetic contribution to common disorders such as cancer, and has investigated the potential role of common variants in genes involved in DNA repair in human disease.

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The University of Wisconsin School of Medicine and Public Health designates this live activity for a maximum of 1.0 AMA PRA Category 1 Credits™.  Physicians should claim only the credit commensurate with the extent of their participation in the activity.

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This lecture is funded in part by the Waisman Center Lynn’s Fragile X Fund.