We are very fortunate in PWS community to have many outstanding researchers who are excited by the challenge that PWS presents scientifically.  Dr. Uta Francke is one such investigator, a physician-scientist who has spent many productive years advancing the field of genetics overall, including PWS specifically.  Dr. Francke’s many contributions to human genetics have included defining the underlying genetics of disorders such as chronic granulomatous disease, adrenal hypoplasia, glycerol kinase definciency and Duchenne muscular dystophy.  But our community is indebted to Dr. Francke for her outstanding work on PWS.

Dr. Francke began her work on PWS in the early 90’s and continued through the end of her bench-research career a few years ago.  FPWR was pleased to support Dr. Francke’s development of a PWS mouse with deletion of the critical “snoRNAs”, Snord116, described below, as well as the continued investigation of the model by her trainee, Dr. F. Ding.   Dr. Francke’s development of the “Snord116 mouse” was one of the early projects FPWR supported, and it’s gratifying to see that the mouse has been / is being used in many subsequent studies to understand the neurobiology of eating in PWS and to evaluate new therapeutic targets and drugs.  Dr. Francke has also given generously of her time and expertise in organizing and leading the genetics section of the PWS Research Strategy Workshop in 2009, and has provided expert review and guidance to FPWR’s grant program.

In addition to many honors throughout her career [including election to the prestigious Institute of Medicine, the European Molecular Biology Organization, and the American Academy of Arts and Sciences], she was recently awarded the William Allen Award, the highest award given annually by the American Society of Human Genetics (ASHG),in recognition of “substantial and far-reaching scientific contributions to human genetics, carried out over a sustained period of scientific inquiry and productivity.”

Below is an excerpt from her Allen Award speech at the most recent ASHG meeting [2012 William Allen Award: Adventures in Cytogenetics, just published in the American Journal of Human Genetics] in which she describes her work on the genetics of PWS, including the development of the Snord116 PWS mouse.  (The speech is given to an audience of geneticists, so please pardon the jargon, but there are some interesting points, including her last sentence).

“……The next challenge in cytogenetics was the dissection of clinically and cytogenetically defined microdeletion syndromes. First, we needed to find all genes in the deletion and then determine which of the many deleted genes are responsible for which of the phenotypes by considering issues of haploinsufficiency and penetrance, gene-gene interactions, genomic imprinting, and potential effects of structural chromosome rearrangements on the expression of neighboring genes. The deletion syndromes we focused on, Williams-Beuren syndrome (WBS) and Prader-Willi syndrome (PWS), are caused by nonallelic homologous recombination (NAHR) between flanking repeats, and therefore the same genes are deleted in most cases…..

In the case of PWS, the deletion involves an imprinted region, i.e., deleted genes are on the paternally inherited chromosome 15, and the maternal copies are silent. The PWS project started with our assignment of the first protein-coding gene, SNRPN (small nuclear ribonucleoprotein polypeptide N), to the deletion region in 1992.  We then systematically searched for expressed sequences in the region and found various expressed noncoding DNA segments and a cluster of small C/D box nucleolar RNAs (snoRNAs) located in introns; we called these PWCR1.  Whereas the ∼100 bp sequences of this snoRNA cluster were moderately conserved between humans and mice, the exons of the noncoding-RNA host genes were not conserved at all, suggesting a functional role for these intronic sequences.

To delineate the minimal deletion region responsible for the PWS phenotype, we studied reciprocal translocation cases by precise molecular mapping of breakpoints. Taking our data together with others in the literature led us to propose that a small region between SNRPN and UBE3A and containing the PWCR1 snoRNA cluster—discovered in our lab93 and independently by Cavaillé et al. (who named it HBII-85) and now called SNORD116—was responsible for the PWS phenotype.

To test this hypothesis, Feng Ding in the lab took on the arduous task of making a mouse model in which the Snord116 cluster was deleted by chromosome engineering in embryonic stem cells. In contrast to previous PWS mouse models that have a high rate of neonatal mortality, the Snord116-deletion mice were viable. Extensive metabolic, dietary, and behavioral studies of mice carrying the deletion on the paternally derived chromosome revealed some PWS-like phenotypes, such as growth delay and hyperphagia, but lacked others, e.g., hypotonia and obesity. Then, surprisingly, Art Beaudet’s lab and others found that human cases with deletions of these snoRNAs met criteria for a PWS diagnosis, as discovered by array comparative genomic hybridization.  How the lack of SNORD116 snoRNAs produces the phenotype is a fascinating question. The answer involves discovering the normal function of SNORD116 snoRNAs. We know that they do not modify rRNA as most known C/D box snoRNAs do, but are they involved in other aspects of RNA processing such as mRNA turnover, alternative splicing, or RNA editing? Transcriptome expression arrays of dissected hypothalamic tissue at postnatal days 5 and 13 revealed similar expression profiles in mice with deletion and normal genotypes at both developmental stages. When I closed my lab in 2008, Feng Ding took a faculty position in China and continues to study these mice. We also deposited them at The Jackson Laboratory to be available for any researcher who wants to tackle these questions……..

…On the basis of what I learned during my personal journey in human genetics, what advice would I give to young people just starting out in the field?

• Acquire skills and knowledge in several areas; look for intriguing and important open questions that can be answered by the combination of various skills and approaches.

• Learn how to extract information from the rapidly growing -omics and medical databases, hone your informatics and computer skills, and don’t be afraid of big data.

• Choose your collaborators wisely—to complement your own skills and knowledge—and treat them with respect; we can learn so much from each other.

• If you are a physician scientist, learn from your patients; the road between the clinic and lab is a two-way street, and with an anchor in both, you can be most productive.”


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