Uta Francke

Title
Professor

Department
Peds/Genetics

Research Interests
Gene discovery for inherited disorders, human mutations and their functional consequences, Marfan syndrome, Williams syndrome, Rett syndrome, genomic imprinting, human and mouse gene mapping.

Email
francke@cmgm.stanford.edu

Phone
725-8089

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Address

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Faculty Research Description
In human molecular genetics, the spectrum of current projects encompasses the search for disease genes and the study of mutations and functions for identified disease genes, as well as the mechanisms of recurrent chromosomal deletions and of parent-specific gene expression.

Williams-Beuren syndrome, a complex disorder with very specific cardiovascular, cognitive and behavioral manifestations, is due to a heterozygous 1.6 megabase deletion on chromosome 7q11.23. We have generated a complete physical map of the genes in the deletion and are now studying their products for function and possible roles in producing the phenotype. Several of the 16 genes so far characterized are involved in transcriptional regulation, signal transduction or neuronal tasks. We are identifying subcellular localization and interacting proteins and are developing functional assays. In addition, cDNA microarray screening is used to identify genes and pathways that are affected by haploinsufficiency for intra-deletion regulatory or structural genes. Mouse models are created by targeting individual genes and generating deletions in embryonic stem cells. The mechanism of the recurrent de novo deletion formation, that is likely related to crossover events in highly identical duplicated regions flanking the deletion, is also investigated.

Rett syndrome is a neurodegenerative disorder with onset in early childhood that affects only girls. We hypothesized that the responsible gene is on the X chromosome and only individuals with two X chromosomes survive because of X inactivation mosaicism by which the mutant X chromosome is inactivated in parts of the brain. By studying rare familial cases, we were able to define a region carrying the putative Rett gene on the X chromosome. Candidate gene testing identified mutations in the gene for methyl-CpG binding protein 2 (MECP2) that is involved in transcriptional silencing of genes with methylated promoter regions. We are now studying the mutational spectrum in individuals with Rett sydrome and clinical variants. Comparative global expression analysis of cell lines with either the normal or mutant X chromosome active is undertaken to identify genes whose expression is affected by mutations in the MECP2 gene.

A model system for genomic imprinting is provided by Prader Willi syndrome (PWS) and Angelman syndrome (AS) that are due to deletions of the same 4 Mb region on the paternal (PWS) or the maternal (AS) chromosome 15. Genes mapping in the deletion that are candidates for the PWS phenotype are identified by their imprinted expression pattern. To get at the underlying mechanism of parent-specific gene expression, we have identified localized differences in the accessibility of DNA to endonucleases on the maternal and paternal copies of chromosome 15 in a region known to control imprinting in cis. We are now studying the proteins that bind to these areas of differential chromatin structure in gametic precursor cells. The status of histone acetylation of the differentially compacted chromatin regions is assessed by chromatin immunoprecipitation assays.

Fibrillin-1 (FBN1), the major component of extracellular microfibrils, is defective in Marfan syndrome and related connective tissue disorders. In our laboratory, a search for mutations in the FBN1 gene has led to the identification of nearly 100 novel mutations whose effects are studied at the RNA and protein levels. We are now working on the definition of clinical subtypes of fibrillinopathies based on our molecular pathogenesis results. A search for mutations in other microfibril-associated protein genes that couldmodulate the phenotype in families with known FBN1 mutations is also pursued. This system can be considered a model for the study of polygenic traits where the contributing genes and their products are known, but their interactions are yet to be determined.

The gene mutated in Wiskott Aldrich syndrome, an X-linked immune deficiency with thrombocytopenia, was discovered by positional cloning in our lab. Mutations have been linked with variable expression patterns and a spectrum of clinical phenotypes. The protein, called WASP, in its normal and mutant forms is being studied for its subcellular localization and interactions with other proteins in cytoplasmic signalling pathways and organization of the actin cytoskeleton

Representative Publication(s): Wang, Y.-K., Spörle, R., Paperna, T., Schughart, K., Francke, U.: Characterization and expression pattern of the frizzled gene Fzd9, the mouse homolog of FZD9 which is deleted in Williams-Beuren syndrome. Genomics 57:235-248 (1999).

Schweizer, J., Zynger, D., Francke, U.: In vivo nuclease hypersensitivity studies reveal multiple sites of parental origin-dependent differential chromatin conformation in the 150 kb SNRPN transcription unit. Hum. Mol.Genet. 8:555-566 (1999).

Schrijver, I., Liu, W., Brenn, T., Furthmayr, H., Francke, U.: Cysteine substitutions in epidermal growth factor-like domains of fibrillin-1: Distinct effects on biochemical and clinical phenotypes. Am. J. Hum. Genet. 65:1007-1020 (1999).

Wan, M., Lee, S.S.J., Zhang, X., Houwink-Manville, I., Song, H.-R., Amir, R.E., Budden, S., Naidu, S., Pereira, J.L.P., Lo, I.F.M., Zoghbi, H.Y., Schanen, N.C., Francke, U.: Rett syndrome and beyond: recurrent spontaneous and familial MECP2 mutations at CpG hotspots. Am. J. Hum. Genet. 65:1520-1529 (1999).

Peoples, R., Franke, Y., Wang, Y.-K., Pérez-Jurado, L.A., Paperna, T., Cisco, M., Francke, U.: A physical map, including a BAC/PAC clone contig, of the Williams-Beuren syndrome deletion region at 7q11.23. Am. J. Hum. Genet. 66:47-68 (2000).

Areas of Study
SBRC