Uta Francke

Current projects focus on the functional consequences of mutations and microdeletions that cause defined clinical syndromes, 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 20 genes so far characterized are involved in transcriptional regulation, signal transduction or neuronal functions. Gene expression microarray hybridization 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 partial deletions of the conserved homeologous region on mouse chromosome 5.

Rett syndrome is a usually sporadic neurodegenerative disorder with onset in early childhood that affects only girls. It is caused by recurrent de novo mutations in the gene for methyl-CpG binding protein 2 (MECP2) on the X chromosome. Null mutations in MECP2 cause Rett syndrome in girls, who are X chromosome inactivation mosaics, but in boys who have only one (mutant) X chromosome MecP2 deficiency causes a lethal neonatal encephalopathy. Missense mutations can cause X-linked mental retardation in boys. Since MeCP2 binds to methylated DNA and recruits a transcriptional repressor complex and histone deacetylases, it may function as a transcriptional silencer by way of chromatin structure modification. To elucidate the pathway leading to neuronal damage, we study the effects of MECP2 mutations on global gene expression patterns and on chromatin modification in comparing clonal cell lines with either the normal or mutant X chromosome active, and in the brain of a male mutant mouse.

The basis and effects of genomic imprinting are studied using Prader Willi syndrome (PWS) and Angelman syndrome (AS) as model systems. These distinct neurogenetic disorders are caused by identical 4 megabase deletions on the paternal (PWS) or the maternal (AS) chromosome 15. To study the mechanism of parent-specific gene expression, we identified localized differences in chromatin structure, as manifested by differential accessibility of DNA to endonucleases and differential histone acetylation patterns. Genes in the deletion that are candidates for the PWS phenotype are identified by their monoallelic expression pattern. We recently discovered a novel cluster of C/D box small nucleolar RNA (snoRNA) genes (called PWCR1) in the deletion region that are expressed only from the paternal chromosome and are absent in PWS tissues. The known function of this class of snoRNAs is to guide methylation of specific sites in rRNA. PWCR1 snoRNAs, however, have no sequence complementarity to rRNA. We are now trying to identify the modification targets and to understand the role of the PWCR1 snoRNAs for the PWS phenotype.