Research in the Krahe laboratory is targeted toward the identification and characterization of the human genes and their mutations that underlie several inherited Mendelian and multi-factorial diseases, using classic genetic and molecular genetic approaches. These include neuromuscular disorders (myotonic dystrophies, DM1, DM2 and DMx) as well as inherited cancers (Li-Fraumeni syndrome, LFS).

DM1 and DM2 are caused by the mutant expansion of unstable (CTG)n and (CCTG)n microsatellite repeats. These repeats need to be transcribed to cause disease and accumulate in ribonuclear inclusions; thus DM1 and DM2 can be considered RNA diseases. However, it remains unclear how exactly these mutant RNAs mediate their disease-causing effects at the molecular and cellular level. To dissect the underlying pathophysiology, we are using a variety of functional genomics approaches and are generating different mouse models. There also is evidence for additional genetic heterogeneity (DMx), and we are positionally cloning at least one other gene for DM.

LFS is a clinically and genetically heterogeneous inherited cancer syndrome. Most cases are due to mutations in the tumor suppressor gene p53. We recently mapped another LFS locus to 1q23, which we are positionally cloning. In both p53 and non-p53 LFS, there is evidence for risk heterogeneity within and between kindreds, suggesting other risk modifiers and factors, including epigenetic alterations in addition to the inherited susceptibility. We are using an integrated genomics approach combining genomic and transcriptomic with epigenomic profiling to gain a better understanding of the complex molecular genetic and epigenetic events underlying the multistep carcinogenesis in LFS. As a childhood cancer, LFS is a unique model to study the underlying genetic events associated with a complex cancer syndrome, presumably because fewer such alterations are needed to give rise to the associated cancer. LFS predisposition and/or modifier genes may also be functionally important in other solid tumor types lacking a clear predisposition and inheritance pattern.

The molecular characterization and classification of sporadic cancers (head and neck and lung cancer, and gliomas) through genomics methodologies to identify genomic, epigenomic and transcriptomic changes underlying tumor initiation, progression and metastasis is another focus. A common underlying theme is the use of the tools developed by the human genome project.

Recent publications