The Rubinstein-Taybi syndrome and other malformations
The Rubinstein-Taybi syndrome (RTS) is characterized by aberrant pattern formation, mental retardation, cardiac abnormalities and increased susceptibility for certain forms of cancer. This syndrome accounts for approximately 1 in 270 institutionalized persons with mental retardation . After several congenital reciprocal translocations involving chromosome 16p13.3 had been reported, we identified submicroscopic deletions in 6 of a series of 24 RTS patients . Remarkably, the same region of 16p was involved in the somatic translocations t(8;16) in a small number of patients with acute myeloid leukemia . We identified the gene encoding the human CREB-binding protein (CBP) to be mutated in both diseases . In RTS a germline mutation is responsible for the syndrome, whereas in leukemia a somatic translocation resulting in a fusion transcript is involved.
is well known that CBP and the highly homologous protein p300 can
associate with a variety of transcriptional activators and repressors, and
function in chromatin remodelling, cell cycle control, and apoptosis.
Consequently, a large number of binding domains for interacting proteins have
been mapped in the CBP protein. besides
the above mentioned microdeletions and transclocations we identified
protein truncating mutations in several patients. We expect that missense
mutations in one or more of these binding domains for interacting proteins
may be responsible for RTS, as well.
By elucidating the mutation spectrum we would
like to identify which of many
signal transduction pathways, influenced by CBP, are disturbed. Several
domains are particularly interesting to screen
for missense mutations. These domains are involved in interactions
with transcription factors GLI3 or NF-kappaB (RelA subunit),
which are crucial for proper development and pattern formation.
Also the Histon Acetyl Transferase (HAT)-domain, important for chromatin
remodelling, is an crucial domain for CBP-function.
Project topics for students Biomedical Sciences, Medicine, Biology, Chemistry and HLO-stagaires.