Seckel Syndrome and related disorders.

Microcephalic primordial dwarfism represents a group of disorders characterised by small heads (microcephaly) and proportionate dwarfism.  These disorders include Seckel Syndrome, Majewski osteodyplastic primordial dwarfism type II (MOPD II) and Meier-Gorlin Syndrome). In 2003, Mark O'Driscoll, whilst a post doctoral scientist in the Jeggo laboratory identifed ATR as a causal genetic defect for Seckel Syndrome. A mutational change causing abnormal splicing was identified in two members of a family displaying Seckel Syndrome. The cells from the patients show defects in ATR signalling. Perhaps suprisingly, further mutations in ATR have not been identified in other patients with Seckel Syndrome.  Subsequently, in collaborative work with Andrew Jackson we identified mutations in Pericentrin (PCNT), a centrosomal protein, in further patients diagnosed as having Seckel Syndrome. PCNT mutations have also been identified in patients classified as MOPDII.  More recently, we have also identified mutations in ORC1, a protein required for DNA licensing, in further patients classified as Seckel Syndromes. These patients had clinical features overlapping with Meier-Gorlin Syndrome (MGS) and, in subsequent analysis of an MGS cohort of patients, mutations in ORC4, ORC6, Cdt1 and Cdc6 have been identified.

Currently, in collaborative work with Mark O'Driscoll, we are studying:

• How defects in ORC1 impact in the cell and how they might contribute to the clinical featurs observed in MGS
• We have observed that ATR-dependent G2/M checkpoint arrest is defective in > 80 % of cell lines derived from MPD patients. Why is this.
• We continue to seek novel genetic defects causing MPD

Collaborators:

Dr. Mark O'Drsicoll, GDSC University of Sussex.

Dr. Andrew Jackson, University of Edinburgh, Scotland.

Dr.  Ernie Bongers, Radbound University, Nijmegen Medical Centre