MCPH1, microcephaly and cancer
Primary microcephaly (MCPH) (OMIM 251200) is a recessive genetic disorder in which the affected individuals are born with a significantly smaller head size and are mentally retarded. We work on MCPH1 (also called BRIT1), which contains three BRCA1 carboxyl-terminal (BRCT) motifs. We and co-workers have shown that MCPH1 is involved in DNA repair and regulation of cell cycle checkpoints, particularly the control of mitosis. MCPH is thought to be a consequence of a mitotic defect during foetal brain development. Abnormalities at mitosis can cause incorrect chromosome organisation and the development of aneuploidy in cancer. Numerous studies have shown that deletions at the MCPH1 (8p22-p23) locus are associated with tumour development and poor prognosis. We are studying the biological function of MCPH1 to determine how disruption of this pathway causes microcephaly and cancer.
CSMD1
We are also investigating the function of another developmental gene CSMD1 (CUB sushi multiple domain protein 1), a large gene adjacent to MCPH1 on 8p23, which is deleted in many cancer types. CSMD1 encodes a 3,508 amino acid transmembrane protein. A significant amount of evidence points to CSMD1 playing a role in tumour development, including its location, expression pattern, protein homologies and function.
Figure 1. MCPH patient illustrating smaller head size. Van den Bosch Ann Hum Genet (1959)
Figure 2. A model for MCPH1/BRIT1 function in DNA repair, identifying BRIT1 as an early regulator of DNA damage response. Chaplet M et al. (2006) Cell Cycle 5:22 279-2583
Bell SM, Zhang L, Saleh M, Walker C, Gray S, Toomes C, Thakker N, Speirs V (2007) CSMD1 a potential adhesion protein with reduced expression in human breast cancer. (Submitted to Clinical Cancer Research).
Trimborn M, Bell SM, Felix C, Rashid Y, Jafri H, Griffiths PD, Neumann LM, Krebs A, Reis A, Sperling K, Neitzel H and Jackson AP (2004) Microcephalin is a regulator of chromosome condensation. Am. J Hum. Genet. 75: (2) 261-266.
Jackson AP, Eastwood H, Bell SM, Adu J, Toomes C, Carr IM, Roberts E, Hampshire DJ, Crow YJ, Mighell AJ, Karbani G, Jafri H, Rashid Y, Muller RF, Markham AF and Woods CG (2002) Identification of Microcephalin, a protein implicated in determining the size of the human brain. Am. J Hum. Genet. 71:136-142.