Primordial Dwarfism

Microcephalic Dwarfism

This is a group of disorders in which growth is markedly impaired from early on in development, resulting in very reduced body size and head size. Often adult height can be as little as 1 metre (3 feet) tall. Primordial dwarfism, includes several conditions such as Majewski’s Osteodysplastic Primordial Dwarfism Type II (MOPD II), and Seckel syndrome. Two genes have been implicated to date for these conditions, ATR, and Pericentrin, and several more genes remain to be found.

(image kindly provided by John Connerty, WWGF)

Current work

The central hypothesis for our current work is that microcephaly genes are components of a common cellular pathway relevant to the growth and evolution of the cerebral cortex. We are pursuing complementary approaches involving human disease gene identification, cell biological studies, and modelling of the disease in human stem cells to address this hypothesis and further define how these conditions are caused. These studies may help us understand how the human brain evolved. They also may provide insights into neural stem cell division, potentially relevant to brain repair for neurodegenerative disorders and spinal trauma. Finally and not least, centrosome function and DNA damage response signalling are key cellular processes perturbed in many important human diseases, from developmental disorders to cancer.

Themes

• Disorders of Human Brain Size:
  Primary Microcephaly
  Primordial Dwarfism
  

• Autoimmune Disease of the Brain
  Aicardi Goutieres Syndrome
  

Other Links

Research Study Information
Laboratory Publications

Brain size and Primordial Dwarfism

Brain size is reduced to a similar level to that seen in Primary microcephaly, and so we believe that similar cellular processes are likely to be involved in both conditions. In both groups of conditions, there is a very marked reduction in brain growth during development, and the brain is reduced to around a third of its normal volume, a similar size to early humans. Despite its reduced size, brain function is surprisingly well preserved.

Genes Determining Brain Size

The size of the cerebral cortex is likely to be determined by neuronal cell number and reflect the amount of cell proliferation and death occurring during development of the brain. The genes identified to date are all involved in cell division (centrosome function) and signalling of DNA damage. Both these processes could modulate brain size, the former through affecting the rate of cell division, and the latter by altering the threshold for cell death.

Pericentrin

Recently, with Penny Jeggo, Mark O’Driscoll, and others, we have identified mutations in Pericentrin, a gene encoding a structural centrosomal protein, in patients with a diagnosis of Seckel syndrome. Surprisingly, we also established that it is a component of the ATR-dependant damage response pathway. This suggest that other known microcephaly genes implicated in either DNA repair responses or centrosomal function, may act in common developmental pathways determining human brain size.