Dr Irene Aligianis: Medical and Developmental Genetics
Identifying genes in brain and eye development
Summary
The aim of our research is to gain novel insights into how the eye and brain develop and function. Our approach is to identify genes that cause inherited disorders (mostly autosomal recessive conditions). Characterization of the proteins encoded for by these genes can lead to definition of gene networks and interactions which can be further explored using cell biology and model organisms. This allows us to gain insights into disease pathogenesis which can used to relate the relevant biological pathways to more common and complex diseases.
Although there is a clear role for the Rab3 pathway in cognition none of the effectors or regulators in this pathway have been involved in structural eye and brain developmental abnormalities such as those seen in Micro syndrome. We have recently identified that mutations in a different gene (MICRO3) cause the same disorder. This is particularly exciting as this is a poorly characterised protein whose role in trafficking is currently unclear. It has not been linked to the Rab3 pathway and its role in the brain and eye is just beginning to be explored. We are investigating the function of this new Micro protein on a cellular level and by identifying the protein network in which this gene functions and its relationship to the RAB3GAP1/2 genes. In addition the role of these proteins in eye and brain development will be evaluated in development using model organisms.
Collaborations within the unit
- Professor Veronica van Heyningen
- Professor Ian Jackson
Outwith the unit
- Professor Eamonn Maher
- Dr Ferenc Muller
University of Birmingham - Professsor Francis Barr
University of Liverpool - Professor Steve Wilson
UCL
Our work is funded by the Medical Research Council
Lab Members
Current lab members involved in this work are:
- Dr Mark Handley Postdoctoral Researcher
- Sarah Carpanini PhD Student
Other links
Purpose
I am a clinical geneticist and the identification of novel disease genes is directly relevant to families affected by these conditions as it provides them accurate molecular genetic diagnosis and insight into how and why these conditions have occurred. Exploring how these genes then function and which biological pathways they perturb, provides further insights into disease pathogenesis which forms the basis for the development of preventative and therapeutic interventions for these and related disorders in the future.
Themes
Warburg Micro syndrome (OMIM 60018) and Martsolf syndrome (OMIM 21270)
Our project focuses on investigating the pathogenesis of Micro and Martsolf syndromes. Children affected with these autosomal recessive disorders have complex eye and brain developmental problems and neurodegeneration.
Affected individuals have specific developmental malformations affecting several organ systems:
- Eye: microphthalmia, microcornea, congenital cataracts and aberrant optic pathway development
- Brain: microcephaly, polymicrogyria (a neuronal migration disorder), severe global developmental delay and spastic quadriplegia
- Genital: hypothalamic hypogonadism manifested by micropenis, or labial and clitoral hypoplasia
Micro syndrome represents the severe end of the spectrum of these disorders while Martsolf syndrome has an overlapping but less severe phenotype. Previously we identified that mutations in genes encoding the RAB3GAP1 cause Micro syndrome (OMIM60018) and RAB3GAP2 cause Martsolf (OMIM 212720) syndromes. RAB3GAP1/2 encode the catalytic and noncatalytic subunits of the heterodimeric enzyme Rab3GAP. RAB3GAP however is a GAP protein that has been shown previously to specifically regulate the Rab3 pathway, which is implicated in regulating neurotransmitter and hormone release.