Identifying genes in brain and eye development

Lead Research Organisation: MRC Human Genetics Unit

Abstract

Inherited disorders that cause brain and eye malformations in humans are a significant cause of childhood disability. The aim of my research is to identify genes that cause such disorders, to unravel how those genes function in normal biology, and to understand what goes wrong when they are mutated. We have identified three genes that cause Micro syndrome, a condition in which children have severe progressive limb spasticity (cerebral palsy), learning difficulties, cataracts and small eyes. The relationship between these genes is currently not clear and we are undertaking cellular and protein studies to elucidate this. Because many genes and their functions are strongly conserved during evolution, we are using model organisms (mice) to investigate how these genes affect brain and eye development and function. The ultimate aim is that such studies may lead to the development of therapies for common neurological diseases as the pathways that are perturbed by these genetic diseases are likely to have roles in non-genetic disease.

Technical Summary

The aim of my research is to gain novel insights into how the eye and brain develop and function by identifying genes that cause human neurogenetic disorders. 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.|Our research currently is focused on investigating the pathogenesis of two related autosomal recessive disorders: Micro and Martsolf syndromes. Affected children have neurodegeneration and complex developmental malformations affecting several organ systems:| Eye: microphthalmia, microcornea, congenital cataracts and aberrant optic pathway development resulting in blindness| 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 |We have thus far identified 3 genes (using autozygosity mapping and candidate gene analysis) that account for about 65% of cases. The first two genes, RAB3GAP1 and RAB3GAP2 encode the catalytic and noncatalytic subunits of the heterodimeric enzyme Rab3GAP. RAB3GAP is a key regulator of the Rab3 pathway, which is implicated in regulating neurotransmitter and hormone release by calcium mediated exocytosis. 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 mutations in a novel gene in a cohort of Micro syndrome families. The role of this gene in trafficking is currently unclear and protein-protein interaction studies to identify how these genes interact and the broader protein network they function in is currently being undertaken. A mouse model for Micro syndrome has been generated by the MRC Mammalian Genetics Unit, Harwell and we shall be using this to characterize the developmental defects and understand the cellular role of these proteins in eye and brain development. |

Publications

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Bem D (2011) Loss-of-function mutations in RAB18 cause Warburg micro syndrome. in American journal of human genetics

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Handley MT (2012) RAB3GAP1, RAB3GAP2 and RAB18: disease genes in Micro and Martsolf syndromes. in Biochemical Society transactions

 
Description Biochemical Investigation of Rab protein regulators 
Organisation University of Oxford
Department Department of Biochemistry
Country United Kingdom 
Sector Academic/University 
PI Contribution Identifcation of RAB regulators and proteins involved in human disease Identifcation of interactiosn between differnt RAb proteins and thier regualtors
Collaborator Contribution Biochemical confirmation and evaluation of Human disease mutations in RAB proteins
Impact PMID: 21473985
Start Year 2009
 
Description Investigation of Pathology in Micro model 
Organisation University of Edinburgh
Department Centre for Integrative Physiology
Country United Kingdom 
Sector Academic/University 
PI Contribution Creation of a model for Micro syndrome
Collaborator Contribution Assistance in investigating the pathology present in the peripheral nervous sytem
Impact in progress
Start Year 2010
 
Description ZEBRAFISH INVESTIGATION OF RAB3GAP1/2 
Organisation University College London
Department Biosciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Expression patterns of the RAB3GAP1/2 genes investiagted- riboprobes designed by us and insitu's performed in London
Collaborator Contribution Joint investigation of gene expression patterns in zebrafish
Impact Publication: 16532399
 
Description rab18 zebrafish model 
Organisation University of Birmingham
Department College of Life and Environmental Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution This collaboration allowed us to generate and characterise a rab18 zebrafish model of Micro syndrome
Collaborator Contribution Publication of rab18 zebrafish model in: Loss-of-function mutations in RAB18 cause Warburg micro syndrome. Pubmed ID: 21473985
Impact This work has been published in the following publication: Loss-of-function mutations in RAB18 cause Warburg micro syndrome. Pubmed ID: 21473985
Start Year 2009
 
Title Molecular testing for Micro syndrome 
Description In conjunction with the West Midlands Regional Genetics lab diagnostic testing for Micro syndrome has been established ( gene testing). 
Type Diagnostic Tool - Non-Imaging
Current Stage Of Development Small-scale adoption
Year Development Stage Completed 2006
Development Status Under active development/distribution
Impact Diagnostic and carrier testing available for families Prenatal diagnosis This has led to earlier diagnosis of Micro syndrome which has prevented several children having cataract surgery 
 
Description !st International Warburg Micro Syndorme Patients Meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Participants in your research and patient groups
Results and Impact Patients support meeting which allowed differnt families to meet and exchange experiences. Presentations given to explain the clinical and sceitnific aspects of the condition.

The second meeting is being oprganised for next year and a UK meeting is sceduled as well for 2012
Year(s) Of Engagement Activity 2011
 
Description Patient support group meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Participants in your research and patient groups
Results and Impact First International Patient Support Meeting for Warburg Micro Sundrome

Second meeting organised for next year
Year(s) Of Engagement Activity 2011
 
Description Patients 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Primary Audience Participants in your research and patient groups
Results and Impact Seeing families with Micro syndrome participating in our research and discussing research findings- genetic counselling

Prenatal diagnosis and carrier testing offered to families- carried out by the West Midlands Regional Genetics Laboratory (NHS) as a service
Year(s) Of Engagement Activity 2006,2007,2008,2009