Disorders of human brain development: genetics and function

Lead Research Organisation: MRC Human Genetics Unit

Abstract

Inherited neurological disorders are an important cause of intellectual and physical disability during childhood. This research program aims to identify genes for such disorders and then establish how mutations in these genes cause disease. We have identified microcephalin as a gene that causes marked reduction in brain size, comparable in size to early hominids. By studying this genes function in cells and in the fruit fly, we are working to understand how this gene is involved in determining brain size, and whether it has contributed to the evolutionary expansion of the human brain.

Technical Summary

Purpose: Identify genes important in brain development from the study of human neurogenetic disorders. Characterise these genes cellular and developmental functions utilising cell biology and model organisms, to gain insights into the pathogenesis of human disease.||Background: Determination of brain size is an important component of neurodevelopment and has experienced significant evolutionary change. Brain size has markedly increased during mammalian evolution, and in the last 2 million years the human brain has more than doubled in size. In this respect, the human disorder of primary microcephaly appears to recapitulate an earlier evolutionary state, with a brain size comparable with that of early hominids. Microcephalin is a protein that I have identified as a cause of primary microcephaly and its further characterisation currently forms the major focus of my work. This protein has been subsequently found to have roles in cell cycle regulation, chromosome organisation and DNA repair.||The gene has also experienced Darwinian adaptive evolution in primates, indicating that the protein may well play a role in the evolutionary expansion of brain size.||Current work||- Identify the molecular mechanisms associated with aberrant regulation of chromosome condensation in microcephalin deficient cells.||- Characterise patient cell lines from individuals with primary microcephaly and related conditions for DNA repair and cell cycle defects.||- Positionally clone novel microcephaly genes (Seckel Syndrome) to identify novel components of the ATR signalling pathway.||- Utilise the Drosophila microcephalin model that we have generated to investigate developmental mechanisms and identify genetic interactions||- Investigate the pathogenic basic of Aicardi-Goutieres syndrome (SCF Fellowship)

Publications

10 25 50
 
Description Lister Research Prize Fellowship (Cellular pathways determining human brain size)
Amount £200,000 (GBP)
Organisation Lister Institute of Preventive Medicine 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2009 
End 12/2014
 
Description MRC Senior Clinical Fellowship
Amount £1,400,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 06/2007 
End 06/2012
 
Description MRCT Development Gap Funding
Amount £91,000 (GBP)
Organisation MRC-Technology 
Sector Private
Country United Kingdom
Start  
 
Title AGS Patient cell lines 
Description Aicardi Goutieres Patient cell lines established 
Type Of Material Cell line 
Year Produced 2007 
Provided To Others? Yes  
Impact none so far 
 
Title Drosophila model mcph1 
Description Drosophila knockout model of MCPH1 gene, relevant to disease, primary microcephaly, and the regulation of brain size 
Type Of Material Model of mechanisms or symptoms - non-mammalian in vivo 
Year Produced 2007 
Provided To Others? Yes  
Impact PMID 17895363 
URL http://europepmc.org/abstract/MED/17895363
 
Title RNaseH2 mouse 
Description Ribonuclease H2 mouse mutants (knockin, and knockout) have been developed to study the mechanisms of RNaseH2 function and disease pathology of Aicardi Goutieres syndrome 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Provided To Others? No  
Impact research still in progress 
 
Title Seckel patient cell lines 
Description patient cell lines from patients with microcephaly and primordial dwarfism 
Type Of Material Cell line 
Year Produced 2007 
Provided To Others? Yes  
Impact PMID: 18157127 
URL http://europepmc.org/abstract/MED/18157127
 
Description Boulton -CRICK 
Organisation Francis Crick Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution identification of mutations in gene, clinical characterisation and obtaining primary cell lines
Collaborator Contribution characterisation of cell lines for gene involved in DNA replication
Impact manuscript about to be submitted to Molecular Cell
Start Year 2017
 
Description Crow-Univeristy of Leeds 
Organisation Medical Research Council (MRC)
Department MRC Functional Genomics Unit
Country United Kingdom 
Sector Academic/University 
PI Contribution identified disease genes. performed functional studies.
Collaborator Contribution contributed DNA samples to sequence and blood samples to make cell lines. genetic mapping information. identification of disease genesbioinformatic analysis leading to identification of new disease genes
Impact 16845400 16845398 17846997
 
Description Crow-Univeristy of Leeds 
Organisation University of Leeds
Department Leeds Institute of Molecular Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution identified disease genes. performed functional studies.
Collaborator Contribution contributed DNA samples to sequence and blood samples to make cell lines. genetic mapping information. identification of disease genesbioinformatic analysis leading to identification of new disease genes
Impact 16845400 16845398 17846997
 
Description Hurles-Sanger 
Organisation The Wellcome Trust Sanger Institute
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution patient material - molecular genetic and cellular studies
Collaborator Contribution expertise and practical assistance in exome sequencing and downstream analysis
Impact PMID: 26595769 25344692 24123394 23995685 23773188 21131973
Start Year 2010
 
Description IMBA-Vienna 
Organisation Austrian Academy of Sciences
Department Institute of Molecular Biotechnology
Country Austria 
Sector Academic/University 
PI Contribution identification of molecular defects in patients with microcephaly and patient derived cell lines/iPS cells
Collaborator Contribution expertise on organoid modelling
Impact 23995685
Start Year 2012
 
Description Jeggo - GDSC 
Organisation University of Edinburgh
Department Institute of Cell and Molecular Biology
Country United Kingdom 
Sector Academic/University 
PI Contribution mapped and identified gene. contributed cell line. performed functional studies.
Collaborator Contribution contributed patient samples enabling mapping and identification of disease gene. Cell lines. performed functional studiesperformed functional studies characterising centrosomes
Impact 18157127 21358633
 
Description Jeggo - GDSC 
Organisation University of Sussex
Department Genome Damage and Stability Centre
Country United Kingdom 
Sector Academic/University 
PI Contribution mapped and identified gene. contributed cell line. performed functional studies.
Collaborator Contribution contributed patient samples enabling mapping and identification of disease gene. Cell lines. performed functional studiesperformed functional studies characterising centrosomes
Impact 18157127 21358633
 
Description Phoebus Lin 
Organisation University of Texas
Department M. D. Anderson Cancer Center
Country United States 
Sector Academic/University 
PI Contribution contribution of cell lines
Collaborator Contribution investigation of the role of MCPH1 in DNA damage and chromatin remodelling
Impact PMID 19525936
Start Year 2007
 
Description RNaseh mitochondrial 
Organisation Medical Research Council (MRC)
Department MRC Mitochondrial Biology Unit
Country United Kingdom 
Sector Academic/University 
PI Contribution contributed reagent publication PMID 22579044
Collaborator Contribution publication PMID 20184890 contributed reagent
Impact publication PMID:20184890 publication PMID:22579044
Start Year 2008
 
Description Little People of America meetings 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Patients, carers and/or patient groups
Results and Impact talk to ~40 families with primordial dwarfism and social/teaching/health professionals associated with the group with discussion and informal 1:1 discussion over 3 days.

more informed patient group.
Year(s) Of Engagement Activity 2010,2011,2012,2013,2015,2016
 
Description WWGF patient conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Patients, carers and/or patient groups
Results and Impact talk to ~20 families with primordial dwarfism and social/teaching/health professionals associated with the group with discussion and informal 1:1 discussion over 2 days.

more informed patient group
Year(s) Of Engagement Activity 2009,2010,2011,2012,2013,2014,2015,2016,2017,2018