The molecular genetics of inherited liver disease: asphyxiating thoracic dystrophy and phenotypic diarrhoea of infancy

Lead Research Organisation: University of Birmingham
Department Name: Health and Population Sciences

Abstract

I am proposing to study two devastating inherited conditions affecting the liver: asphyxiating thoracic dystrophy (ATD) and phenotypic diarrhoea of infancy (PDI).
ATD affects many parts of the body. It varies in severity, from death in the first weeks of life to survival into adulthood. The syndrome may affect cilia (part of a cell), so studying ATD will also help our understanding of other disorders where cilia are affected. With PDI, child often develop liver disease as babies, but the life-threatening symptom is diarrhoea. By understanding the cause of diarrhoea, therapies can be developed which could also be used in other diarrhoeal conditions, a leading cause of disease and death in children worldwide.
The aim is to identify the specific genetic defects (mutations) in key genes, so providing a robust test when either of the conditions are suspected on clinical grounds. This will help in counselling families and will also provide a prenatal diagnostic test. Researching how the disease gene affects the cell will also identify areas for specific medicines to treat the conditions.

Technical Summary

The overall research purpose is to understand the pathophysiology of liver disease by identifying the genetic basis and relating it to function. Within this I will concentrate on two devastating conditions, asphyxiating thoracic dystrophy (ATD) and phenotypic diarrhoea of infancy (PDI). The research aim is (1) identity the gene(s) that, when mutated, cause ATD and PDI; and (2) develop a greater understanding of the role of the encoded protein(s) in normal human development.
Autozygosity mapping will be the method used to identify the affected genes. In work leading to this application, I have identified novel loci for these conditions using 10K SNP-based genome-wide linkage scans of consanguineous patients. I now propose to (1) fine-map these loci using fluorescently labelled microsatellite markers to confirm the locus and identify the secure boundaries of a candidate interval; and (2) identify pathogenic mutations in candidate genes selected by a positional-candidate strategy and putative function from these intervals using web based databases.
For patients the identification of disease genes for ATD and PDI will enable genetic testing by mutation or linkage analysis, carrier testing and prenatal diagnosis to be offered to at-risk relatives. This will not only confirm the clinical diagnosis so improving management of the child but it will also enable families to make informed decisions regarding future pregnancies. Examination of any phenotype-genotype correlations will be particularly valuable for ATD, because of the broad phenotype, and may allow prognostic counselling for the first time.
This research is scientifically important as ATD and PDI are challenging conditions affecting a number of different organ systems where the unifying pathological mechanisms are unknown. It is predicted that ATD may be a disorder of primary cilia (ciliopathy). Ciliopathies affect multiple organ systems so linking the pathogenesis of a constellation of clinical symptoms, such as in Meckel Gruber syndrome which has recently been described as a ciliopathy. Identification of the ATD gene(s) will facilitate knowledge of function and interactions in the normal and disease state so aiding recognition of the pathogenesis of other conditions in which cilia are affected. Novel insights into gene function and disease pathogenesis may ultimately result in new therapeutic approaches. For many types of protracted diarrhoea the underlying pathology is unknown. With the knowledge gained from studying the gene for PDI, the understanding of the underlying mechanisms and therapeutics for other forms of diarrhoeal illnesses may also be facilitated.

Publications

10 25 50
 
Description Birmingham Children's Hospital Research Foundation, Small Project Grant
Amount £9,000 (GBP)
Organisation BCH Charities 
Sector Charity/Non Profit
Country United Kingdom
Start 07/2008 
End 07/2015
 
Description Children's Liver Fund Small Project Grant
Amount £17,000 (GBP)
Organisation Children's Liver Fund 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2009 
End 03/2010
 
Description Newlife- Small Project grant
Amount £9,000 (GBP)
Organisation Newlife 
Sector Charity/Non Profit
Country United Kingdom
Start 11/2008 
End 11/2009
 
Description Birmingham University 
Organisation University of Birmingham
Department College of Medical and Dental Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Through collaboration with others abnormal platelets were identified. This collaboration conducted the platelet investigations for me. I collected samples and learnt the techniques
Collaborator Contribution Conducted studies on platelets
Impact Paper at peer review
Start Year 2006
 
Description Canada patients 
Organisation University of Toronto
Country Canada 
Sector Academic/University 
PI Contribution I carried out all the molecular genetic investigation of the study
Collaborator Contribution Provided more patients
Impact paper in peer review. Posters at BSHG and ASHG conferences
Start Year 2006
 
Description Canada platelets 
Organisation University of Toronto
Country Canada 
Sector Academic/University 
PI Contribution I carried out all the molecular genetic investigation of the project
Collaborator Contribution Initial identification of abnormal platelets and more studies conducted
Impact Paper at peer review
Start Year 2006
 
Description IFT80 P Beales 
Organisation University College London
Department Institute of Child Health
Country United Kingdom 
Sector Academic/University 
PI Contribution Shared specimens, sequenced the most informative patient to confirm mutations in the first gene for Jeune syndrome. I sequenced alot of controls as well as other affacted families
Collaborator Contribution The collaboration was formed prior to obtaining the MRC research fellowship and helped me make a substantial application for funding
Impact 17468754 . It also helped in forming other collaborations
Start Year 2006
 
Description IHC Kings liver 
Organisation King's College London
Department School of Medicine KCL
Country United Kingdom 
Sector Academic/University 
PI Contribution I have carried out the molecular genetic investigation. This colaborator carried out immunohistochemical staining but it was inconclusive.
Impact paper under peer review
Start Year 2009
 
Description IHC staining 
Organisation Johns Hopkins University
Country United States 
Sector Academic/University 
PI Contribution I have carried out all the molecular genetics work and identified a novel gene and mutations. The work carried out by the collaborator forwarded this
Collaborator Contribution Provided expert immunohistochemical staining on probands
Impact Paper in peer review
Start Year 2009