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Title: Hereditary haemorrhagic telangiectasia : linkage mapping and identification of the second locus
Author: Berg, Jonathan N.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1998
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The work presented in this thesis aimed to identify the second gene for HHT (HHT2) and compare features of patients with mutations in this gene, and those with mutations in Endoglin. Members of 5 new families who suffer from HHT were assessed. Three of these families show exclusion of the chromosome 9 locus on linkage analysis. Linkage analysis of these 3 families in conjunction with analysis of other families previously described demonstrated a second locus for HHT on chromosome 12. A candidate interval of approximately 1cM was defined by haplotype analysis, looking at critical recombination events. A strong candidate gene was identified within this region. This gene, ALK-1, is a type I serine-threonine kinase receptor with expression demonstrated solely in endothelial cells. The ALK-1 gene was sequenced in 12 patients. Mutations in ALK-1 were identified in all 6 patients from families with evidence of linkage to 12q or exclusion of linkage of 9q34. Three mutations were also identified in 6 patients from whom no linkage data was available. The mutations identified left the transmembrane domain of the ALK-1 receptor intact, but are predicted to disrupt either kinase function, or ligand binding to the extracellular domain. Whether expression of an abnormal protein is necessary for disease causation, or whether mutations lead to a null allele remains to be established. The identification of ALK-1 as a second gene responsible for HHT is the first evidence that there is an interaction between ALK-1 and Endoglin in the endothelial cell.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available