MOLECULAR STUDIES ON ADENOSINE-DEAMINASE DEFICIENCY AND HEREDITARY HEMORRHAGIC TELANGIECTASIA

1, This manuscript describes two different strategies to progress from the clinical assessment of patients to the identification of disease- causing mutations, In the first disease, recognition of a metabolic ab normality allowed direct molecular analysis of the causal gene, In con trast, localization of the second disease gene by linkage analysis was critical to implicate a gene with a previously unsuspected disease ro le, 2, Two sisters with chronic respiratory disease and recurrent infe ctions were identified as the first cases of adult onset immunodeficie ncy due to adenosine deaminase deficiency, Autosomal recessive inherit ance of two mutations in the adenosine deaminase gene was demonstrated , Enzyme replacement therapy improved the patients' immunological and clinical status, 3, Individuals with pulmonary arteriovenous malformat ions were used to identify families with hereditary haemorrhagic telan giectasia (HHT, Rendu-Osler-Weber Syndrome), Linkage studies mapped th e HHT disease gene in some families to chromosome 9, and demonstrated genetic heterogeneity, The chromosome 9 disease interval was refined, and several candidate genes were assessed, Following the first descrip tion of disease-segregating mutations, a complete analysis of the endo glin gene (which encodes an endothelial cell transforming growth facto r-beta receptor) identified seven novel mutations, Two mutations did n ot produce mutant mRNA, and disease severity was comparable between fa milies, indicating that HHT results from stoichiometric insufficiency of endoglin, 4, Each study has implications extending beyond the relat ively rare disease analysed, The adenosine-deaminase-deficient patient s highlight a treatable cause of HIV-negative CD4+ lymphopenia in adul ts, perhaps accounting for further cases of non-HIV AIDS', The HHT stu dies have illuminated a novel area of vascular pathophysiology, with p otential relevance to further disease states.