Molecular basis of inborn errors of ketone body metabolism, especially succinyl-CoA : 3-ketoacid CoA transferase deficiency

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1) SCOT deficieicny : We revealed the structure and sequence of human SCOT gene, made tertiary structural model of human SCOT protein, and identified and characterized gene mutations in 3 SCOT deficient patients. We now can screen SCOT gene mutations at the genomic level. We analyzed 5' flanking regions of human SCOT gene in order to clarify the mechanism for specific SCOT gene supression in hepatocytes. We determined the sequence of 3 kb in the region, and revealed that Sp1 basically drive the SCOT gene expression. We also searched cis-elements responsible for specific supression in hepatocytes.2) T2 deficiency : We analyzed character of amino acid alternations (gene mutations) identified in 5 spanish T2 deficient patients on teritiary structural model of T2 protein. In one patient, we identified a novel splicing mutation 380C>T.This mutation located on exon 3 activated pre-exsisting cryptic splice site on exon 3, resulting in exclusive splicing at the cryptic site. We have identified gene mutations in 26 T2 deficient patients. We collected clinical information from the physicians for these patients with the use of questionnaire to search clinical courses and outcome and to clarifiy genotype/phenotype correlation in T2 deficiency. By the study, we concluded that (1) T2 deficiency has a favorable outcome in general ; (2) severe ketoacidotic attack can be avoidable after confirmation of the diagnosis ; (3) there is no apparent phenotype/genotype correlation.The head investigator was honored to write chapters in "Methods in Enzymology" and in "Metabolic ＆ Molecular Bases of Inherited Disease".