SUCCINYL-COA-3-KETOACID-COA-TRANSFERASE (SCOT) DEFICIENCY - 2 PATHOGENIC MUTATIONS, V133E AND C456F, IN JAPANESE SIBLINGS

Succinyl CoA:3-ketoacid CoA transferase (SCOT; EC 2.8.3.5; locus symbo l OXCT) is the key enzyme of ketone body utilization, Hereditary SCOT deficiency (MIM 245050) causes episodes of severe ketoacidosis. We dev eloped a transient expression system for mutant SCOT cDNAs, using immo rtalized SCOT-deficient fibroblasts. This paper describes and characte rizes three missense mutations in two SCOT deficient siblings from Jap an. They are genetic compounds who inherited the mutation C456F (c1367 G-->T) from their mother. Their paternal allele contains two mutation s in cis, T58M (c173 C-->T) and V133E (c398T-->A). Expression of SCOT cDNAs containing either V133E or C456F produces no detectable SCOT act ivity, whereas T58M is functionally neutral. T58M is a rare sequence v ariant not detected in 100 control Japanese alleles, In fibroblasts fr om the proband (GSO2), in whom immunoblot demonstrated no detectable S COT peptide, we measured an apparent residual SCOT activity of 20-35%, We hypothesize that the high residual SCOT activity in homogenates ma y be an artifact caused by use of the substrate, acetoacetyl CoA by ot her enzymes. Expression of mutant SCOT cDNAs more accurately reflects the residual activity of SCOT than do currently available assays in ce ll or tissue homogenates. Hum Mutat 12:83-88, 1998. (C) 1998 Wiley-Lis s, Inc.