Aberrant rnRNA splicing associated with coding region mutations in children with carnitine-acylcarnitine translocase deficiency

This report describes three infants with genetic defects of carnitine-acylc arnitine translocase (CACT), an inner mitochondrial membrane carrier that i s essential for long-chain fatty acid oxidation. Two of the patients were o f European and Chinese origin; the third was from consanguineous Turkish pa rents. CACT activity was totally deficient in cultured skin fibroblasts fro m all three patients. Patient I was heterozygous for a paternal frameshift mutation (120 del T in exon 1) and a maternal lariat branch point mutation (-10 T --> G in intron 2). Patient 2 was heterozygous for the same lariat b ranch point (-10T --> G intron 2) mutation, derived from the father, and a maternal frameshift mutation (362 del G in exon 3). Patient 3 was homozygou s for a frameshift mutation (306 del C in exon 3). All of the three framesh ift mutations give rise to the same stop codon at amino acid residue 127 wh ich is predicted to cause premature protein truncation. In addition, cDNA t ranscript analysis showed that these coding sequence mutations also increas e the amount of aberrant mRNA splicing and exon skipping at distances up to 7.7 kb nucleotides from mutation sites. The data suggest that the stabilit y of mRNA transcripts is decreased or the frequency of aberrant splicing is increased in the presence of CACT coding sequence mutations. These results confirm that CACT is the genetic locus of the recessive mutations responsi ble for the fatal defects of fatty acid metabolism previously associated wi th deficiency of translocase activity in these three cases. (C) 2001 Academ ic Press.