MATERNAL ACUTE FATTY LIVER OF PREGNANCY-ASSOCIATED WITH FETAL TRIFUNCTIONAL PROTEIN-DEFICIENCY - MOLECULAR CHARACTERIZATION OF A NOVEL MATERNAL MUTANT ALLELE

Acute fatty liver of pregnancy (AFLP) is a devastating late gestationa l complication with many similarities to the inherited disorders of mi tochondrial fatty acid oxidation. We report the molecular defects in a woman with AFLP and her infant who subsequently was diagnosed with tr ifunctional protein (TFP) deficiency. We used single-stranded conforma tion variance and DNA sequence analyses of the human TFP alpha-subunit gene, which encodes the long chain 3-hydroxyacyl-CoA dehydrogenase (L CHAD) activity, to demonstrate a C to T mutation (C1678T) in exon 16 p resent on one allele in the mother and the affected infant, This creat es a premature termination codon (R524Stop) in the LCHAD domain. Using reverse transcriptase-PCR amplification of the alpha-subunit mRNA fro m cultured fibroblasts, we demonstrated that transcripts containing th is R524Stop mutation are present at very low levels, presumably becaus e of rapid mRNA degradation. The affected infant also had the common E 474Q mutation (nucleotide G1528C) on the second allele. Thus, he is a compound heterozygote. The father and two normal siblings are heterozy gous for this E474Q mutation. This initial delineation of the R524Stop mutation provides evidence of the heterogeneity of genetic defects re sponsible for TFP deficiency and AFLP.