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 gestational complication with many similarities to the inherited disorders of mitochondrial fatty acid oxidation. We report the molecular defects in a woman with AFLP and her infant who subsequently was diagnosed with trifunctional protein (TFP) deficiency. We used single-stranded conformation variance and DNA sequence analyses of the human TFP alpha-subunit gene, which encodes the long chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) activity, to demonstrate a C to T mutation (C1678T) in exon 16 present on one allele in the mother and the affected infant. This creates a premature termination codon (R524Stop) in the LCHAD domain. Using reverse transcriptase-PCR amplification of the alpha-subunit mRNA from cultured fibroblasts, we demonstrated that transcripts containing this R524Stop mutation are present at very low levels, presumably because of rapid mRNA degradation. The affected infant also had the common E474Q mutation (nucleotide G1528C) on the second allele. Thus, he is a compound heterozygote. The father and two normal siblings are heterozygous for this E474Q mutation. This initial delineation of the R524Stop mutation provides evidence of the heterogeneity of genetic defects responsible for TFP deficiency and AFLP.