Genetic basis of total kininogen deficiency in Williams' trait.

High and low molecular weight kininogens (HK and LK) modulate inflammatory responses, serve as precursors of kinins, inhibit cysteine proteinases, and modulate thrombin activation of platelets. Differential splicing yields two different mRNAs for HK and LK. We report the first molecular characterization of a kininogen gene mutation in a patient lacking LK and HK. No gross DNA deletion or insertion was detected by Southern blots, and LK and HK mRNAs were normal size on Northern blots. Exon sequences amplified by polymerase chain reaction showed a C-->T transition at nucleotide 587, resulting in a CGA (Arg)--> TGA (Stop) mutation in exon 5 before the splice site in exon 10, thus preventing synthesis of both HK and LK. The mutation eliminated the recognition site of the restriction enzyme Csp45I. Results of Csp45I digestion of the polymerase chain reaction-amplified exon 5 DNA fragment of the patient (lacking kininogens), three daughters (approximately 50% HK), and 1 granddaughter (normal HK) revealed that the patient was homozygous, while the three daughters were heterozygous, and the granddaughter was normal. We conclude that a single base mutation in the kininogen gene exon 5 was responsible for kininogen deficiency in the Williams family.