PROTEIN-S DEFICIENCY TYPE-I - IDENTIFICATION OF POINT MUTATIONS IN 9 OF 10 FAMILIES

We identified potentially causative mutations in the active protein S gene (PROS 1) by direct sequencing of PROS 1-specific polymerase chain reaction (PCR) products of all 15 exons, including exon-intron bounda ries in 10 families with hereditary protein S deficiency type I. Seven different mutations were found in 9 of 10 families, including one fra me shift mutation, a previously published splice site mutation (both o ccurring in two unrelated families), four missense mutations, and a st op codon at the beginning of exon 12. In family studies, cosegregation of the mutation with the disease could be demonstrated for five mutat ions; for two missense mutations, this was not possible due to limited family data. All seven mutations were the only abnormalities identifi ed in the respective index patients and were absent in 44 to 62 normal individuals. Therefore, they most likely represent the causal gene de fects. For five mutations, analysis of ectopic RNA could be performed. Mutant transcripts were present in the case of the frame shift and th ree of the missense mutations, while no mutant RNA could be detected i n the case of the stop codon. (C) 1995 by The American Society of Hema tology.