Congenital thrombotic thrombocytopenic purpura (TTP) is a rare autosomal recessive genetic disorder caused by mutations in the gene. Approximately 200 mutations of the gene have been identified, although only a few have been characterized through in vitro expression studies. We conducted an investigation on a male congenital TTP patient with reduced plasma levels of activity. DNA sequence analysis revealed two mutations on chromosome 9 () in the patient's gene. One mutation was a non-synonymous mutation (), while the other was a nonsense mutation (). Both mutations were found to be heterozygous. The patient's parents had no history of thrombocytopenia or neurological symptoms. DNA sequence analysis showed t... More
Congenital thrombotic thrombocytopenic purpura (TTP) is a rare autosomal recessive genetic disorder caused by mutations in the gene. Approximately 200 mutations of the gene have been identified, although only a few have been characterized through in vitro expression studies. We conducted an investigation on a male congenital TTP patient with reduced plasma levels of activity. DNA sequence analysis revealed two mutations on chromosome 9 () in the patient's gene. One mutation was a non-synonymous mutation (), while the other was a nonsense mutation (). Both mutations were found to be heterozygous. The patient's parents had no history of thrombocytopenia or neurological symptoms. DNA sequence analysis showed the patient's father was a heterozygote for the nonsense mutation of the gene (), while the mother was a heterozygote for the non-synonymous mutation of the gene (exon 5: ). To investigate the mechanism behind deficiency in this patient, wild type (WT), , and were transiently expressed in 293-6E cells. Expression studies revealed a significant reduction in enzyme activity and secretion, although the protease was detected within the cells. The 3D structures of the natural and mutated proteins were partially reconstructed using the Phyre2 web server. The mutation that replaces the tyrosine residue at amino acid position 177 with cysteine may result in decreased steric hindrance and a looser structure. This mutation affects the binding of calcium ions and the secretion of the enzyme from intracellular to extracellular compartments.
