In a man with thrombophilia due to thrombomodulin defect (614486) resulting in an occlusive myocardial infarction at age 52 years, Kunz et al. (2000) found a heterozygous frameshift insertion mutation, 1689insT, in the THBD gene. The mutation predicts an elongated gene product because of substitution of the last 12 C-terminal amino acids by 61 abnormal residues. Pedigree analysis suggested that a brother who had suffered a fatal myocardial infarction probably also carried the mutation. Known risk factors for myocardial infarction, including smoking, increased blood pressure, elevated triglycerides, and elevated cholesterol, were present in the proband and other family members. Carriers of the mutant allele expressed significantly lower amounts of thrombomodulin on the surface of their monocytes and lower levels of soluble thrombomodulin in plasma. Transfection of the mutation in COS-7 cells resulted in reduced cell surface expression of mutant THBD associated with impaired translocation through the endoplasmic reticulum/Golgi apparatus compared to wildtype. In addition, cells expressing abnormal thrombomodulin had a 2.5-fold reduced ability to accelerate the thrombin (F2; 176930)-mediated activation of protein C (PROC; 612283).
