Molecular Defects Associated with Antithrombin Deficiency and Dilated Cardiomyopathy in a Japanese Patient

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Objective The molecular basis for the antithrombin (AT) deficiency and dilated cardiomyopathy (DCM) combined in a Japanese patient was investigated. Methods We analyzed candidate genes -SERPINC1 for AT deficiency, and TNNT2 and LMNA for DCM. In addition, we examined the characteristics of recombinant mutant AT and evaluated the LMNA mutation associated with DCM by molecular modeling. Results Genome sequencing of SERPINC1 revealed a C-to-A transversion in exon 6 that resulted in a p.Pro439Thr mutation of AT, which was previously reported as a pleiotropic effect type II AT deficiency (AT Budapest5). However, expression experiments with recombinant 439Thr-AT showed normal heparin affinity, slightly reduced secretion, and low specific activity, which suggested that this mutation exhibits an intermediate feature of type I and type II AT deficiencies. In a survey of gene abnormalities causing DCM, we found no causative gene defect in TNNT2; however, we identified a G-to-C transversion in LMNA that resulted in a novel p.Asp357His mutation in lamin A/C. This acidic-to-basic residue substitution might have impaired the head-to-tail association of two lamin dimers leading to DCM. Further, we identified both SERPINC1 and LMNA mutations in the patients daughter and son, both of whom had AT deficiency. These data suggested that a p.Pro439Thr mutation in SERPINC1 and a p.Asp357His mutation in LMNA might have cosegregated in this family, associated with AT deficiency and DCM, respectively. Conclusions We identified missense mutations in SERPINC1 and LMNA genes to be associated with AT deficiency and DCM, respectively, which might have cosegregated in the family of the patient.
社団法人　日本内科学会の論文

Molecular Defects Associated with Antithrombin Deficiency and Dilated Cardiomyopathy in a Japanese Patient

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