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Molecular defects associated with antithrombin deficiency and dilated cardiomyopathy in a Japanese patient
Yuta Fujimori1, Hidemi Okimatsu, Takahiro Kashiwagi
1Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya.
Insights
Researchers investigated the genetic causes of combined antithrombin deficiency and dilated cardiomyopathy in a Japanese patient. They identified novel mutations in SERPINC1 and LMNA genes, suggesting cosegregation within the family.
Area of Science:
- Genetics
- Cardiology
- Molecular Biology
Background:
- Antithrombin (AT) deficiency and dilated cardiomyopathy (DCM) are distinct conditions.
- Investigating combined genetic defects can reveal novel molecular pathways.
Observation:
- A Japanese patient presented with both AT deficiency and DCM.
- Genetic analysis revealed a p.Pro439Thr mutation in SERPINC1 and a novel p.Asp357His mutation in LMNA.
Findings:
- The SERPINC1 mutation showed intermediate characteristics of type I and type II AT deficiencies.
- The LMNA mutation, an acidic-to-basic residue substitution, may impair lamin A/C function, leading to DCM.
- Both mutations were found to cosegregate in the patient's offspring, who exhibited AT deficiency.
Implications:
- Identified missense mutations in SERPINC1 and LMNA are associated with AT deficiency and DCM, respectively.
- These findings highlight the potential for combined genetic disorders and their inheritance patterns.
- Understanding these mutations provides insights into the molecular mechanisms underlying both conditions.
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 patient's 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.
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