1239 Oral Cat: Genetic determinants of coronary heart disease/cardiomyopathies
A NOVEL LAMIN A/C MUTATION IN A DUTCH FAMILY WITH
PREMATURE ATHEROSCLEROSIS
A.A. Weterings 1 , I.A. Van Rijsingen 2 , A.S. Plomp 3 , A.H. Zwinderman 4 ,
R.H. Lekanne Deprez
3
, M.M. Mannens
3
, M.A. Van Den Bergh Weerman
5
,
A.C. Van Der Wal
5
, S.J. Pinto-Sietsma 1,4
1. Academic Medical Center, Department of Vascular Medicine, Amsterdam, Netherlands
2. Academic Medical Center, University of Amsterdam, Department of Cardiology, Amsterdam,
Netherlands
3. Academic Medical Center, Department of Clinical Genetics, Amsterdam, Netherlands
4. Academic Medical Center, Department of Clinical Epidemiology Biostatistics &
Bioinformatics, Amsterdam, Netherlands
5. Academic Medical Center, Department of Pathology, Amsterdam, Netherlands
Background: Premature atherosclerosis sometimes runs an autosomal dominate course within families. Despite that, no major genetic defect has been identified yet. It has been suggested that many different genes might be related to premature atherosclerose and therefore, no major gene effect can be anticipated. We report a novel lamin A/C (LMNA) mutation, c.667G>A, in a family with extensive premature atherosclerosis, diabetes mellitus and steatosis hepatis.
Methods: In silico analysis (using Alamut version 2.2), co-segregation analysis, electron microscopy, extensive phenotypic evaluation and literature comparison were used to determine the significance of this mutation.
Results: The father of three siblings died at the age of 45 years. The three siblings and the brother and sister of the father were referred to the cardiovascular genetics department, because of the premature atherosclerosis and dysmorphic characteristics observed in the father at autopsy. Clinical evaluation revealed a LMNA mutation in the father and the two sons and showed atherosclerosis, insulin resistance and hypertension in the father and dyslipidemia and hepatic steatosis in all individuals with the mutation. Furthermore, skin biopsies of both sons showed nuclear blebbing.
Conclusion: Based on the facts that in silico analysis predicts a possibly pathogenic mutation, the mutation co-segregates with the specific disease characteristics, fibroblasts of mutation carriers showed nuclear blebbing and a similar phenotype was reported to be due to certain missense mutations in LMNA, we conclude that the novel mutation we found is a pathogenic mutation, resembling Dunnigan-type familial partial lipodystrophy.