Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
Atherosclerosis. 2013 Jul;229(1):169-73. doi: 10.1016/j.atherosclerosis.2013.04.016. Epub 2013 Apr 20.
We report a novel lamin A/C (LMNA) mutation, p.Glu223Lys, in a family with extensive atherosclerosis, diabetes mellitus and steatosis hepatis.
Sequence analysis of LMNA (using Alamut version 2.2), co-segregation analysis, electron microscopy, extensive phenotypic evaluation of the mutation carriers and literature comparison were used to determine the loss of function of this mutation.
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. The novel LMNA mutation, p.Glu223Lys, was identified in the proband and his two sons. Clinical evaluation revealed atherosclerosis, insulin resistance and hypertension in the proband and dyslipidemia and hepatic steatosis in all the patients with the mutation.
Based on the facts that in silico analysis predicts a possibly pathogenic mutation, the mutation co-segregates with the disease, only fibroblasts from mutation carriers show nuclear blebbing and a similar phenotype was reported to be due to missense mutations in LMNA we conclude that we deal with a pathogenic mutation. We conclude that the phenotype is similar to Dunnigan-type familial partial lipodystrophy.
我们报道了一个家族性广泛动脉粥样硬化、糖尿病和肝脂肪变性中新型的核纤层蛋白 A/C（LMNA）突变，p.Glu223Lys。
使用 Alamut 版本 2.2 对 LMNA 进行序列分析，共分离分析，电子显微镜检查，对突变携带者进行广泛的表型评估以及文献比较，以确定该突变的功能丧失。
三个兄弟姐妹的父亲在 45 岁时去世。由于在父亲尸检中观察到早发性动脉粥样硬化和畸形特征，这三个兄弟姐妹以及父亲的兄弟姐妹被转介到心血管遗传学部门。在先证者及其两个儿子中发现了新型的 LMNA 突变，p.Glu223Lys。临床评估显示先证者和所有突变携带者均存在动脉粥样硬化，胰岛素抵抗和高血压，而血脂异常和肝脂肪变性。
基于以下事实，即计算机分析预测了可能的致病性突变，突变与疾病共分离，只有突变携带者的成纤维细胞显示核泡状，并且类似的表型据报道是由于 LMNA 的错义突变所致，我们得出结论，我们处理的是一种致病性突变。我们得出的结论是，表型类似于 Dunnigan 型家族性部分脂肪营养不良。
