Hegele R A, Cao H, Anderson C M, Hramiak I M
Robarts Research Institute and Department of Medicine, University of Western Ontario, London, Canada.
J Clin Endocrinol Metab. 2000 Sep;85(9):3431-5. doi: 10.1210/jcem.85.9.6822.
We previously identified a novel mutation, namely LMNA R482Q, that was found to underlie Dunnigan-type partial lipodystrophy (FPLD) and diabetes in an extended Canadian kindred. We have since sequenced LMNA in five additional Canadian FPLD probands and herein report three new rare missense mutations in LMNA: V440M, R482W, and R584H. One severely affected subject was a compound heterozygote for both V440M and R482Q. The findings indicated that 1) a spectrum of LMNA mutations underlies FPLD; 2) aberrant lamin A, and not lamin C, is likely to underlie FPLD, as R584H occurs within LMNA sequence that is specific for lamin A; 3) the V440M mutation may not cause lipodystrophy on its own; 4) compound heterozygosity for V440M and R482Q is associated with a relatively more severe FPLD phenotype, but not with complete lipodystrophy; and 5) variation in the severity of the phenotype might be related to environmental factors.
我们之前鉴定出一种新的突变，即LMNA基因R482Q突变，在一个加拿大的大家族中发现该突变是邓尼根型部分脂肪营养不良（FPLD）和糖尿病的病因。此后，我们对另外5名加拿大FPLD先证者的LMNA基因进行了测序，在此报告LMNA基因中的3个新的罕见错义突变：V440M、R482W和R584H。一名严重受累的受试者是V440M和R482Q的复合杂合子。这些发现表明：1）一系列LMNA基因突变是FPLD的病因；2）异常的核纤层蛋白A而非核纤层蛋白C可能是FPLD的病因，因为R584H发生在核纤层蛋白A特有的LMNA基因序列内；3）V440M突变本身可能不会导致脂肪营养不良；4）V440M和R482Q的复合杂合性与相对更严重的FPLD表型相关，但与完全性脂肪营养不良无关；5）表型严重程度的差异可能与环境因素有关。
