Heterogeneity of nuclear lamin A mutations in Dunnigan-type familial partial lipodystrophy

We previously identified a novel mutation, namely LMNA.R482Q, that was foun d 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 comp ound heterozygote for both V440M and R482Q. The findings indicated that I) a spectrum of LMNA mutations underlies FPLD; 2) aberrant lamin A, and not l amin C, is likely to underlie FPLD, as R584H occurs within LMNA sequence th at is specific for lamin A; 3) the V440M mutation may not cause lipodystrop hy on its own; 4) compound heterozygosity for V440M and R482Q is associated with a relatively more severe FPLD phenotype, but not with complete lipody strophy; and 5) variation in the severity of the phenotype might be related to environmental factors.