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

• Published in: The journal of clinical endocrinology and metabolism 2000-09, Vol.85 (9), p.3431-3435
• Main Authors: HEGELE, Robert A, HENIAN CAO, ANDERSON, Carol M, HRAMIAK, Irene M
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Dermatology; DNA - analysis; DNA - genetics; Genotype; Hereditary diseases of the skin. Congenital diseases of the skin. Haemangioma of the skin, of mucosae and of soft tissue; Heterozygote; Humans; Lamin Type A; Lamins; Lipodystrophy - genetics; Medical sciences; Mutation, Missense - genetics; Nuclear Proteins - genetics; Pedigree; Phenotype
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.85.9.3431

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.