This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Morel, C. F. Articles by Hegele, R. A. Search for Related Content PubMed PubMed Citation Articles by Morel, C. F. Articles by Hegele, R. A. Related Collections Pediatric Endocrinology Lipid Diabetes and Insulin Metabolism

A LMNA Splicing Mutation in Two Sisters with Severe Dunnigan-Type Familial Partial Lipodystrophy Type 2

Department of Human Genetics (C.F.M., M.A.T., W.D.F.), McGill University, Montréal, Québec, Canada H3A 1B1; Division of Medical Genetics (W.D.F.), Department of Medicine, McGill University Health Centre, Montréal, Québec, Canada H3T 1E2; Vascular Biology Group (H.C., C.H.O., J.G.P., R.A.H.), Robarts Research Institute, London, Ontario, Canada N6A 5K8; and Department of Medicine (J.G.P., R.A.H.), Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada N6A 5C1

Address all correspondence and requests for reprints to: Robert A. Hegele, M.D., F.R.C.P.C., F.A.C.P., Blackburn Cardiovascular Genetics Laboratory, Robarts Research Institute, London, Ontario, Canada N6A 5K8. E-mail: hegele{at}robarts.ca.

Context: To date, all cases of familial partial lipodystrophy type 2 (FPLD2; Mendelian Inheritance in Man 151660) result from missense mutations in LMNA, which encodes nuclear lamin A/C (Mendelian Inheritance in Man 150330).

Objective: The objective of the study was to carry out mutational analysis of LMNA in two sisters with a particularly severe FPLD2 phenotype.

Design: This was a descriptive case report with molecular studies.

Setting: The study was conducted at a referral center.

Patients: We report two sisters of South Asian origin. The first presented with acanthosis nigricans at age 5 yr, diabetes with insulin resistance, hypertension and hypertriglyceridemia at age 13 yr, and partial lipodystrophy starting at puberty. Her sister and their mother had a similar metabolic profile and physical features, and their mother died of vascular disease at age 32 yr.

Interventions: There were no interventions.

Main Outcome Measures and Results: LMNA sequencing showed that the sisters were each heterozygous for a novel G>C mutation at the intron 8 consensus splice donor site, which was absent from the genomes of 300 healthy individuals. The retention of intron 8 in mRNA predicted a prematurely truncated lamin A isoform (516 instead of 664 amino acids) with 20 nonsense 3'-terminal residues. The mutant lamin A isoform failed to interact normally with emerin and failed to localize to the nuclear envelope.

Conclusions: This is the first LMNA splicing mutation to be associated with FPLD2, and it causes a severe clinical and metabolic phenotype.

This article has been cited by other articles:

				C.-Y. Tsao and J. R. Mendell Partial Epilepsy in an Adolescent Male With Limb-Girdle Muscular Dystrophy 1B J Child Neurol, March 1, 2009; 24(3): 346 - 348. [Abstract] [PDF]

				A. Decaudain, M.-C. Vantyghem, B. Guerci, A.-C. Hecart, M. Auclair, Y. Reznik, H. Narbonne, P.-H. Ducluzeau, B. Donadille, C. Lebbe, et al. New Metabolic Phenotypes in Laminopathies: LMNA Mutations in Patients with Severe Metabolic Syndrome J. Clin. Endocrinol. Metab., December 1, 2007; 92(12): 4835 - 4844. [Abstract] [Full Text] [PDF]

				R. A. Hegele, T. R. Joy, S. A. Al-Attar, and B. K. Rutt Thematic review series: Adipocyte Biology. Lipodystrophies: windows on adipose biology and metabolism J. Lipid Res., July 1, 2007; 48(7): 1433 - 1444. [Abstract] [Full Text] [PDF]