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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.

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