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.
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.
Authors: Beryl B Cummings; Jamie L Marshall; Taru Tukiainen; Monkol Lek; Sandra Donkervoort; A Reghan Foley; Veronique Bolduc; Leigh B Waddell; Sarah A Sandaradura; Gina L O'Grady; Elicia Estrella; Hemakumar M Reddy; Fengmei Zhao; Ben Weisburd; Konrad J Karczewski; Anne H O'Donnell-Luria; Daniel Birnbaum; Anna Sarkozy; Ying Hu; Hernan Gonorazky; Kristl Claeys; Himanshu Joshi; Adam Bournazos; Emily C Oates; Roula Ghaoui; Mark R Davis; Nigel G Laing; Ana Topf; Peter B Kang; Alan H Beggs; Kathryn N North; Volker Straub; James J Dowling; Francesco Muntoni; Nigel F Clarke; Sandra T Cooper; Carsten G Bönnemann; Daniel G MacArthur Journal: Sci Transl Med Date: 2017-04-19 Impact factor: 17.956
Authors: Gregory P Holmes-Hampton; Daniel R Crooks; Ronald G Haller; Shuling Guo; Susan M Freier; Brett P Monia; Tracey A Rouault Journal: Hum Mol Genet Date: 2016-12-01 Impact factor: 6.150
Authors: Marc Gregory Yu; Hillary A Keenan; Hetal S Shah; Scott G Frodsham; David Pober; Zhiheng He; Emily A Wolfson; Stephanie D'Eon; Liane J Tinsley; Susan Bonner-Weir; Marcus G Pezzolesi; George Liang King Journal: J Clin Invest Date: 2019-07-02 Impact factor: 14.808
Authors: Laura S Kremer; Daniel M Bader; Christian Mertes; Robert Kopajtich; Garwin Pichler; Arcangela Iuso; Tobias B Haack; Elisabeth Graf; Thomas Schwarzmayr; Caterina Terrile; Eliška Koňaříková; Birgit Repp; Gabi Kastenmüller; Jerzy Adamski; Peter Lichtner; Christoph Leonhardt; Benoit Funalot; Alice Donati; Valeria Tiranti; Anne Lombes; Claude Jardel; Dieter Gläser; Robert W Taylor; Daniele Ghezzi; Johannes A Mayr; Agnes Rötig; Peter Freisinger; Felix Distelmaier; Tim M Strom; Thomas Meitinger; Julien Gagneur; Holger Prokisch Journal: Nat Commun Date: 2017-06-12 Impact factor: 14.919
Authors: Ragesh Panikkath; Deepa Panikkath; S Sanchez-Iglesias; D Araujo-Vilar; Joaquin Lado-Abeal Journal: J Investig Med High Impact Case Rep Date: 2016-07-15