A novel phenotypic expression associated with a new mutation in LMNA gene, characterized by partial lipodystrophy, insulin resistance, aortic stenosis and hypertrophic cardiomyopathy.
BACKGROUND
Lipodystrophies are a heterogeneous group of diseases characterized by abnormal fat distribution. Familial partial lipodystrophy 2 (FPLD2) is due to mutations in the LMNA gene. Previous studies have suggested that LMNA mutations 5' to the nuclear localization signal (NLS) are more likely to underlie laminopathies with cardiac or skeletal muscle involvement, while mutations 3' to the NLS are more likely to underlie lipodystrophy and progeroid syndromes.


OBJECTIVE
To study the clinical and molecular features of a subject with FPLD.


METHODS
We carried out mutational analysis of LMNA gene in a woman with FPLD phenotype and in her relatives. Insulin resistance was evaluated by minimal model. Body composition was evaluated by dual-energy X-ray absorptiometry (DEXA). Echocardiography was done in affected subjects. 3T3-L1 preadipocytes were transfected with wild-type or mutant prelamin A constructs. In transfected cells, lamin A was detected using a Cy3-conjugated monoclonal anti-FLAG antibody.


RESULTS
The patient showed atypical fat distribution, insulin resistance, severe aortic stenosis and hypertrophic cardiomyopathy. She has an affected 11-year-old son, not yet lipodystrophic but with an incipient aortic disease. LMNA sequencing showed that mother and son were both heterozygous for a novel c.1772G > T missense mutation in exon 11, which causes the substitution of the cysteine at residue 591 by a phenylalanine (C591F). In mouse preadipocytes transfected with the mutant human LMNA gene, the mutant lamin A isoform was mislocated in the nucleus.


CONCLUSIONS
This patient shows a novel clinical form of FPLD2, due to a mutation affecting lamin A only, with cardiac involvement.
Araújo-Vilar
David
D
Thyroid and Metabolic Diseases Unit (UETeM), Department of Medicine, School of Medicine, University of Santiago de Compostela, Santiago de Compostela, Spain. medarvi@usc.es
Lado-Abeal
Joaquin
J
Palos-Paz
Fernando
F
Lattanzi
Giovanna
G
Bandín
Manuel A
MA
Bellido
Diego
D
Domínguez-Gerpe
Lourdes
L
Calvo
Carlos
C
Pérez
Oscar
O
Ramazanova
Alia
A
Martínez-Sánchez
Noelia
N
Victoria
Berta
B
Costa-Freitas
Ana Teresa
AT
D041721:3T3-L1 Cells; D000328:Adult; D000818:Animals; D001024:Aortic Valve Stenosis / Q000150:complications / Q000235:genetics*; D001483:Base Sequence; D002312:Cardiomyopathy, Hypertrophic / Q000150:complications / Q000235:genetics*; D005260:Female; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D034904:Lamin Type A / Q000235:genetics*; D052496:Lipodystrophy, Familial Partial / Q000150:complications / Q000235:genetics*; D051379:Mice; D009154:Mutation / Q000502:physiology; D010375:Pedigree; D010641:Phenotype
C494847:LMNA protein, human; D034904:Lamin Type A