The Journal of clinical endocrinology and metabolism · 2006
A LMNA splicing mutation in two sisters with severe Dunnigan-type familial partial lipodystrophy type 2.
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Morel Chantal F, Thomas Mary Ann, Cao Henian, O'Neil Caroline H, Pickering J Geoffrey, Foulkes William D, Hegele Robert A
Аннотация
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.
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.
Предметные рубрики MeSH
Acanthosis NigricansAdultAsiaBlotting, WesternCanadaDNA Mutational AnalysisDiabetes Mellitus, LipoatrophicDiabetes Mellitus, Type 2FemaleFluorescent Antibody TechniqueHeterozygoteHumansHypertensionHypertriglyceridemiaInsulin ResistanceIntronsLamin Type AMembrane ProteinsMicroscopy, FluorescenceMutationNuclear ProteinsPhenotypeRNA SplicingRNA, MessengerThymopoietinsTransfection