A LMNA Splicing Mutation in Two Sisters with Severe Dunnigan-Type Familial Partial Lipodystrophy Type 2
CF Morel, MA Thomas, H Cao, CH O'Neil… - The Journal of …, 2006 - academic.oup.com
The Journal of Clinical Endocrinology & Metabolism, 2006•academic.oup.com
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 …
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 …
Abstract
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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