Lamin A/C gene - Sex-determined expression of mutations in dunnigan-type familial partial lipodystrophy and absence of coding mutations in congenitaland acquired generalized lipoatrophy

Missense mutations of the lamin A/C gene, LMNA, have been recently identifi ed in Dunnigan-type familial partial lipodystrophy (FPLD), which belongs to a heterogeneous group of rare disorders affecting adipose tissue distribut ion and metabolism. In this study, we sequenced the LMNA coding region from patients presenting with FPLD or other forms of lipodystrophy. We identifi ed two heterozygous mutations in exon 8, R482W and R482Q, in FPLD patients (six families and one individual) with various clinical presentations. In a ddition, we found a novel heterozygous mutation (R584H) in exon 11, encodin g specifically the lamin A isoform, in a patient with typical FPLD. Clinica l and biochemical investigations in FPLD patients revealed that the express ion and the severity of the phenotype were markedly dependent on sex, with female patients being more markedly affected. In subjects with generalized lipoatrophy, either congenital (13 case subjects) or acquired (14 case subj ects), or Barraquer-Simon syndrome (2 case subjects), the entire LMNA codin g sequence was normal. Although FPLD mutations are predominantly localized in exon 8 of LMNA, the finding of a novel mutation at codon 584, together w ith the R582H heterozygous substitution recently described, confirms that t he C-terminal region specific to the lamin A isoform is a second susceptibi lity region for mutations in FPLD.