Lamin A/C gene: sex-determined expression of mutations in Dunnigan-type familial partial lipodystrophy and absence of coding mutations in congenital and acquired generalized lipoatrophy.

Abstract

Missense mutations of the lamin A/C gene, LMNA, have been recently identified in Dunnigan-type familial partial lipodystrophy (FPLD), which belongs to a heterogeneous group of rare disorders affecting adipose tissue distribution and metabolism. In this study, we sequenced the LMNA coding region from patients presenting with FPLD or other forms of lipodystrophy. We identified two heterozygous mutations in exon 8, R482W and R482Q, in FPLD patients (six families and one individual) with various clinical presentations. In addition, we found a novel heterozygous mutation (R584H) in exon 11, encoding specifically the lamin A isoform, in a patient with typical FPLD. Clinical and biochemical investigations in FPLD patients revealed that the expression 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 subjects), or Barraquer-Simon syndrome (2 case subjects), the entire LMNA coding sequence was normal. Although FPLD mutations are predominantly localized in exon 8 of LMNA, the finding of a novel mutation at codon 584, together with the R582H heterozygous substitution recently described, confirms that the C-terminal region specific to the lamin A isoform is a second susceptibility region for mutations in FPLD.

Human lipodystrophies linked to mutations in A-type lamins and to HIV protease inhibitor therapy are both associated with prelamin A accumulation, oxidative stress and premature cellular senescence

“…Six female patients with insulin resistance and/ or diabetes associated with abnormal body fat distribution, with lipoatrophy or android habitus, were referred to our laboratory for LMNA genetic testing. They were found to harbor the R482W mutation associated with familial partial lipodystrophy of the Dunnigan type (patient P6) 33 or previously undescribed heterozygous LMNA substitutions (D47Y, L92F, L387V, R399H, L421P). Only the patient with the LMNA D47Y mutation exhibited clinical signs of premature ageing.…”

Mouse models of the laminopathies

“…These changes begin at puberty. Prior to adolescence, children are overtly normal, suggesting a possible hormonal influence on the initiation of disease phenotypes [33]. Progressive insulin resistance accompanies the redistribution or remodeling of adipose tissue, often resulting in frank type II diabetes mellitus.…”

Familial partial lipodystrophy associated with compound heterozygosity for novel mutations in the LMNA gene

“…It was suggested that the fact that the R582H mutation is lamin A specific (exon 11 is not transcribed in lamin C), as opposed to exon 8 mutations which affect the structure of lamins A and C, might account for the subtle Köbberling-type FPL phenotype seen in carriers of this mutation [4]. However, this explanation is not supported by two reports describing carriers of an R584H mutation with typical Dunnigan-type FPL [5,6]. Three patients in kindred C (subjects CI, CIV and CVI) were notable for a lack of subcutaneous truncal as well as subcutaneous limb fat (Fig.…”

“…Serine 583 and threonine 528 are highly conserved residues (identical in human, rat, mouse, chick and Xenopus). The S583L mutation is bracketed by two known mutations in exon 11, R582H [4] and R584H [5,6], which are only expressed in lamin A. Although the T528M mutation is not expected to alter the structure of the globular C-terminal domain substantially, it may modify the phenotypic impact of the S583L mutation.…”