Mutational and haplotype analyses of families with familial partial lipodystrophy (Dunnigan variety) reveal recurrent missense mutations in the globular C-terminal domain of lamin A/C

Abstract

Familial partial lipodystrophy (FPLD), Dunnigan variety, is an autosomal dominant disorder characterized by marked loss of subcutaneous adipose tissue from the extremities and trunk but by excess fat deposition in the head and neck. The disease is frequently associated with profound insulin resistance, dyslipidemia, and diabetes. We have localized a gene for FPLD to chromosome 1q21-q23, and it has recently been proposed that nuclear lamin A/C is altered in FPLD, on the basis of a novel missense mutation (R482Q) in five Canadian probands. This gene had previously been shown to be altered in autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD-AD) and in dilated cardiomyopathy and conduction-system disease. We examined 15 families with FPLD for mutations in lamin A/C. Five families harbored the R482Q alteration that segregated with the disease phenotype. Seven families harbored an R482W alteration, and one family harbored a G465D alteration. All these mutations lie within exon 8 of the lamin A/C gene-an exon that has also been shown to harbor different missense mutations that are responsible for EDMD-AD. Mutations could not be detected in lamin A/C in one FPLD family in which there was linkage to chromosome 1q21-q23. One family with atypical FPLD harbored an R582H alteration in exon 11 of lamin A. This exon does not comprise part of the lamin C coding region. All mutations in FPLD affect the globular C-terminal domain of the lamin A/C protein. In contrast, mutations responsible for dilated cardiomyopathy and conduction-system disease are observed in the rod domain of the protein. The FPLD mutations R482Q and R482W occurred on different haplotypes, indicating that they are likely to have arisen more than once.

Figure 1

Pedigrees of families with FPLD, Dunnigan variety. The pedigrees and each family member are numbered for identification. Unblackened squares denote unaffected males; blackened squares, affected males; unblackened circles, unaffected females; blackened circles, affected females; circles and squares with a diagonal slash, deceased subjects; gray-shaded circles and squares, phenotype uncertain. Vertical arrows denote subjects for which DNA was available, whereas slanting arrows indicate probands from each family.

Figure 2

Amino-acid-sequence alignment of lamins A, B, and C from various species. A, Conservation of Gly465 and Arg482 of lamin A/C is shown in boldface type. B, Conservation of Arg582 of lamin A is shown in boldface type. Xenopus = Xenopus laevis.

Figure 3

Locations of mutations in lamin A/C in EDMD-AD (squares), dilated cardiomyopathy with conduction-system-disease defects (ovals), and FPLD (diamonds). Organization of the proteins is also indicated, and locations of the hydrophobic head and carboxy-terminal regions, with respect to the rod domain, are shown. The regions of lamin A and C that diverge from each other are indicated at the carboxyl-termini.