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
Ra. Speckman et al., 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, AM J HU GEN, 66(4), 2000, pp. 1192-1198
Citations number
26
Categorie Soggetti
Research/Laboratory Medicine & Medical Tecnology","Molecular Biology & Genetics
Familial partial lipodystrophy (FPLD), Dunnigan variety, is an autosomal do
minant disorder characterized by marked loss of subcutaneous adipose tissue
from the extremities and trunk but by excess fat deposition in the head an
d neck. The disease is frequently associated with profound insulin resistan
ce, dyslipidemia, and diabetes. We have localized a gene for FPLD to chromo
some 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 aut
osomal 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 alteratio
n that segregated with the disease phenotype. Seven families harbored an R4
82W alteration, and one family harbored a G465D alteration. All these mutat
ions lie within exon 8 of the lamin A/C gene-an exon that has also been sho
wn 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 t
here was linkage to chromosome 1q21-q23. One family with atypical FPLD harb
ored 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 globul
ar C-terminal domain of the lamin A/C protein. In contrast, mutations respo
nsible for dilated cardiomyopathy and conduction-system disease are observe
d in the rod domain of the protein. The FPLD mutations R482Q and R482W occu
rred on different haplotypes, indicating that they are likely to have arise
n more than once.