TY - JOUR
T1 - Mutational and haplotype analyses of families with familial partial lipodystrophy (Dunnigan variety) reveal recurrent missense mutations in the global C-terminal domain of lamin A/C
AU - Speckman, Rebecca A.
AU - Garg, Abhimanyu
AU - Du, Fenghe
AU - Bennett, Lynda
AU - Veile, Rose
AU - Arioglu, Elif
AU - Taylor, Simeon I.
AU - Lovett, Michael
AU - Bowcock, Anne M.
N1 - Funding Information:
We thank the members of the families studied, for their invaluable contribution to this project; Drs. David C. Robbins, Robert A. Kreisberg, Andrea Dunaif, Richard Legro, Mark D. Shepherd, Irene Sills, Margo Denke, Steven Aronoff, Noralane M. Lindor, Tu T. Nguyen, and Evelyn Cintron, for referring family members for investigation; Angela Osborn and Rebecca Cochran, for technical help; and the nursing and dietetic services of the General Clinical Research Center, for patient care support. This work was supported by National Institutes of Health grants R01-DK54387 and M01-RR00633, the Southwestern Medical Foundation, and the Washington University Medical Center Division of Human Genetics.
PY - 2000
Y1 - 2000
N2 - 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.
AB - 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.
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U2 - 10.1086/302836
DO - 10.1086/302836
M3 - Article
C2 - 10739751
AN - SCOPUS:0033912260
SN - 0002-9297
VL - 66
SP - 1192
EP - 1198
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 4
ER -