Nuclear envelope disorganization in fibroblasts from FPLD patients

The familial partial lipodystrophy of the Dunnigan type (FPLD) is a rare autosomal dominant disease characterized by a post-pubertal regression of the subcutaneous fat from limbs and trunk contrasting with its accumulation in face and neck. This lipodystrophy is associated with insulin resistance and hypertriglyceridemia, which could be secondary to adipose tissue involution. Missense heterozygous mutations in the LMNA gene, affecting the C-terminal domain of lamins A and C, have been recently shown to be responsible for the disease (Cao and Hegele, 2000; Shackleton et al., 2000; Speckman et al., 2000; Vigouroux et al., 2000). However, the link between a mutation in lamins A and C (LaA/C), ubiquitous nuclear envelope (NE) proteins and the selective regression of adipose tissue is elusive. Furthermore, other alterations in LMNA, widely distributed all along the gene, result in skeletal or cardiac muscular diseases, or both (Bonne et al., 1999; Fatkin et al., 1999; Muchir et al., 2000). Lamins A and C are major components of the nuclear lamina. They are members of the intermediate filaments protein family, with a similar primary and secondary structure (McKeon et al., 1986; Fisher et al., 1986). The LMNA gene generates lamin A and lamin C by alternative RNA splicing (Lin and Worman, 1993). These proteins are identical for their first 566 amino acids, which encompass the N-terminal head, the central rod helicoidal domain, and most of the tail domain. Thus the R482Q/W mutations, which are the most frequent mutations in FPLD, affect both A and C lamins. Lamins B1 and B2 are the other major components of the lamin family of proteins and are coded by different genes (Stuurman et al., 1998; Worman and Courvalin, 2000). Aand B-type lamins polymerize in various ratios to form the nuclear lamina, a protein network that is located between inner nuclear membrane and chromatin. Lamin genes are differentially expressed during development and cell maturation; B-type lamins are constitutive and A-type lamins are preferentially expressed in differentiated nonproliferating cells (Stewart and Burke, 1987; Guilly et al., 1987; Guilly et al., 1990). A specific set of nuclear integral proteins interacts with lamina and could mediate its attachment to the inner nuclear membrane (INM) (Worman and Courvalin, 2000). Among these proteins, the lamin B receptor (LBR) and lamina associated protein 2 β (LAP2β) interact more specifically with B-type lamins (Furukawa et al., 1995; Worman et al., 1988), whereas emerin preferentially binds to A-type lamins (Fairley et al., 1999; Sullivan et al., 1999; Clements et al., 2000). The lamina is tightly associated with nuclear pore complexes 4459