Concerning the Gly15Gly polymorphism, the TT genotype was found in 275 subjects (79.9%), the TG genotype in 67 subjects (19.5%) and the GG genotype in 2 subjects (0.6%): one with maturity onset diabetes of young age (MODY-diabetes) and one with Lipoatrophic Diabetes Syndrome (LPDS).
Homozygous defects in LMNA, encoding lamin A/C nuclear-envelope proteins, cause autosomal recessive axonal neuropathy in human (Charcot-Marie-Tooth disorder type 2) and mouse.
In agreement with these in vitro results indicating conversion of FPLD2 brown preadipocytes toward the white lineage, adipose tissue from FPLD2 patient neck, an area of brown adipogenesis, showed a white phenotype reminiscent of its brown origin.
In contrast, both overexpression of LMNAR482W in primary human preadipocytes and endogenous expression of A-type lamins R482W in FPLD2 patient fibroblasts, reduce A-type lamins-SREBP1 in situ interactions and upregulate a large number of SREBP1 target genes.
In our experience, PCOS secondary to a missense mutation in the LMNA gene, known as familial partial lipodystrophy type 2 (FPLD2), is the most frequent form of PCOS secondary to severe IR due to genetically determined lipodystrophy.
In patients with unexplained pancreatitis and hypertriglyceridemia, lipodystrophies such as familial partial lipodystrophy type 2 (FPLD2; Dunnigan type, due to LMNA mutations) should be considered.
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.
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.
Nuclear envelope alterations in fibroblasts from patients with muscular dystrophy, cardiomyopathy, and partial lipodystrophy carrying lamin A/C gene mutations.
On the other hand, patients with FPLD2 presented significant higher levels of insulin (median 11.2 vs 5.3; p = 0.015), triglycerides (184.9 ± 75.4 vs 89.1 ± 51.0; p < 0.01) and DPP4 (4.89 ± 0.92 vs 3.93 ± 1.08; p = 0.04).
Our data demonstrate that lamin A/C gene mutations responsible for FPLD2 and related lipodystrophies are associated with transforming growth factor-β activation and an extracellular matrix imbalance in adipose tissue, suggesting that targeting these alterations could be the basis of novel therapies.
Patients with lipoatrophic diabetes (BSCL) have high serum concentrations of sclerostin, normal or high BMD, and reasonable trabecular bone mass measured by TBS.