Species: human
Mutation name:
type: None
fertility: None
Comment: Lipodystrophies: rare disorders causing metabolic syndrome# https://www.ncbi.nlm.nih.gov/pubmed/18728124 The metabolic syndrome or insulin resistance syndrome is defined in relationship to generalized or regional adiposity. The criteria for definition of ‘‘metabolic syndrome’’ include measures of obesity, such as waist circumference [1]. Although these definitions are appropriate for the populations at large, several patients develop the metabolic syndrome and complications related to insulin resistance, such as diabetes mellitus, impaired glucose tolerance, hypertriglyceridemia, low levels of high-density lipoprotein (HDL) cholesterol, hepatic steatosis, acanthosis nigricans, polycystic ovarian syndrome, and hyperuricemia, without being overtly obese. Many of these patients have lipodystrophies that are characterized by selective loss of adipose tissue from the body [2]. In comparison to generalized or regional adiposity, lipodystrophies are relatively rare disorders. A simplistic view may suggest that lipodystrophies are mirror images of the disorders of obesity. For example, in contrast to patients with obesity in whom the degree of adipose tissue excess determines the prevalence and severity of insulin resistance and its associated complications, among patients with lipodystrophies, the extent of adipose tissue loss is the major determinant of the insulin resistance and its complications [2]. The underlying mechanisms that cause insulin resistance and the metabolic syndrome in patients with obesity and lipodystrophies may be similar, however. For example, in patients with severe forms of obesity and lipodystrophies, there may be limitation in further storage of triglycerides in adipose tissue, which results indiversion of triglycerides to aberrant sites such as the liver and skeletal muscles and results in insulin resistance [3]. Recent insights into the molecular mechanisms underlying various types of genetic lipodystrophies have added to the understanding of adipocyte biology and have revealed potential pathways that may be implicated in causing insulin resistance [4]. These advances eventually may unravel the mechanisms by which common forms of obesity induce insulin resistance. In this article, we review these recent advances in our knowledge of the clinical features, metabolic abnormalities, and pathogenetic or other bases of various types of lipodystrophies. These disorders may be classified as genetic or acquired types. Further subtypes have been classified according to phenotypic and genotypic features (Box 1). The prevalence of manifestations of the metabolic syndrome varies among the different subtypes of lipodystrophies (Table 1). It is interesting to note that although patients with lipodystrophies have increased prevalence of diabetes, dyslipidemia, and hepatic steatosis, a clear increase in the prevalence of hypertension has not been described. Usually hypertension has been reported after the onset of diabetic nephropathy in most patients.

Species: human
Mutation name:
type: None
fertility: None
Comment: https://www.ncbi.nlm.nih.gov/pubmed/17299075: Familial partial lipodystrophy (FPLD) results from coding sequence mutations either in LMNA, encoding nuclear lamin A/C, or in PPARG, encoding peroxisome proliferator-activated receptor-gamma (PPARgamma). The LMNA form is called FPLD2 (MIM 151660) and the PPARG form is called FPLD3 (MIM 604367). OBJECTIVE: Our objective was to investigate whether the clinical phenotype of this proband is due to mutation(s) in PPARgamma. DESIGN: This is a case report. Patient and Setting: A 31-yr-old female with the clinical phenotype of FPLD3, i.e. lipodystrophy and early childhood diabetes with extreme insulin resistance and hypertriglyceridemia leading to recurrent pancreatitis, was assessed at an academic medical center. RESULTS: The proband was heterozygous for a novel C-->T mutation in the PPARG gene that led to the substitution of arginine 194 in PPARgamma2 isoform, a conserved residue located in the zinc finger structure involved in DNA binding, by tryptophan (R194W). The mutation was absent from the genomes of 100 healthy Caucasians. In vitro analysis of the mutated protein showed that R194W (and R166W in PPARgamma1 isoform) could not bind to DNA and had no transcriptional activity. Furthermore, R194W had no dominant-negative activity. CONCLUSIONS: The R194W mutation in PPARG disrupts its DNA binding activity and through haploinsufficiency leads to clinical manifestation of FPLD3 and the associated metabolic disturbances.