Instituto Valenciano de Microbiología

Masía El Romeral
Ctra. de Bétera a San Antonio Km. 0.3
46117 Bétera (Valencia)
Phone. 96 169 17 02
Fax 96 169 16 37
CIF B-96337217


Congenital generalized lipodystrophy – AGPAT2, BSCL2, CAV1 and CAVIN1 genes

Congenital generalized lipodystrophy, also known as Berardinelli-Seip syndrome or Berardinelli-Seip congenital lipodystrophy (BSCL), is a rare disease characterized by the absence of adipose tissue. This deficiency entails having to store fats in other parts of the body, such as the liver and muscles, which causes serious health problems. The signs and symptoms of this syndrome are evident from birth or early childhood. Frequent features of this process include hypertriglyceridemia and insulin resistance. Insulin resistance in adolescence can become diabetes mellitus. This syndrome also produces liver steatosis, with consequent damage to the liver. The accumulation of fats in the heart can cause hypertrophic cardiomyopathy, which can cause heart failure, arrhythmia and sudden death.

Likewise, individuals with this syndrome have a distinctive physical appearance, since the combination of the almost total absence of adipose tissue and excessive growth of muscle tissue makes them appear very muscular. They also tend to have a large chin, prominent orbital ridges and navel, and large hands and feet. Affected women may suffer from clitoromegaly, hirsutism, irregular menstrual periods and ovarian cysts, which may be related to hormonal changes. Individuals with acanthosis nigricans have also been found, an alteration in which the areas of the body where there are more folds (armpits, elbows, knees), the skin appears more thickened, dark and velvety.

Four forms of congenital generalized lipodystrophy have been described, which are fundamentally distinguished by their genetic cause, although the types also have some differences in their typical signs and symptoms. For example, in addition to the features described above, some people with type 1 develop cysts in the long bones of the arms and legs after puberty. Type 2 may be associated with intellectual disability, which is usually mild to moderate. Type 3 seems to lead to poor growth and short stature, along with other health problems. Type 4 is associated with muscle weakness, developmental delay, joint abnormalities, pyloric stenosis, and severe arrhythmia that can cause sudden death.

This syndrome is due to mutations in the AGPAT2, BSCL2, CAV1 and CAVIN1 genes, which are responsible for types I, II, III and IV, respectively. The proteins encoded by these genes play important roles in the development and function of adipocytes, so mutations in any of these genes disrupt the normal development or function of adipocytes. Consecuently, the body is unable to metabolize and store fats correctly, so the almost total absence of body fat underlies the various signs and symptoms of this syndrome.

Mutations in the AGPAT2 (1-acylglycerol-3-phosphate O-acetyltransferase 2) gene, located on the long arm of chromosome 9 (9q34.3), are responsible for type I. This gene encodes the enzyme AGPAT2, which plays a critical role in the growth and development of adipocytes. This enzyme encodes two important types of lipids: glycerophospholipids and triacylglycerides, which convert lysophosphatidic acid (LPA) into phosphatidic acid (PA). At least 26 mutations in the AGPAT2 gene have been identified in people with this syndrome. The abnormal AGPAT2 enzyme can reduce the production and storage of triglycerides in adipocytes, which would make these cells unable to store fats. The defective enzyme can also reduce the concentrations of glycerophospholipids in adipocytes, modifying the structure of the cell membrane and disrupting normal signaling inside these cells.

The BSCL2 gene is affected in type II. This gene is located on the long arm of chromosome 11 (11q12.3) and encodes the synthesis of the seipine protein, which is found in the membrane of the endoplasmic reticulum of cells and whose function is unknown. The BSCL2 gene is active in all cells, particularly in motor neurons and brain cells. This gene is also present in adipocytes, and it is suggested that seipin protein may play a critical role in the early development of these cells. The protein encoded from the BSCL2 gene is also present in the brain and in the testicles, although its function in these tissues is unknown. A loss of this protein in the brain could explain why many people with type II Berardinelli-Seip syndrome have intellectual disability. At least 25 mutations in the BSCL2 gene have been described as responsible for type II. Most genetic changes result in the synthesis of a non-functional seipin that causes the development of abnormal adipocytes.

 Mutations in the CAV1 gene (caveolin 1), located on the long arm of chromosome 7 (7q31.2), are responsible for type III. This gene encodes the caveolin-1 protein, which seems to have various functions in cells and tissues throughout the body. Caveolin-1 is the main component of caveolae, which are invaginations of the plasma membrane involved in endocytosis, intracellular processing of molecules, maintenance of cell structure, and in the regulation of chemical signaling pathways. Caveolae are particularly numerous in adipocytes, where they appear to be essential for proper transport, processing and storage of fats. Caveolin-1 is also found in other cells, where they regulate various chemical signaling pathways, through which it participates in the regulation of growth and proliferation, movement, differentiation, survival and apoptosis of these cells. The functions of caveolin-1 probably differ depending on the type of cell and the part of the cell where the protein is found. At least one mutation has been identified in the CAV1 gene that replaces an amino acid with a premature stop signal at position 38 of the caveolin-1 protein (Glu38Ter or E38X.) This mutation inhibits the synthesis of any functional caveolin-1. Although it is not clear how the absence of this protein gives rise to the particular characteristics of congenital lipodystrophy type III, its absence probably alters the development and normal function of adipocytes.

Mutations in the CAVIN1 (caveolae associated protein 1) gene, located on the long arm of chromosome 17 (17q21.2), are responsible for type IV Berardinelli-Seip syndrome. This gene encodes the protein cavin-1, which is found in cells and tissues throughout the body, although it is more abundant in several types of cells: osteoblasts, muscle cells and adipocytes. It is believed that cavin-1 plays, like caveolin-1 (encoded by CAV1), an essential role in the formation and stabilization of caveolae. In addition, studies suggest that this protein is involved in the repair of damage to the outer cell membrane, cell growth and division, cell movement, cell senescence and the regulation of various chemical signaling pathways. The functions of cavin-1 probably differ depending on the type of cell and the part of the cell where the protein is found. At least ten mutations in the CAVIN1 gene have been identified in individuals with type IV disease. These mutations inhibit the synthesis of any functional cavin-1, which probably alters the formation of caveolae. Although the deficiency of these structures in the cell membrane alters many cellular functions, it is not specifically known how the absence of cavin-1 results in a loss of body fat and the other associated health problems.

This disease is inherited with an autosomal recessive pattern, which means that both copies of the gene in each cell must have mutations for the alteration to be expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually do not show signs and symptoms of the disease.

Tests performed in IVAMI: in IVAMI we perform the detection of mutations associated with congenital generalized lipodystrophy, by means of the complete PCR amplification of the exons of the AGPAT2, BSCL2, CAV1 and CAVIN1 genes, and their subsequent sequencing.

Recommended samples: non-coagulated blood obtained with EDTA for separation of blood leukocytes, or a card with a dried blood sample (IVAMI can mail the card to deposit the blood sample).