Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Congenital generalized lipodystrophy, or Berardinelli-Seip syndrome (BSCL), is a rare autosomal recessive disease characterized by a near-absence of adipose tissue from birth or early infancy and severe insulin resistance. Other clinical and biological features include acanthosis nigricans, hyperandrogenism, muscular hypertrophy, hepatomegaly, altered glucose tolerance or diabetes mellitus, and hypertriglyceridemia. A locus (BSCL1) has been mapped to 9q34 with evidence of heterogeneity. Here, we report a genome screen of nine BSCL families from two geographical clusters (in Lebanon and Norway). We identified a new disease locus, designated BSCL2, within the 2.5-Mb interval flanked by markers D11S4076 and D11S480 on chromosome 11q13. Analysis of 20 additional families of various ethnic origins led to the identification of 11 families in which the disease cosegregates with the 11q13 locus; the remaining families provide confirmation of linkage to 9q34. Sequence analysis of genes located in the 11q13 interval disclosed mutations in a gene homologous to the murine guanine nucleotide-binding protein (G protein), gamma3-linked gene (Gng3lg) in all BSCL2-linked families. BSCL2 is most highly expressed in brain and testis and encodes a protein (which we have called seipin) of unknown function. Most of the variants are null mutations and probably result in a severe disruption of the protein. These findings are of general importance for understanding the molecular mechanisms underlying regulation of body fat distribution and insulin resistance.
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PMID:Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13. 1147 39

Congenital generalized lipodystrophy (CGL) is a rare disorder characterized by the absence of body fat and insulin resistance and accompanied by other features, including acanthosis nigricans, organomegaly, hyperandrogenism, and diabetes. We have examined case subjects from 11 families in Oman with CGL. All subjects were the progeny of consanguineous marriages; therefore, a homozygosity mapping strategy was used to investigate the reported loci, 11q13 and 9q34. Three subjects could be linked to 11q13, and mutations were found within the seipin gene. An additional eight subjects were linked to 9q34, but the locus was in a 9-cM interval with no known microsatellites, so further fine mapping was not possible. However, two sibships (four subjects) did not map to either locus, raising the possibility of more than two lipodystrophy loci within the Oman population.
Diabetes 2002 Apr
PMID:Molecular analysis of Berardinelli-Seip congenital lipodystrophy in Oman: evidence for multiple loci. 1191 58

Generalised lipodystrophy of the Berardinelli-Seip type (BSCL) is a rare autosomal recessive human disorder with severe adverse metabolic consequences. A gene on chromosome 9 (BSCL1) has recently been identified, predominantly in African-American families. More recently, mutations in a previously undescribed gene of unknown function (BSCL2) on chromosome 11, termed seipin, have been found to be responsible for this disorder in a number of European and Middle Eastern families. We have studied the genotype/phenotype relationships in 70 affected subjects from 44 apparently unrelated pedigrees of diverse ethnic origin. In all subjects, hepatic dysfunction, hyperlipidaemia, diabetes mellitus, and hypertrophic cardiomyopathy were significant contributors to morbidity with no clear differences in their prevalence between subjects with BSCL1 or BSCL2 and those with evidence against cosegregation with either chromosome 9 or 11 (designated BSCLX). BSCL2 appears to be a more severe disorder than BSCL1 with a higher incidence of premature death and a lower prevalence of partial and/or delayed onset of lipodystrophy. Notably, subjects with BSCL2 had a significantly higher prevalence of intellectual impairment than those with BSCL1 or BSCLX (p<0.0001, OR 17.0, CI 3.6 to 79.0). The higher prevalence of intellectual impairment and the increased risk of premature death in BSCL2 compared to BSCL1 emphasise the importance of molecular diagnosis of this syndrome and have clear implications for genetic counselling.
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PMID:Genotype-phenotype relationships in Berardinelli-Seip congenital lipodystrophy. 1236 29

Mutations in the gene encoding seipin cause Berardinelli-Seip congenital lipodystrophy 2, with symptoms including near-absence of adipose tissue and altered glucose tolerance. Radiation hybrid analysis localized the seipin gene (Bscl2) in rat to a major quantitative trait locus in rat chromosome 1 linked to glucose intolerance in the Goto-Kakizaki (GK) rat model of Type 2 diabetes. We determined the genomic organization of Bscl2 and screened coding exons and flanking intron sequences for mutations in GK, Wistar and Brown Norway rats, as well as in the Otsuka Long-Evans Tokushima Fatty (OLETF) diabetic rat. Two silent single nucleotide polymorphisms that were identified also were found in non-diabetic rat strains. We conclude that mutations in the gene for seipin are unlikely to contribute to diabetes in GK and OLETF rats.
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PMID:Localization, cDNA sequence and genomic organization of the rat seipin gene (Bscl2) and sequence analysis in inbred rat models of Type 2 diabetes mellitus. 1258 44

Berardinelli-Seip congenital lipodystrophy (BSCL) is a heterogeneous genetic disease characterized by near absence of adipose tissue and severe insulin resistance. We have previously identified mutations in the seipin gene in a subset of our patients' cohort. Recently, disease-causing mutations in AGPAT2 have been reported in BSCL patients. In this study, we have performed mutation screening in AGPAT2 and the related AGPAT1 in patients with BSCL or other forms of lipodystrophy who have no detectable mutation in the seipin gene. We found 38 BSCL patients from 30 families with mutations in AGPAT2. Three of the known mutations were frequently found in our families. Of the eight new alterations, six are null mutations and two are missense mutations (Glu172Lys and Ala238Gly). All the patients harboring AGPAT2 mutations presented with typical features of BSCL. We did not find mutations in patients with other forms of lipodystrophies, including the syndromes of Lawrence, Dunnigan, and Barraquer-Simons, or with type A insulin resistance. In conclusion, mutations in the seipin gene and AGPAT2 are confined to the BSCL phenotype. Because we found mutations in 92 of the 94 BSCL patients studied, the seipin gene and AGPAT2 are the two major genes involved in the etiology of BSCL.
Diabetes 2003 Jun
PMID:Prevalence of mutations in AGPAT2 among human lipodystrophies. 1276 73

Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by marked lack of body fat since birth, which results in striking muscular appearance. Patients develop extreme insulin resistance and its complications, such as diabetes, hyperlipidemia and fatty liver. Mutations in the BSCL2 (which encodes seipin, a protein of unknown function) and AGPAT2 (which encodes 1-acylglycerol-3-phosphate O-acyltransferase 2) genes have been reported in patients with CGL. AGPAT2 is a key enzyme involved in triglyceride and phospholipid biosynthesis and, thus, the discovery of AGPAT2 mutations has heightened interest in the biochemical pathways of triglyceride synthesis and their implications in human physiology and in the pathophysiology of obesity, lipodystrophies and other adipose tissue disorders. All enzymes involved in triglyceride synthesis, including AGPAT, have several known isoforms encoded by different genes. Assuming different substrate specificities of these enzymes, the human body might have many forms of triglycerides and phospholipids. Here, we discuss the significance of these in energy storage, in addition to the normal functioning of cell membranes.
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PMID:Congenital generalized lipodystrophy: significance of triglyceride biosynthetic pathways. 1282 27

Primary lipodystrophies represent a heterogeneous group of very rare diseases with a prevalence of less than 1 case for 100.000, inherited or acquired, caracterized by a loss of body fat either generalized or localized (lipoatrophy). In some forms, lipoatrophy is associated with a selective hypertrophy of other fat depots. Clinical signs of insulin resistance are often present: acanthosis nigricans, signs of hyperandrogenism. All lipodystrophies are associated with dysmetabolic alterations with insulin resistance, altered glucose tolerance or diabetes and hypertriglyceridemia leading to a risk of acute pancreatitis. Chronic complications are those resulting from diabetes involving the retina, kidney and nerves, cardiovascular complications and steatotic liver lesions that could result in cirrhosis. Genetic forms of generalized lipodystrophy (or Berardinelli-Seip syndrome) result, in most cases, from recessive mutations in one of two genes: either BSCL2 coding seipin or BSCL1 coding AGPAT2, an acyl-transferase involved in triglyceride synthesis. Acquired generalized lipodystrophy (Lawrence syndrome) is of unknown origin but is sometimes associated with signs of autoimmunity. Partial lipodystrophies can be familial with dominant transmission. Heterozygous mutations have been identified in the LMNA gene encoding nuclear lamin A/C belonging to the nuclear lamina, or in PPARG encoding the adipogenic transcription factor PPARgamma. Some less typical lipodystrophies, associated with signs of premature aging, have been linked to mutations in LMNA or in the ZMPSTE24 gene encoding the protease responsible for the maturation of prelamin A into lamin A. Acquired partial lipodystrophy (Barraquer-Simons syndrome) is characterized by cephalothoracic fat loss. Its aetiology is unknown but mutations in LMNB2, encoding the lamina protein lamin B2, could represent susceptibility factors. Highly active antiretroviral treatments for HIV infection are currently the most frequent cause of acquired secondary lipodystrophic syndromes. The genetic diagnosis is performed in specialized laboratories and, in the most severe forms, antenatal diagnosis could be proposed. Treatment of diabetes, dyslipidemia and complications involves the classical intervention strategies. Insulino-sensitizing drugs are useful. Therapeutic trials with recombinant human leptin in patients with very low leptin levels reported good results with respect to the metabolic and liver alterations. The prognosis is linked to the precocity and severity of the diabetic, cardiovascular and liver complications.
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PMID:[Primary lipodystrophies]. 1732 32

Lipodystrophy is a disorder characterized by a loss of adipose tissue often accompanied by severe hypertriglyceridemia, insulin resistance, diabetes, and fatty liver. It can be inherited or acquired. The most severe inherited form is Berardinelli-Seip Congenital Lipodystrophy Type 2, associated with mutations in the BSCL2 gene. BSCL2 encodes seipin, the function of which has been entirely unknown. We now report the identification of yeast BSCL2/seipin through a screen to detect genes important for lipid droplet morphology. The absence of yeast seipin results in irregular lipid droplets often clustered alongside proliferated endoplasmic reticulum (ER); giant lipid droplets are also seen. Many small irregular lipid droplets are also apparent in fibroblasts from a BSCL2 patient. Human seipin can functionally replace yeast seipin, but a missense mutation in human seipin that causes lipodystrophy, or corresponding mutations in the yeast gene, render them unable to complement. Yeast seipin is localized in the ER, where it forms puncta. Almost all lipid droplets appear to be on the ER, and seipin is found at these junctions. Therefore, we hypothesize that seipin is important for droplet maintenance and perhaps assembly. In addition to detecting seipin, the screen identified 58 other genes whose deletions cause aberrant lipid droplets, including 2 genes encoding proteins known to activate lipin, a lipodystrophy locus in mice, and 16 other genes that are involved in endosomal-lysosomal trafficking. The genes identified in our screen should be of value in understanding the pathway of lipid droplet biogenesis and maintenance and the cause of some lipodystrophies.
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PMID:The lipodystrophy protein seipin is found at endoplasmic reticulum lipid droplet junctions and is important for droplet morphology. 1809 37

Human lipodystrophies represent a heterogeneous group of diseases characterized by generalized or partial fat loss, with fat hypertrophy in other depots when partial. Insulin resistance, dyslipidemia and diabetes are generally associated, leading to early complications. Genetic forms are uncommon: recessive generalized congenital lipodystrophies result in most cases from mutations in the genes encoding seipin or the 1-acyl-glycerol-3-phosphate-acyltransferase 2(AGPAT2). Dominant partial familial lipodystrophies result from mutations in genes encoding the nuclear protein lamin A/C or the adipose transcription factor PPARgamma. Importantly, lamin A/Cmutations are also responsible for metabolic laminopathies, resembling the metabolic syndrome and progeria, a syndrome of premature aging. A number of lipodystrophic patients remain undiagnosed at the genetic level. Acquired lipodystrophy can be generalized, resembling congenital forms, or partial, as the Barraquer-Simons syndrome, with loss of fat in the upper part of the body contrasting with accumulation in the lower part. Although their etiology is generally unknown, they could be associated with signs of autoimmunity. The most common forms of lipodystrophies are iatrogenic. In human immunodeficiency virus-infected patients, some first-generation antiretroviral drugs were strongly related with peripheral lipoatrophy and metabolic alterations. Partial lipodystrophy also characterize patients with endogenous or exogenous long-term corticoid excess. Treatment of fat redistribution can sometimes benefit from plastic surgery. Lipid and glucose alterations are difficult to control leading to early occurrence of diabetic, cardiovascular and hepatic complications.
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PMID:Human lipodystrophies: genetic and acquired diseases of adipose tissue. 2055 64

Lipodystrophy is a rare disorder characterized by loss of adipose tissue and low leptin levels. This condition is characterized by severe dyslipidemia, insulin resistance, diabetes mellitus, and steatohepatitis. Another phenotypic feature that occurs with considerable frequency in generalized lipodystrophy is cardiomyopathy. We report here the cardiac findings in a cohort of patients with generalized congenital and acquired lipodystrophy, and present a literature review of the cardiac findings in patients with generalized lipodystrophy. We studied 44 patients with generalized congenital and acquired lipodystrophy, most of them enrolled in a clinical trial of leptin therapy. Patients underwent electrocardiograms and transthoracic echocardiograms to evaluate their cardiac status. We followed these patients for an extended time period, some of them up to 8 years. Evaluation of our cohort of patients with generalized lipodystrophy shows that cardiomyopathy is a frequent finding in this population. Most of our patients had hypertrophic cardiomyopathy, and only a small number had features of dilated cardiomyopathy. Hypertrophic cardiomyopathy was more frequent in patients with seipin mutation, a finding consistent with the literature. The underlying mechanism for cardiomyopathy in lipodystrophy is not clear. Extreme insulin resistance and the possibility of a "lipotoxic cardiomyopathy" should be entertained as possible explanations.
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PMID:Cardiomyopathy in congenital and acquired generalized lipodystrophy: a clinical assessment. 2061 64


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