Clinical and genetic characterization of Chanarin–Dorfman syndrome

Bruno, Claudio; Bertini, Enrico; Rocco, Maja Di; Cassandrini, Denise; Ruffa, G; Toni, Teresa De; Seri, Marco; Spada, Marco; Volti, Giovanni Li; D’Amico, Adele; Trucco, Federica; Arca, Marcello; Casali, Carlo; Angelini, C.; DiMauro, Salvatore; Minetti, Carlo

doi:10.1016/j.bbrc.2008.03.010

Cited by 72 publications

(53 citation statements)

References 16 publications

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“…Patients with CDS often have hepatomegaly, myopathy, microcephaly, cataracts, hearing loss, ataxia, mild mental retardation, and short stature ( 29,30,(32)(33)(34)(35)(36)(37)(38)(39)(40).…”

Section: Creation Of Cgi-58 Fl Oxed Mice and Livko Micementioning

confidence: 99%

Deficiency of liver Comparative Gene Identification-58 causes steatohepatitis and fibrosis in mice

Guo

Kadegowda

et al. 2013

Journal of Lipid Research

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Mammals store excess triglyceride (TG) in the large lipid droplet (LD) of white adipose tissue . During a period of starvation or increased energy demand, the stored TG is used as an energy source via a process called lipolysis. Excessive lipid accumulation in nonadipose tissues ("ectopic" fat deposition) is lipotoxic ( 1 ). Increased TG accumulation in liver hepatocytes is a hallmark of nonalcoholic fatty liver disease (NAFLD) ( 2, 3 ). NAFLD is the most common liver disease in the United States ( 4-6 ). In the general population, the estimated prevalence of NAFLD is as high as 24% ( 6 ). The highest estimates of NAFLD are among obese individuals after bariatric surgery, which range from 84% to 96% of all patients undergoing this procedure ( 6 ). It is estimated that 17-33% of Americans may have hepatic steatosis ( 5 ), a condition that is often associated with insulin resistance, type 2 diabetes, and central obesity. The prevalence of NAFLD is increasing worldwide and is expected to more than double by the year 2025 ( 5 ).NAFLD includes a spectrum of liver pathological changes ranging from simple hepatic steatosis to advanced abnor-

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Section: Creation Of Cgi-58 Fl Oxed Mice and Livko Micementioning

confidence: 99%

Deficiency of liver Comparative Gene Identification-58 causes steatohepatitis and fibrosis in mice

Guo

Kadegowda

et al. 2013

Journal of Lipid Research

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“…Egg phosphatidylcholine (PC) and soy PI were purchased from Avanti Polar Lipids. Radiolabeled [9,10(N) 3 H]triolein and [oleoyl- [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]oleoyl-CoA were purchased from PerkinElmer Life Sciences (Boston, MA). Hydrofl uor scintillation cocktail was purchased from National Diagnostics, and ScintiVerse BD Cocktail was purchased from Fisher Scientifi c. Silica gel hard layer fl uorescent TLC plates were obtained from Analtech (Newark, DE).…”

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confidence: 99%

Comparative gene identification 58/α/β hydrolase domain 5 lacks lysophosphatidic acid acyltransferase activity

McMahon

Dinh

Kurz

et al. 2014

Journal of Lipid Research

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Mutations in the gene encoding comparative gene identifi cation-58 [CGI-58; also ␣ / ␤ hydrolase domain 5 (ABHD5)] cause Chanarin-Dorfman syndrome (CDS) ( 1 ), a neutral lipid storage disorder characterized by excessive accumulation of triacylglycerols (TAGs) in cells and tissues, including liver, skeletal muscle, intestinal epithelia, leukocytes, keratinocytes, and skin fi broblasts, leading to hepatomegaly, ichthyosis, and mild muscle weakness ( 2-7 ). These early observations suggested that CGI-58 plays an important role in TAG homeostasis in multiple tissues. Although CGI-58 is a member of the lipase subfamily of ␣ / ␤ hydrolase domain proteins, it lacks a serine residue in a conserved sequence (GXSXG) that normally harbors the nucleophilic component of the catalytic triad ( 1 ). Identifi cation of CGI-58 as a coactivator of the widely expressed adipose TG lipase (ATGL) ( 8 ) provided a mechanistic explanation for the phenotype of CDS patients; loss of functional CGI-58 reduces ATGL-mediated hydrolysis of TAGs, in turn increasing TAG storage in tissues. Individuals with mutations in ATGL show similarities to CDS patients with TAG accumulation in various tissues including liver and skeletal muscle ( 9 ); however, these individuals lack ichthyosis and have more severe skeletal muscle myopathy than individuals with CDS, as well as cardiomyopathy. The phenotypic differences between individuals with mutations in CGI-58 and those with mutations in ATGL suggest that CGI-58 serves one or more functions distinct from coactivation of ATGL.Abstract Mutations in the gene encoding comparative gene identifi cation 58 (CGI-58)/ ␣ / ␤ hydrolase domain 5 (ABHD5) cause Chanarin-Dorfman syndrome, characterized by excessive triacylglycerol storage in cells and tissues. CGI-58 has been identifi ed as a coactivator of adipose TG lipase (ATGL) and a lysophosphatidic acid acyltransferase (LPAAT). We developed a molecular model of CGI-58 structure and then mutated predicted active site residues and performed LPAAT activity assays of recombinant WT and mutated CGI-58. When mutations of predicted catalytic residues failed to reduce LPAAT activity, we determined that LPAAT activity was due to a bacterial contaminant of affi nity purifi cation procedures, plsC, the sole LPAAT in Escherichia coli . Purifi cation protocols were optimized to reduce plsC contamination, in turn reducing LPAAT activity. When CGI-58 was expressed in SM2-1(DE3) cells that lack plsC, lysates lacked LPAAT activity. Additionally, mouse CGI-58 expressed in bacteria as a glutathione-S -transferase fusion protein and human CGI-58 expressed in yeast lacked LPAAT activity. Previously reported lipid binding activity of CGI-58 was revisited using protein-lipid overlays. Recombinant CGI-58 failed to bind lysophosphatidic acid, but interestingly, bound phosphatidylinositol 3-phosphate [PI (3)

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“…2,3 The CDS (Chanarin-Dorfman syndrome) (MIM 275630), also known as NLSD with ichthyosis, is defined as an NLSD with ichthyosis, often associated with mild myopathy, cirrhosis, growth retardation, ataxia, hearing loss and mild mental retardation. 4,5 CDS is caused by the mutations of the CGI-58 gene. Neutral lipid storage disease with myopathy (NLSDM: MIM 610717) referred to those NLSD patients with myopathy but without ichthyosis.…”

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confidence: 99%

Novel PNPLA2 gene mutations in Chinese Han patients causing neutral lipid storage disease with myopathy

Lin

Wen

et al. 2012

J Hum Genet

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Neutral lipid storage disease with myopathy (NLSDM) referred to those neutral lipid storage disease (NLSD) patients with myopathy but without ichthyosis. Recently, NLSDM has been attributed to mutations in the PNPLA2 gene. Until now, 19 patients with PNPLA2 mutations have been reported. In the present study, we describe the clinical and genetic findings in three Chinese patients with NLSDM. Sequence analysis of PNPLA2 gene was performed. In our patients we identified four novel mutations in the PNPLA2 gene including two splicing mutations. The identification and study of mutations found in PNPLA2 is also particularly important to define the clinical spectrum and genotype-phenotype correlations of the PNPLA2 gene.

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Clinical and genetic characterization of Chanarin–Dorfman syndrome

Cited by 72 publications

References 16 publications

Deficiency of liver Comparative Gene Identification-58 causes steatohepatitis and fibrosis in mice

Deficiency of liver Comparative Gene Identification-58 causes steatohepatitis and fibrosis in mice

Comparative gene identification 58/α/β hydrolase domain 5 lacks lysophosphatidic acid acyltransferase activity

Novel PNPLA2 gene mutations in Chinese Han patients causing neutral lipid storage disease with myopathy

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