Lucia Magnolo

Università degli Studi di Modena e Reggio Emilia, Modena, Emilia-Romagna, Italy

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Publications (14)37.44 Total impact

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    ABSTRACT: Extremely low LDL-cholesterol concentrations are very unusual and generally related with comorbidities accompanying malnutrition. Less frequently low LDL-cholesterol levels result from mutations in the APOB, PCSK9, ANGPTL3, SAR1B and MTTP genes (primary hypobetalipoproteinemia). We investigated three patients with plasma LDL-cholesterol levels below the fifth percentile of the Spanish population. We recorded data on demographic and anthropometric characteristics, life style habits, physical examination, liver ultrasound and lipid and lipoprotein levels, in the probands and their first-degree relatives. Secondary causes of hypocholesterolemia were ruled out by clinical study, complementary tests and follow-up. The APOB, MTTP and SAR1B genes were sequenced. Patients were found to be heterozygotes for point mutations located in the exon 26 of the APOB gene. One patient, with fatty liver, carried a previously described mutation (c.7600C>T) (Arg2507X), causing the formation of truncated Apo B-55.25. The other two mutations producing truncations are new. One asymptomatic patient carried the Arg3672X (Apo B-80.93) and the other with fatty liver and steatorrhea carried the Ser2184fsVal2193X (Apo B-48.32). Our study reinforces the concept that in the heterozygous carriers of truncated Apo Bs, the clinical manifestations of FHBL are dependent on the size of the truncations.
    Gene 08/2013; · 2.20 Impact Factor
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    ABSTRACT: Monogenic hypobetalipoproteinemias include three disorders: abetalipoproteinemia (ABL) and chylomicron retention disease (CMRD) with recessive transmission and familial hypobetalipoproteinemia (FHBL) with dominant transmission. We investigated three unrelated Tunisian children born from consanguineous marriages, presenting hypobetalipoproteinemia associated with chronic diarrhea and retarded growth. Proband HBL-108 had a moderate hypobetalipoproteinemia, apparently transmitted as dominant trait, suggesting the diagnosis of FHBL. However, she had no mutations in FHBL candidate genes (APOB, PCSK9 and ANGPTL3). The analysis of MTTP gene was also negative, whereas SAR1B gene resequencing showed that the patient was homozygous for a novel mutation (c.184G>A), resulting in an amino acid substitution (p.Glu62Lys), located in a conserved region of Sar1b protein. In the HBL-103 and HBL-148 probands, the severity of hypobetalipoproteinemia and its recessive transmission suggested the diagnosis of ABL. The MTTP gene resequencing showed that probands HBL-103 and HBL-148 were homozygous for a nucleotide substitution in the donor splice site of intron 9 (c.1236+2T>G) and intron 16 (c.2342+1G>A) respectively. Both mutations were predicted in silico to abolish the function of the splice site. In vitro functional assay with splicing mutation reporter MTTP minigenes showed that the intron 9 mutation caused the skipping of exon 9, while the intron 16 mutation caused a partial retention of this intron in the mature mRNA. The predicted translation products of these mRNAs are non-functional truncated proteins. The diagnosis of ABL and CMRD should be considered in children born from consanguineous parents, presenting chronic diarrhea associated with hypobetalipoproteinemia.
    Gene 10/2012; · 2.20 Impact Factor
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    ABSTRACT: Lecithin:cholesterol acyltransferase (LCAT) is responsible for cholesterol esterification in plasma. Mutations of LCAT gene cause familial LCAT deficiency, a metabolic disorder characterized by hypoalphalipoproteinemia. Apolipoprotein B (apoB) is the main protein component of very-low-density lipoproteins and low-density lipoprotein (LDL). Mutations of APOB gene cause familial hypobetalipoproteinemia, a codominant disorder characterized by low plasma levels of LDL cholesterol and apoB. This was a genetic and biochemical analysis of an Italian kindred with hypobetalipoproteinemia whose proband presented with hypoalphalipoproteinemia and severe chronic kidney disease. Plasma lipids and apolipoproteins, cholesterol esterification, and high-density lipoprotein (HDL) subclass distribution were analyzed. LCAT and APOB genes were sequenced. The proband had severe impairment of plasma cholesterol esterification and high preβ-HDL content. He was heterozygote for the novel LCAT P406L variant, as were two other family members. The proband's wife and children presented with familial hypobetalipoproteinemia and were heterozygotes for the novel apoB H1401R variant. Cholesterol esterification rate of apoB H1401R carriers was reduced, likely attributable to the low amount of circulating LDL. After renal transplantation, proband's lipid profile, HDL subclass distribution, and plasma cholesterol esterification were almost at normal levels, suggesting a mild contribution of the LCAT P406L variant to his pretransplantation severe hypoalphalipoproteinemia and impairment of plasma cholesterol esterification. LCAT P406L variant had a mild effect on lipid profile, HDL subclass distribution, and plasma cholesterol esterification. ApoB H1401R variant was identified as possible cause of familial hypobetalipoproteinemia and resulted in a reduction of cholesterol esterification rate.
    Journal of Clinical Lipidology 05/2012; 6(3):244-50. · 3.59 Impact Factor
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    ABSTRACT: Angiopoietin-like protein 3 (ANGPTL3) affects lipid metabolism by inhibiting the activity of lipoprotein and endothelial lipases. Angptl3 knockout mice have marked hypolipidemia, and heterozygous carriers of ANGPLT3, loss-of-function mutations were found among individuals in the lowest quartile of plasma triglycerides in population studies. Recently, 4 related individuals with primary hypolipidemia were found to be compound heterozygotes for ANGPTL3 loss-of-function mutations. We resequenced ANGPTL3 in 4 members of 3 kindreds originally identified for very low levels of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol (0.97±0.16 and 0.56±0.20 mmol/L, respectively) in whom no mutations of known candidate genes for monogenic hypobetalipoproteinemia and hypoalphalipoproteinemia had been detected. These subjects were found to be homozygous or compound heterozygous for ANGPTL3 loss-of-function mutations (p.G400VfsX5, p.I19LfsX22/p.N147X) associated with the absence of ANGPTL3 in plasma. They had reduced plasma levels of triglyceride-containing lipoproteins and of HDL particles that contained only apolipoprotein A-I and pre-β-high-density lipoprotein. In addition, their apolipoprotein B-depleted sera had a reduced capacity to promote cell cholesterol efflux through the various pathways (ABCA1-, SR-BI-, and ABCG1-mediated efflux); however, these subjects had no clinical evidence of accelerated atherosclerosis. Heterozygous carriers of the ANGPTL3 mutations had low plasma ANGPTL3 and moderately reduced low-density lipoprotein cholesterol (2.52±0.38 mmol/L) but normal plasma high-density lipoprotein cholesterol. Complete ANGPTL3 deficiency caused by loss-of-function mutations of ANGPTL3 is associated with a recessive hypolipidemia characterized by a reduction of apolipoprotein B and apolipoprotein A-I-containing lipoproteins, changes in subclasses of high-density lipoprotein, and reduced cholesterol efflux potential of serum. Partial ANGPTL3 deficiency is associated only with a moderate reduction of low-density lipoprotein.
    Circulation Cardiovascular Genetics 11/2011; 5(1):42-50. · 6.73 Impact Factor
  • S Zhong, L Magnolo, Z Yao, P Tarugi
    Atherosclerosis Supplements - ATHEROSCLER SUPPL. 01/2009; 10(2).
  • Nutrition Metabolism and Cardiovascular Diseases - NUTR METAB CARDIOVASC DIS. 01/2009; 19.
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    ABSTRACT: Abetalipoproteinemia (ABL) and Homozygous Familial Hypobetalipoproteinemia (Ho-FHBL) are rare monogenic diseases characterised by very low plasma levels of cholesterol and triglyceride and the absence or a great reduction of apolipoprotein B (apoB)-containing lipoproteins. ABL results from mutations in the MTP gene; Ho-FHBL may be due to mutations in the APOB gene. We sequenced MTP and APOB genes in three Tunisian children, born from consanguineous marriage, with very low levels of plasma apoB-containing lipoproteins associated with severe intestinal fat malabsorption. Two of them were found to be homozygous for two novel mutations in intron 5 (c.619-3T>G) and in exon 8 (c.923 G>A) of the MTP gene, respectively. The c.619-3T>G substitution caused the formation of an abnormal mRNA devoid of exon 6, predicted to encode a truncated MTP of 233 amino acids. The c.923 G>A is a nonsense mutation resulting in a truncated MTP protein (p.W308X). The third patient was homozygous for a novel nucleotide deletion (c.2172delT) in exon 15 of APOB gene resulting in the formation of a truncated apoB of 706 amino acids (apoB-15.56). These mutations are expected to abolish the apoB lipidation and the assembly of apoB-containing lipoproteins in both liver and intestine.
    Clinica chimica acta; international journal of clinical chemistry 12/2008; 401(1-2):51-6. · 2.54 Impact Factor
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    ABSTRACT: Familial hypobetalipoproteinemia (FHBL) is a co-dominant disorder characterized by reduced plasma levels of low density lipoprotein cholesterol (LDL-C) and its protein constituent apolipoprotein B (apoB), which may be due to mutations in APOB gene, mostly located in the coding region of this gene. We report two novel APOB gene mutations involving the acceptor splice site of intron 11 (c.1471-1G>A) and of intron 23 (c.3697-1G>C), respectively, which were identified in two patients with heterozygous FHBL associated with severe fatty liver disease. The effects of these mutations on APOB pre-mRNA splicing were assessed in COS-1 cells expressing the mutant APOB minigenes. The c.1471-1G>A APOB minigene generated two abnormal mRNAs. In one mRNA the entire intron 11 was retained; in the other mRNA exon 11 joined to exon 12, in which the first nucleotide was deleted due to the activation of a novel acceptor splice site. The predicted products of these mRNAs are truncated proteins of 546 and 474 amino acids, designated apoB-12.03 and apoB-10.45, respectively. The c.3697-1G>C APOB minigene generated a single abnormal mRNA in which exon 23 joined to exon 25, with the complete skipping of exon 24. This abnormal mRNA is predicted to encode a truncated protein of 1220 amino acids, designated apoB-26.89. These splice site mutations cause the formation of short truncated apoBs, which are not secreted into the plasma as lipoprotein constituents. This secretion defect is the major cause of severe fatty liver observed in carriers of these mutations.
    Molecular Genetics and Metabolism 12/2008; 96(2):66-72. · 2.83 Impact Factor
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    ABSTRACT: Cholesteryl ester transfer protein (CETP) is a plasma glycoprotein that catalyses the transfer of cholesteryl esters from HDL to the other plasma lipoproteins. Genetic deficiency of CETP is one of the known causes of elevation of plasma HDL-C (primary hyperalphalipoproteinemia, HALP). We sequenced CETP gene in a group of 24 Italian subjects with primary HALP (HDL-C>80 mg/dl) suspected to have CETP deficiency. Two unrelated subjects both coming from the same geographical district, were found to be heterozygous for a nucleotide substitution in exon 6 (c.544C>T) and another subject was found to be heterozygous for a C>T transition in exon 9 (c.802C>T). Both mutations introduce a premature stop codon and are predicted to cause the production of truncated proteins (Q165X and R268X, respectively) devoid of function. The fourth proband was found to carry a T>C substitution in intron 15 (c.1407+2T>C) predicted to abolish the function of the donor splice site. To define the effect of this mutation on CETP pre-mRNA splicing we analysed CETP mRNA in COS-1 cells expressing a CETP minigene harbouring the mutation. The analysis of minigene transcript in COS-1 cells showed that IVS15+2T>C mutation caused the formation of an abnormal mRNA in which exon 14 joins directly to exon 16, predicted to encode a truncated peptide of 435 amino acids. In mutation carriers plasma CETP activity was found to be reduced by 38-60%. These are the first mutations in the CETP gene found in Italian subjects with HALP.
    Atherosclerosis 09/2008; 204(1):202-7. · 3.71 Impact Factor
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    ABSTRACT: Homozygous familial hypobetalipoproteinaemia (Ho-FHBL) is a rare co-dominant disorder characterized by extremely low levels of low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apoB). Most patients with Ho-FHBL have mutations in APOB gene resulting in truncated apoBs. Some patients are asymptomatic, while others have fatty liver, intestinal fat malabsorption and neurological dysfunctions. We investigated three adult subjects with severe hypobetalipoproteinaemia and a family history of FHBL. Proband FHBL-47 had liver cirrhosis with hepatocarcinoma and a renal carcinoma but no clinical manifestations related to FHBL. He was a compound heterozygote for a 7-bp deletion in exon 21 and a base insertion in exon 26 resulting in truncated apoBs (apoB-22.46/apoB-66.51). Proband FHBL-53, with severe hepatic steatosis and fibrosis, had a nonsense mutation in exon 19 resulting in a truncated apoB (apoB-20.61) and a rare nucleotide substitution in intron 14 (c.2068-4T>A). The latter was also present in her daughter, found to have low plasma LDL-C and apoB. Proband FHBL-82 had chronic diarrhoea and steatorrhoea. She was found to be homozygous for a nonsense mutation in exon 24 resulting in a truncated apoB (apoB-26.65). In adult subjects, the presence of chronic liver disease and chronic diarrhoea, when associated with severe hypobetalipoproteinaemia, may lead to the diagnosis of Ho-FHBL.
    Clinical Genetics 05/2008; 74(3):267-73. · 4.25 Impact Factor
  • Atherosclerosis Supplements - ATHEROSCLER SUPPL. 01/2008; 9(1):22-22.
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    ABSTRACT: Primary hypobetalipoproteinemia (HBL) includes a group of genetic disorders: abetalipoproteinemia (ABL) and chylomicron retention disease (CRD), with a recessive transmission, and familial hypobetalipoproteinemia (FHBL) with a co-dominant transmission. ABL and CRD are rare disorders due to mutations in the MTP and SARA2 genes, respectively. Heterozygous FHBL is much more frequent. FHBL subjects often have fatty liver and, less frequently, intestinal fat malabsorption. FHBL may be linked or not to the APOB gene. Most mutations in APOB gene cause the formation of truncated forms of apoB which may or may be not secreted into the plasma. Truncated apoBs with a size below that of apoB-30 are not detectable in plasma; they are more frequent in patients with the most severe phenotype. Only a single amino acid substitution (R463W) has been reported as the cause of FHBL. Approximately 50% of FHBL subjects are carriers of pathogenic mutations in APOB gene; therefore, a large proportion of FHBL subjects have no apoB gene mutations or are carriers of rare amino acid substitutions in apoB with unknown effect. In some kindred FHBL is linked to a locus on chromosome 3 (3p21) but the candidate gene is unknown. Recently a FHBL plasma lipid phenotype was observed in carriers of mutations of the PCSK9 gene causing loss of function of the encoded protein, a proprotein convertase which regulates LDL-receptor number in the liver. Inactivation of this enzyme is associated with an increased LDL uptake and hypobetalipoproteinemia. HBL carriers of PCSK9 mutations do not develop fatty liver disease.
    Atherosclerosis 01/2008; 195(2):e19-27. · 3.71 Impact Factor
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    ABSTRACT: Familial hypobetalipoproteinaemia (FHBL) is a codominant disorder characterised by fatty liver and reduced plasma levels of low-density lipoprotein (LDL) and its protein constituent apolipoprotein B (apoB). FHBL is linked to the APOB gene in some but not all known cases. In a group of 59 patients with FHBL genotyped for APOB gene mutations, we found three novel splice-site mutations: c.904+4A-->G in intron 8, c.3843-2A-->G in intron 24 and c.4217-1G-->T in intron 25. To assess the effects of these mutations on apoB pre-mRNA splicing. ApoB mRNA was analysed in the liver of one proband and in cells expressing APOB minigenes harbouring the mutations found in the other probands. In the liver of the c.3843-2A-->G carrier, an apoB mRNA devoid of exon 25 was identified, predicted to encode a truncated peptide of 1260 amino acids. The analysis of minigene transcripts in COS-1 cells showed that the c.904+4A-->G mutation caused the formation of an mRNA devoid of exon 8, predicted to encode a short apoB of 247 amino acids. The minigene harbouring the c.4217-1G-->T mutation in intron 25 generated an mRNA in which exon 25 joined to a partially deleted exon 26, resulting from the activation of an acceptor site in exon 26; this mRNA is predicted to encode a truncated protein of 1380 amino acids. All these truncated apoBs were not secreted as constituents of plasma lipoproteins. These findings demonstrate the pathogenic effect of rare splice-site mutations of the APOB gene found in FHBL.
    Journal of Medical Genetics 03/2007; 44(3):219-24. · 5.70 Impact Factor
  • Atherosclerosis Supplements. 01/2007; 8(1):46-47.