Mutations in the ANGPTL3 gene and familial combined hypolipidemia

A clinical and biochemical characterization

Ilenia Minicocci, Anna Montali, Marius Robert Robciuc, Fabiana Quagliarini, Vincenzo Censi, Giancarlo Labbadia, Claudia Gabiati, Giovanni Pigna, Maria Laura Sepe, Fabio Pannozzo, Dieter Lütjohann, Sergio Fazio, Matti Jauhiainen, Christian Ehnholm, Marcello Arca

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

Context: Familial combined hypolipidemia causes a global reduction of plasma lipoproteins. Its clinical correlates and metabolic implications have not been well defined. Objective: The objective of the study was to investigate the genetic, clinical, and metabolic characteristics of a cohort of subjects with familial combined hypolipidemia. Design: The design of the study included candidate gene screening and the comparison of the clinical and metabolic characteristics between carrier and noncarrier individuals. Setting: The study was conducted in a general community. Subjects: Participants in the study included individuals belonging to nine families with familial combined hypolipidemia identified in a small town (Campodimele) as well as from other 352 subjects living in the same community. Main Outcomes Measures: Serum concentrations of lipoproteins, Angiopoietin-like 3 (Angptl3) proteins, and noncholesterol sterols were measured. Results: The ANGPTL3 S17X mutation was found in all probands, 20 affected family members, and 32 individuals of the community. Two additional frame shift mutations, FsE96del and FsS122, were also identified in two hypocholesterolemic individuals. Homozygotes for the ANGPTL3 S17X mutation had no circulating Angptl3 and a marked reduction of all plasma lipids (P <0.001). Heterozygotes had42% reduction in Angptl3 level compared with noncarriers (P <0.0001) but a significant reduction of only total cholesterol and high-density lipoprotein cholesterol.Nodifferences were observed in the plasma noncholesterol sterols between carriers and noncarriers. No association between familial combined hypolipidemia and the risk of hepatic or cardiovascular diseases were detected. Conclusions: Familial combined hypolipidemia segregates as a recessive trait so that apolipoprotein B-and apolipoprotein A-I-containing lipoproteins are comprehensively affected only by the total deficiency of Angptl3. Familial combined hypolipidemia does not perturbwhole-body cholesterol homeostasis and is not associated with adverse clinical sequelae.

Original languageEnglish (US)
JournalJournal of Clinical Endocrinology and Metabolism
Volume97
Issue number7
DOIs
StatePublished - Jul 2012
Externally publishedYes

Fingerprint

Angiopoietins
Genes
Lipoproteins
Mutation
Sterols
Plasmas
Cholesterol
Frameshift Mutation
Apolipoprotein A-I
Homozygote
Apolipoproteins B
Heterozygote
HDL Cholesterol
Screening
Homeostasis
Cardiovascular Diseases
Outcome Assessment (Health Care)
Association reactions
Lipids
Liver

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Endocrinology
  • Biochemistry, medical
  • Endocrinology, Diabetes and Metabolism

Cite this

Mutations in the ANGPTL3 gene and familial combined hypolipidemia : A clinical and biochemical characterization. / Minicocci, Ilenia; Montali, Anna; Robciuc, Marius Robert; Quagliarini, Fabiana; Censi, Vincenzo; Labbadia, Giancarlo; Gabiati, Claudia; Pigna, Giovanni; Sepe, Maria Laura; Pannozzo, Fabio; Lütjohann, Dieter; Fazio, Sergio; Jauhiainen, Matti; Ehnholm, Christian; Arca, Marcello.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 97, No. 7, 07.2012.

Research output: Contribution to journalArticle

Minicocci, I, Montali, A, Robciuc, MR, Quagliarini, F, Censi, V, Labbadia, G, Gabiati, C, Pigna, G, Sepe, ML, Pannozzo, F, Lütjohann, D, Fazio, S, Jauhiainen, M, Ehnholm, C & Arca, M 2012, 'Mutations in the ANGPTL3 gene and familial combined hypolipidemia: A clinical and biochemical characterization', Journal of Clinical Endocrinology and Metabolism, vol. 97, no. 7. https://doi.org/10.1210/jc.2012-1298
Minicocci, Ilenia ; Montali, Anna ; Robciuc, Marius Robert ; Quagliarini, Fabiana ; Censi, Vincenzo ; Labbadia, Giancarlo ; Gabiati, Claudia ; Pigna, Giovanni ; Sepe, Maria Laura ; Pannozzo, Fabio ; Lütjohann, Dieter ; Fazio, Sergio ; Jauhiainen, Matti ; Ehnholm, Christian ; Arca, Marcello. / Mutations in the ANGPTL3 gene and familial combined hypolipidemia : A clinical and biochemical characterization. In: Journal of Clinical Endocrinology and Metabolism. 2012 ; Vol. 97, No. 7.
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abstract = "Context: Familial combined hypolipidemia causes a global reduction of plasma lipoproteins. Its clinical correlates and metabolic implications have not been well defined. Objective: The objective of the study was to investigate the genetic, clinical, and metabolic characteristics of a cohort of subjects with familial combined hypolipidemia. Design: The design of the study included candidate gene screening and the comparison of the clinical and metabolic characteristics between carrier and noncarrier individuals. Setting: The study was conducted in a general community. Subjects: Participants in the study included individuals belonging to nine families with familial combined hypolipidemia identified in a small town (Campodimele) as well as from other 352 subjects living in the same community. Main Outcomes Measures: Serum concentrations of lipoproteins, Angiopoietin-like 3 (Angptl3) proteins, and noncholesterol sterols were measured. Results: The ANGPTL3 S17X mutation was found in all probands, 20 affected family members, and 32 individuals of the community. Two additional frame shift mutations, FsE96del and FsS122, were also identified in two hypocholesterolemic individuals. Homozygotes for the ANGPTL3 S17X mutation had no circulating Angptl3 and a marked reduction of all plasma lipids (P <0.001). Heterozygotes had42{\%} reduction in Angptl3 level compared with noncarriers (P <0.0001) but a significant reduction of only total cholesterol and high-density lipoprotein cholesterol.Nodifferences were observed in the plasma noncholesterol sterols between carriers and noncarriers. No association between familial combined hypolipidemia and the risk of hepatic or cardiovascular diseases were detected. Conclusions: Familial combined hypolipidemia segregates as a recessive trait so that apolipoprotein B-and apolipoprotein A-I-containing lipoproteins are comprehensively affected only by the total deficiency of Angptl3. Familial combined hypolipidemia does not perturbwhole-body cholesterol homeostasis and is not associated with adverse clinical sequelae.",
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T1 - Mutations in the ANGPTL3 gene and familial combined hypolipidemia

T2 - A clinical and biochemical characterization

AU - Minicocci, Ilenia

AU - Montali, Anna

AU - Robciuc, Marius Robert

AU - Quagliarini, Fabiana

AU - Censi, Vincenzo

AU - Labbadia, Giancarlo

AU - Gabiati, Claudia

AU - Pigna, Giovanni

AU - Sepe, Maria Laura

AU - Pannozzo, Fabio

AU - Lütjohann, Dieter

AU - Fazio, Sergio

AU - Jauhiainen, Matti

AU - Ehnholm, Christian

AU - Arca, Marcello

PY - 2012/7

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N2 - Context: Familial combined hypolipidemia causes a global reduction of plasma lipoproteins. Its clinical correlates and metabolic implications have not been well defined. Objective: The objective of the study was to investigate the genetic, clinical, and metabolic characteristics of a cohort of subjects with familial combined hypolipidemia. Design: The design of the study included candidate gene screening and the comparison of the clinical and metabolic characteristics between carrier and noncarrier individuals. Setting: The study was conducted in a general community. Subjects: Participants in the study included individuals belonging to nine families with familial combined hypolipidemia identified in a small town (Campodimele) as well as from other 352 subjects living in the same community. Main Outcomes Measures: Serum concentrations of lipoproteins, Angiopoietin-like 3 (Angptl3) proteins, and noncholesterol sterols were measured. Results: The ANGPTL3 S17X mutation was found in all probands, 20 affected family members, and 32 individuals of the community. Two additional frame shift mutations, FsE96del and FsS122, were also identified in two hypocholesterolemic individuals. Homozygotes for the ANGPTL3 S17X mutation had no circulating Angptl3 and a marked reduction of all plasma lipids (P <0.001). Heterozygotes had42% reduction in Angptl3 level compared with noncarriers (P <0.0001) but a significant reduction of only total cholesterol and high-density lipoprotein cholesterol.Nodifferences were observed in the plasma noncholesterol sterols between carriers and noncarriers. No association between familial combined hypolipidemia and the risk of hepatic or cardiovascular diseases were detected. Conclusions: Familial combined hypolipidemia segregates as a recessive trait so that apolipoprotein B-and apolipoprotein A-I-containing lipoproteins are comprehensively affected only by the total deficiency of Angptl3. Familial combined hypolipidemia does not perturbwhole-body cholesterol homeostasis and is not associated with adverse clinical sequelae.

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