Apolipoprotein C-II Deficiency with No Rare Variant in the APOC2 Gene

Satoru Takase; Jun-ichi Osuga; Hayato Fujita; Kazuo Hara; Motohiro Sekiya; Masaki Igarashi; Mikio Takanashi; Yoshinori Takeuchi; Yoshihiko Izumida; Keisuke Ohta; Masayoshi Kumagai; Makiko Nishi; Midori Kubota; Yukari Masuda; Yoshino Taira; Sachiko Okazaki; Yoko Iizuka; Naoya Yahagi; Ken Ohashi; Hiroshi Yoshida; Hidekatsu Yanai; Norio Tada; Takanari Gotoda; Shun Ishibashi; Takashi Kadowaki; Hiroaki Okazaki

doi:10.5551/jat.16592

Original Article

Apolipoprotein C-II Deficiency with No Rare Variant in the APOC2 Gene

Satoru Takase, Jun-ichi Osuga, Hayato Fujita, Kazuo Hara, Motohiro Sekiya, Masaki Igarashi, Mikio Takanashi, Yoshinori Takeuchi, Yoshihiko Izumida, Keisuke Ohta, Masayoshi Kumagai, Makiko Nishi, Midori Kubota, Yukari Masuda, Yoshino Taira, Sachiko Okazaki, Yoko Iizuka, Naoya Yahagi, Ken Ohashi, Hiroshi Yoshida, Hidekatsu Yanai, Norio Tada, Takanari Gotoda, Shun Ishibashi, Takashi Kadowaki, Hiroaki Okazaki

Author information

Satoru Takase
Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo.
Jun-ichi Osuga
Division of Endocrinology and Metabolism, Department of Medicine, Jichi Medical University.
Hayato Fujita
Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo.
Kazuo Hara
Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo.
Motohiro Sekiya
Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo.
Masaki Igarashi
Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo.
Mikio Takanashi
Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo.
Yoshinori Takeuchi
Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo.
Yoshihiko Izumida
Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo.
Keisuke Ohta
Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo.
Masayoshi Kumagai
Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo.
Makiko Nishi
Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo.
Midori Kubota
Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo.
Yukari Masuda
Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo.
Yoshino Taira
Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo.
Sachiko Okazaki
Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo.
Yoko Iizuka
Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo.
Naoya Yahagi
Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo.
Ken Ohashi
Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo.
Hiroshi Yoshida
Department of Laboratory Medicine, Jikei University Kashiwa Hospital.
Hidekatsu Yanai
Division of General Medicine, Jikei University Kashiwa Hospital.
Norio Tada
Division of General Medicine, Jikei University Kashiwa Hospital.
Takanari Gotoda
Department of Clinical and Molecular Epidemiology, 22nd Century Medical and Research Center, University of Tokyo Hospital.
Shun Ishibashi
Division of Endocrinology and Metabolism, Department of Medicine, Jichi Medical University.
Takashi Kadowaki
Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo.
Hiroaki Okazaki
Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo.
Molecular Medicinal Sciences on Metabolic Regulation, Graduate School of Medicine, The University of Tokyo.

Keywords: Chylomicronemia, Apolipoprotein C-II deficiency, Single nucleotide polymorphism, cis-regulatory region, Rare variant

JOURNAL OPEN ACCESS

2013 Volume 20 Issue 5 Pages 481-493

DOI https://doi.org/10.5551/jat.16592

Browse “Advance online publication” version

Details

Abstract

Aim: Familial apolipoprotein C-II (apoC-II) deficiency is a rare autosomal recessive disorder with marked hypertriglyceridemia resulting from impaired activation of lipoprotein lipase. In most cases of apoC-II deficiency, causative mutations have been found in the protein-coding region of APOC2; however, several atypical cases of apoC-II deficiency were reported to have markedly reduced, but detectable levels of plasma apoC-II protein (hereafter referred to as hypoapoC-II), which resulted from decreased promoter activity or improper splicing of apoC-II mRNA due to homozygous mutations in APOC2. Here we aim to dissect the molecular bases of a new case of hypoapoC-II.
Methods: We performed detailed biochemical/genetic analyses of our new case of hypoapoC-II, manifesting severe hypertriglyceridemia (plasma triglycerides, 3235 mg·dL^-1) with markedly reduced levels of plasma apoC-II (0.6 mg·dL^-1).
Results: We took advantage of a monocyte/macrophage culture system to prove that transcription of apoC-II mRNA was decreased in the patient’s cells, which is compatible with the reported features of hypoapoC-II. Concomitantly, transcriptional activity of the minigene reporter construct of the patient’s APOC2 gene was decreased; however, no rare variant was detected in the patient’s APOC2 gene. Fifty single nucleotide variants were detected in the patient’s APOC2, but all were common variants (allele frequencies ＞35%) that are supposedly not causative.
Conclusions: A case of apoC-II deficiency was found that is phenotypically identical to hypoapoC-II but with no causative mutations in APOC2, implying that other genes regulate apoC-II levels. The clinical entity of hypoapoC-II is discussed.

Corresponding author

Register with J-STAGE for free!