Genetic and Functional Analyses of Patients with Marked Hypo-High-Density Lipoprotein Cholesterolemia

Yasuhisa Furuta; Yoshinori Osaki; Yoshimi Nakagawa; Song-Iee Han; Masaya Araki; Akito Shikama; Nami Ohuchi; Daichi Yamazaki; Erika Matsuda; Seitaro Nohara; Yuhei Mizunoe; Kenta Kainoh; Yasuhito Suehara; Hiroshi Ohno; Yoshinori Takeuchi; Takafumi Miyamoto; Yuki Murayama; Yoko Sugano; Hitoshi Iwasaki; Ken-ichi Hirano; Masahiro Koseki; Shogo Nakano; Hiroaki Tokiwa; Motohiro Sekiya; Naoya Yahagi; Takashi Matsuzaka; Kiyotaka Nakamagoe; Yasushi Tomidokoro; Jun Mitsui; Shoji Tsuji; Hiroaki Suzuki; Hitoshi Shimano

doi:10.5551/jat.64579

Yasuhisa Furuta, Yoshinori Osaki, Yoshimi Nakagawa, Song-Iee Han, Masaya Araki, Akito Shikama, Nami Ohuchi, Daichi Yamazaki, Erika Matsuda, Seitaro Nohara, Yuhei Mizunoe, Kenta Kainoh, Yasuhito Suehara, Hiroshi Ohno, Yoshinori Takeuchi, Takafumi Miyamoto, Yuki Murayama, Yoko Sugano, Hitoshi Iwasaki, Ken-ichi Hirano, Masahiro Koseki, Shogo Nakano, Hiroaki Tokiwa, Motohiro Sekiya, Naoya Yahagi, Takashi Matsuzaka, Kiyotaka Nakamagoe, Yasushi Tomidokoro, Jun Mitsui, Shoji Tsuji, Hiroaki Suzuki, Hitoshi Shimano

Author information

Yasuhisa Furuta
Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba
Yoshinori Osaki
Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba
Yoshimi Nakagawa
Division of Complex Biosystem Research, Department of Research and Development, Institute of Natural Medicine, University of Toyama
Song-Iee Han
Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance, University of Tsukuba
Masaya Araki
Division of Complex Biosystem Research, Department of Research and Development, Institute of Natural Medicine, University of Toyama
Akito Shikama
Department of Endocrinology and Metabolism, Ibaraki Prefectural Central Hospital, Ibaraki Cancer Center
Nami Ohuchi
Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba
Daichi Yamazaki
Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba
Erika Matsuda
Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba
Seitaro Nohara
Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba
Yuhei Mizunoe
Laboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of Science
Kenta Kainoh
Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba
Yasuhito Suehara
Department of Hematology, University of Tsukuba Hospital
Hiroshi Ohno
Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba
Yoshinori Takeuchi
Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba
Takafumi Miyamoto
Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba
Yuki Murayama
Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba
Yoko Sugano
Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba
Hitoshi Iwasaki
Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba
Ken-ichi Hirano
Laboratory of Novel, Non-invasive, and Nutritional Therapeutics (CNT), Department of Triglyceride Science, Graduate School of Medicine, Osaka University
Masahiro Koseki
Division of Cardiovascular Medicine, Department of Medicine, Osaka University Graduate School of Medicine
Shogo Nakano
Department of Food and Nutritional Sciences, Graduate School of Integrated Pharmaceutical and Nutritional Sciences, University of Shizuoka
Hiroaki Tokiwa
Laboratory of Organic Chemistry, Gifu Pharmaceutical University
Motohiro Sekiya
Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba
Naoya Yahagi
Division of Endocrinology and Metabolism, Department of Internal Medicine, Jichi Medical University School of Medicine
Takashi Matsuzaka
Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba
Kiyotaka Nakamagoe
Department of Neurology, Faculty of Medicine, University of Tsukuba
Yasushi Tomidokoro
Department of Neurology, Faculty of Medicine, University of Tsukuba
Jun Mitsui
Department of Neurology, Graduate School of Medicine, The University of Tokyo
Shoji Tsuji
Department of Neurology, Graduate School of Medicine, The University of Tokyo
Institute of Medical Genomics, International University of Health and Welfare
Hiroaki Suzuki
Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba
Hitoshi Shimano
Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba

Keywords: Tangier disease, ABCA1, HDL, Cholesterol efflux

JOURNAL OPEN ACCESS Advance online publication

Article ID: 64579

DOI https://doi.org/10.5551/jat.64579

Details

Abstract

Aim: This study aimed to analyze two cases of marked hypo-high-density lipoprotein (HDL) cholesterolemia to identify mutations in ATP-binding cassette transporter A1 (ABCA1) and elucidate the molecular mechanism by which these novel pathological mutations contribute to hypo-HDL cholesterolemia in Tangier disease.

Methods: Wild type and mutant expression plasmids containing a FLAG tag inserted at the C-terminus of the human ABCA1 gene were generated and transfected into HEK293T cells. ABCA1 protein expression and cholesterol efflux were evaluated via Western blotting and efflux assay. The difference in the rate of change in protein expression was evaluated when proteolytic and protein-producing systems were inhibited.

Results: In case 1, a 20-year-old woman presented with a chief complaint of gait disturbance. Her HDL-C level was only 6.2 mg/dL. Tangier disease was suspected because of muscle weakness, decreased nerve conduction velocity, and splenomegaly. Whole-exome analysis showed compound heterozygosity for a W484* nonsense mutation and S1343I missense mutation, which confirmed Tangier disease. Cholesterol efflux decreased by a mixture of W484* and S1343I mutations. The S1343I mutation decreased the protein production rate but increased the degradation rate, decreasing the protein levels. This patient also had Krabbe disease. The endogenous ABCA1 protein level of macrophage cell decreased by knocking down its internal galactocerebrosidase.

Case 2, a 51-year-old woman who underwent tonsillectomy presented with peripheral neuropathy, corneal opacity, and HDL-C of 3.4 mg/dL. Whole-exome analysis revealed compound heterozygosity for R579* and R1572* nonsense mutations, which confirmed Tangier disease.

Conclusion: Case 1 is a new ABCA1 mutation with complex pathogenicity, namely, a W484*/S1343I compound heterozygote with marked hypo-HDL cholesterolemia. Analyses of the compound heterozygous mutations indicated that decreases in ABCA1 protein levels and cholesterol efflux activity caused by the novel S1343I mutation combined with loss of W484* protein activity could lead to marked hypo-HDL cholesterolemia. Galactocerebrosidase dysfunction could also be a potential confounding factor for ABCA1 protein function.

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