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Exome sequencing identifies novel ApoB loss-of-function mutations causing hypobetalipoproteinemia in type 1 diabetes

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Abstract

Aim

Diabetic patients commonly suffer from disturbances in production and clearance of plasma lipoproteins, known as diabetic dyslipidemia, resulting in an increased risk of coronary heart disease. The study aimed to examine the cause of hypobetalipoproteinemia in two patients with type 1 diabetes.

Methods

The Diabetes Control and Complications Trial (DCCT) is a study demonstrating that intensive blood glucose control delays the onset and progression of type 1 diabetes complications. Hypobetalipoproteinemia was present in two DCCT subjects, IDs 1427 and 1078, whose LDL-C levels were 36 and 28 mg/dL, respectively, and triglyceride levels were 20 and 28 mg/dL, respectively. We performed exome sequencing on genomic DNA from the two patients with hypobetalipoproteinemia.

Results

The subjects 1427 and 1078 had heterozygous loss-of-function mutations in the gene apolipoprotein B (ApoB), and these mutations resulted in premature stop codons at amino acid 1333 (ApoB-29) and 3680 (ApoB-81), respectively. Indeed, the plasma ApoB level of subject 1427 (19 mg/dL) was the lowest and that of subject 1078 (26 mg/dL) was the second to the lowest among all the 1,441 DCCT participants. Sequencing genomic DNA of family members showed that probands 1427 and 1078 inherited the mutations from the father and the mother, respectively.

Conclusions

The identification of ApoB loss-of-function mutations in type 1 diabetic patients presents innovative cases to study the interaction between hypobetalipoproteinemia and insulin deficiency.

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Abbreviations

ApoB:

Apolipoprotein B

BMI:

Body mass index

DCCT:

Diabetes control and complications trial

EDIC:

Epidemiology of diabetes interventions and complications

FHBL:

Familial hypobetalipoproteinemia

HDL-C:

High-density lipoprotein cholesterol

LDL:

Low-density lipoprotein

LDL-C:

Low-density lipoprotein cholesterol

Lp(a):

Lipoprotein (a)

NIDDK:

National Institute of Diabetes and Digestive and Kidney diseases

SNP:

Single nucleotide polymorphism

TAG:

Triacylglycerol

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Acknowledgments

The current study was supported in part by a fund from Wayne State University to R.Z., NNSF of China (90408028) to C.T.Z. and (31171238) to F.G. and the China National 863 High-Tech Program (2015AA020101) to F.G.

Conflict of interest

Feng Gao, Hao Luo, Zhiyao Fu, Chun-Ting Zhang and Ren Zhang declare that they have no conflict of interest.

Human and Animal Rights disclosure

All procedures followed were in accordance with the ethical standards of the Institutional Review Boards of Wayne State University School of Medicine and of the Detroit Medical Center, and with the Helsinki Declaration of 1975, as revised in 2008 (5).

Informed consent disclosure

Informed consent was obtained from all participants being included in the study.

Author information

Authors and Affiliations

  1. Department of Physics, Tianjin University, Tianjin, China

    Feng Gao, Hao Luo & Chun-Ting Zhang

  2. Center for Molecular Medicine and Genetics, and the Cardiovascular Research Institute, School of Medicine, Wayne State University, Detroit, MI, USA

    Zhiyao Fu & Ren Zhang

Authors
  1. Feng Gao
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  2. Hao Luo
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  3. Zhiyao Fu
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  4. Chun-Ting Zhang
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Corresponding authors

Correspondence to Chun-Ting Zhang or Ren Zhang.

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Gao, F., Luo, H., Fu, Z. et al. Exome sequencing identifies novel ApoB loss-of-function mutations causing hypobetalipoproteinemia in type 1 diabetes. Acta Diabetol 52, 531–537 (2015). https://doi.org/10.1007/s00592-014-0687-7

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  • DOI: https://doi.org/10.1007/s00592-014-0687-7

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