Clinical, Biochemical, and Molecular Characterization of Novel Mutations in ABCA1 in Families with Tangier Disease

  • Liam R. Brunham
  • Martin H. Kang
  • Clara Van Karnebeek
  • Singh N. Sadananda
  • Jennifer A. Collins
  • Lin-Hua Zhang
  • Bryan Sayson
  • Fudan Miao
  • Sylvia Stockler
  • Jiri Frohlich
  • David Cassiman
  • Simon W. Rabkin
  • Michael R. Hayden
Research Report
Part of the JIMD Reports book series (JIMD, volume 18)

Abstract

Tangier disease is a rare, autosomal recessive disorder caused by mutations in the ABCA1 gene and is characterized by near absence of plasma high-density lipoprotein cholesterol, accumulation of cholesterol in multiple tissues, peripheral neuropathy, and accelerated atherosclerosis. Here we report three new kindreds with Tangier disease harboring both known and novel mutations in ABCA1. One patient was identified to be homozygous for a nonsense mutation, p.Gln1038*. In a remarkably large Tangier disease pedigree with four affected siblings, we identified compound heterozygosity for previously reported missense variants, p.Arg937Val and p.Thr940Met, and show that both of these mutations result in significantly impaired cholesterol efflux in transfected cells. In a third pedigree, the proband was identified to be compound heterozygous for two novel mutations, a frameshift (p.Ile1200Hisfs*4) and an intronic variant (c.4176-11T>G), that lead to the creation of a cryptic splice site acceptor and premature truncation, p.Ser1392Argfs*6. We demonstrate that this mutation arose de novo, the first demonstration of a pathogenic de novo mutation in ABCA1 associated with Tangier disease. We also report results of glucose tolerance testing in a Tangier disease kindred for the first time, showing a gene–dose relationship between ABCA1 activity and glucose tolerance and suggesting that Tangier disease patients may have substantially impaired islet function. Our findings provide insight into the diverse phenotypic manifestations of this rare disorder, expand the list of pathogenic mutations in ABCA1, and increase our understanding of how specific mutations in this gene lead to abnormal cellular and physiological phenotypes.

Notes

Acknowledgements

We are grateful to the patients and their families who participated in this research. This work was supported by grants from the Canadian Institutes of Health Research (to MRH) and a microgrant from the Rare Disease Foundation of Canada (to LRB), as well as by the Biomedical Research Council of the Association for Science, Technology, and Research of Singapore and the National University of Singapore.

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Copyright information

© SSIEM and Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Liam R. Brunham
    • 1
    • 2
  • Martin H. Kang
    • 3
  • Clara Van Karnebeek
    • 3
    • 4
  • Singh N. Sadananda
    • 1
  • Jennifer A. Collins
    • 3
  • Lin-Hua Zhang
    • 3
  • Bryan Sayson
    • 4
  • Fudan Miao
    • 3
  • Sylvia Stockler
    • 4
  • Jiri Frohlich
    • 5
    • 6
  • David Cassiman
    • 7
  • Simon W. Rabkin
    • 6
    • 8
  • Michael R. Hayden
    • 1
    • 2
    • 3
  1. 1.Translational Laboratory in Genetic Medicine, Association for Science, Technology and ResearchSingaporeSingapore
  2. 2.Department of MedicineYong Loo Lin School of Medicine, National University of SingaporeSingaporeSingapore
  3. 3.Centre for Molecular Medicine and Therapeutics, Child and Family Research InstituteUniversity of British ColumbiaVancouverCanada
  4. 4.Division of Biochemical Diseases, Department of PediatricsUniversity of British ColumbiaVancouverCanada
  5. 5.Department of Pathology and Laboratory Medicine, Heart and Lung Institute, St. Paul’s HospitalUniversity of British ColumbiaVancouverCanada
  6. 6.Healthy Heart Program Prevention Clinic, St. Paul’s HospitalVancouverCanada
  7. 7.Department of HepatologyUniversity Hospital GasthuisbergLeuvenBelgium
  8. 8.Division of Cardiology, Department of MedicineUniversity of British ColumbiaVancouverCanada

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