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.
Competing interests: None declared
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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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The authors of this manuscript declare that they have no conflict of interest.
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All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients for being included in the study. No identifying information about patients is included in this manuscript.
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Author Contributions
Liam R. Brunham: Designed and conducted experiments, characterized patients, analyzed data, wrote manuscript, guarantor
Martin H. Kang: Conducted experiments
Clara Van Karnebeek: Characterized patients, wrote manuscript
Singh N. Sadananda: Conducted experiments
Jennifer A. Collins: Wrote manuscript
Lin-Hua Zhang: Conducted experiments
Bryan Sayson: Wrote manuscript
Fudan Miao: Conducted experiments
Sylvia Stockler: Characterized patients, wrote manuscript
Jiri Frohlich: Characterized patients
David Cassiman: Characterized patients
Simon W. Rabkin: Characterized patients
Michael R. Hayden: Designed experiments, characterized patients, wrote manuscript
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Brunham, L.R. et al. (2014). Clinical, Biochemical, and Molecular Characterization of Novel Mutations in ABCA1 in Families with Tangier Disease. In: Zschocke, J., Baumgartner, M., Morava, E., Patterson, M., Rahman, S., Peters, V. (eds) JIMD Reports, Volume 18. JIMD Reports, vol 18. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2014_348
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DOI: https://doi.org/10.1007/8904_2014_348
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