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Identification of 83 novel alpha-mannosidosis-associated sequence variants: Functional analysis of MAN2B1 missense mutations

Authors

  • Hilde Monica Frostad Riise Stensland,

    Corresponding author
    1. Division of Child and Adolescent Health, Department of Medical Genetics, University Hospital of North-Norway, Tromsø, Norway
    • Division of Child and Adolescent Health, Department of Medical Genetics, University Hospital of North-Norway, N-9038 Tromsø, Norway
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  • Helle Bagterp Klenow,

    1. Division of Child and Adolescent Health, Department of Medical Genetics, University Hospital of North-Norway, Tromsø, Norway
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  • Lam Van Nguyen,

    1. Division of Child and Adolescent Health, Department of Medical Genetics, University Hospital of North-Norway, Tromsø, Norway
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  • Gaute Martin Hansen,

    1. Faculty of Medicine, Department of Tumor Biology, University of Tromsø, Tromsø, Norway
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  • Dag Malm,

    1. Division of Medicine, Department of Internal Medicine, University Hospital of North-Norway, Tromsø, Norway
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  • Øivind Nilssen

    1. Division of Child and Adolescent Health, Department of Medical Genetics, University Hospital of North-Norway, Tromsø, Norway
    2. Department of Clinical Medicine–Medical Genetics, University of Tromsø, Tromsø, Norway
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Errata

This article is corrected by:

  1. Errata: Identification of 83 Novel Alpha-Mannosidosis-Associated Sequence Variants: Functional Analysis of MAN2B1 Missense Mutations Volume 37, Issue 8, 827, Article first published online: 12 May 2016

  • Elizabeth F. Neufeld

Abstract

The lysosomal storage disorder alpha-mannosidosis is caused by deficiency of the enzyme lysosomal alpha-mannosidase (MAN2B1). In this study, 96 disease-associated sequence variants were identified in 130 unrelated alpha-mannosidosis patients from 30 countries. Eighty-three novel variants were detected, extending the mutation spectrum from 42 to 125. In total, 256 of the 260 mutant alleles (98.5%) were identified. Most of the variants were unique to each family, however, c.2248C>T (p.Arg750Trp) was detected in 50 patients from 16 countries, and accounted for 27.3% of the disease alleles. Haplotype analysis revealed that the c.2248T variant was present on four MAN2B1 haplotype backgrounds, where one major haplotype accounted for 95% of the alleles. The distribution of the c.2248T-associated haplotypes differed remarkably from those of the control populations, suggesting that c.2248C>T has occurred on a few ancestral haplotypes where the major haplotype subsequently has spread by founder effects. The disease-associated missense mutations were introduced into the human MAN2B1 cDNA, expressed in cell culture and assayed for MAN2B1 activity. The majority of the variants were inactive, however, ten showed MAN2B1 activity above background, and more detailed studies are necessary to further evaluate the pathogenicity of these variants. Hum Mutat 33:511–520, 2012. © 2011 Wiley Periodicals, Inc.

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