A1 Journal article – refereed
Molecular and cellular characterization of novel alpha-mannosidosis mutations




List of Authors: Kuokkanen E, Stensland HMFR, Smith W, Buvang EK, Nguyen L, Nilssen Ø, Heikinheimo P
Publisher: OXFORD UNIV PRESS
Publication year: 2011
Journal: Human Molecular Genetics
Journal name in source: HUMAN MOLECULAR GENETICS
Journal acronym: HUM MOL GENET
Number in series: 13
Volume number: 20
Issue number: 13
ISSN: 0964-6906

Abstract
alpha-Mannosidosis is a lysosomal storage disorder caused by mutations in the MAN2B1 gene. The clinical presentation of alpha-mannosidosis is variable, but typically includes mental retardation, skeletal abnormalities and immune deficiency. In order to understand the molecular aetiology of alpha-mannosidosis, we describe here the subcellular localization and intracellular processing of 35 MAN2B1 variants, including 29 novel missense mutations. In addition, we have analysed the impact of the individual mutations on the three-dimensional structure of the human MAN2B1. We categorize the MAN2B1 missense mutations into four different groups based on their intracellular processing, transport and secretion in cell culture. Impaired transport to the lysosomes is a frequent cause of pathogenicity and correlates with a lack of protein processing (groups 1 and 3). Mutant MAN2B1 proteins that find their way to the lysosomes are processed, but less efficiently than the wild-types (groups 2 and 4). The described four categories of missense mutations likely represent different pathogenic mechanisms. We demonstrate that the severity of individual mutations cannot be determined based only on their position in the sequence. Pathogenic mutations cluster into amino acids which have an important role on the domain interface (arginines) or on the folding of the enzyme (prolines, glycines, cysteines). Tolerated mutations generally include surface mutations and changes without drastic alteration of residue volume. The expression system and structural details presented here provide opportunities for the development of pharmacological therapy by screening or design of small molecules that might assist MAN2B1 folding and hence, transport and activity.


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