About the alpha-Mannosidosis mutation database

This database was last updated in January 2019. Unfortunately, due to lack of resources there will be no further updates.

The alpha-Mannosidosis Mutation Database has been developed at the University of Tromsø and the University Hospital of North Norway, Tromsø, Norway, in collaboration with the 6th framework HUE-MAN EU-project: “Towards the development of an effective enzyme therapy for human alpha-Mannosidosis”, and the 7th framework ALPHA-MAN EU-project: "Clinical development of Enzyme Replacement Therapy in alpha-Mannosidosis patients using recombinant human enzyme".The database compiles all alpha-Mannosidosis mutations that have been reported in the published literature. This information is useful to compile patterns and to draw hypotheses on disease etiology. It also allows the analysis of genotype/phenotype relationships.

Performing regular review of the literature on alpha-Mannosidosis mutations and their functional impact. Developing electronic formats for the compilation, retrieval and analysis of mutation data. Performing research on the spectrum of alpha-Mannosidosis mutations, as well as on the impact of mutations on enzyme activity, structure, processing, localization and clinical features.

The following information is freely available as a service to the scientific community: Published data on disease causing mutations and benign polymorphisms and their effect on enzyme activity, protein conformation, processing and localization. Clinical and demographic data are available as statistical summaries. Sensitive information and unpublished data are protected.

Alpha-mannosidosis is lysosomal storage disorder caused by deficiency of lysosomal alpha mannosidase (MAN2B1). Typical symptoms include facial characteristics, mental retardation, ataxia, hearing impairment, impaired speech, recurrent infections, skeletal malformation, muscular pain and weakness. The clinical variation is considerable, encompassing a continuum from mild to severe.

Alpha-mannosidosis is inherited in an autosomal recessive manner. Each pregnancy of a couple in which both partners are heterozygous for a disease-causing mutation of the MAN2B1 gene has a 25% chance of having an affected child, a 50% chance of having an unaffected child who is a carrier, and a 25% chance of having an unaffected child who is not a carrier.

Lysosomal alpha-mannosidase is an exoglycosidase that cleaves alpha-linked mannose residues from the non-reducing end during the ordered degradation of N-linked glycoproteins. The enzyme is synthesized as a single-chain precursor that is processed into three glycopeptides of 70, 42, and 15 kd. The 70-kd peptide is further partially proteolysed into three more peptides that are joined by disulfide bridges. The MAN2B1 precursor contains 1011 amino acids, of which the 49 N-terminal residues constitute the signal peptide. Without the signal peptide, the predicted molecular mass is 108.6 kd. The active enzyme exists as a dimer.

The MAN2B1 gene spans 21.5 kb and contains 24 exons (chr. 19 cen-q12). Abnormal alleles include exonic missense and nonsense mutations, splice junction mutations, and deletions and insertions of one or more nucleotides. A few disease alleles are likely to result from larger gene rearrangements such as large deletions that include several exons. MAN2B1 mutations are predicted to result in protein miss-folding or active site lesion, mRNA instability, and/or severely truncated protein.

Novel MAN2B1 sequence variants can be submitted using the amamutdb.no Contacts webpage. Sequence variants should be annotated using the latest HGVS guidelines (www.hgvs.org/mutnomen) and numbered using the reference sequence NM_000528.3. Results from diagnostic enzyme assays in peripheral blood cells, or in cultured fibroblast cells, should be included. A questionnaire for the recording of clinical data is available upon request.