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Partners

Participants 8a & 8b

University Tromsoe

Partner 8a: Department of Medicine, University Hospital of Tromsoe, N-9038 Tromsoe, NORWAY Team leader/Responsible Scientist: Ass. prof. Dag Malm, MD, PhD, Key skills: Clinical judgement, Medical insight, Contact for Clinicians, patients and patient organisations.

Background: Leader Professional Advisory Board in The International Society for Mannosidosis. The main effort of partner 8a has been directed towards the sampling of clinical data from patients world-wide. Contact is established through clinical contacts or direct contact with the patients through the internet in order to achieve as much clinical information as possible. Partner 8a has further studied the nature of the immunodeficiency in alpha-mannosidosis in a recently published paper.

Capacity to contribute to the project: MD with the authorisation to handle confidential information. Clinical judgement to classify/ interpret the single mannosidosis case and the natural course of alphamannosidosis. Reviewer of literature with clinical relevance. Potential planner of clinical therapy in humans. Contact person for the further collection of clinical data and biological material together with partner 8b. Will characterise clinical aspects of the disease and genotype/ phenotype correlation with partner 8b. Further investigations in the mechanisms of the immunodeficiency focusing on immunological/ microbiological aspects together with partner 9 (Michalski). Members involved: One PhD student to perform in vitro experiments on immunogenic properties of mannosidosis metabolism (12 pm).

Contributing members of the laboratory: Prof. Dag Malm, head of group. Clinical judgement, Medical insight, Contact for Clinicians, patients and patient organisations. (6 pm), One PhD student to perform in vitro experiments on immunogenic properties of mannosidosis metabolism (12 pm)

TOTAL EXPECTED EFFORT: 30 pm

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University Tromsoe

Partner 8b: Department of Medical Genetics, Institute of Clinical Medicine, University of Tromsoe, N-9037, Norway Team leader/Responsible Scientist: Prof. Dr. Oivind Nilssen. Key skills: Mutation identification, studies of mutant enzyme phenotypes.

Laboratory (clinical) background and technical information: Partner 8b will be engaged in the construction of a mutation database, in studying the genetic epidemiology of alpha-mannosidosis as well as in studying the natural history of the disease (including mutation detection). The laboratory is equipped to provide genetic diagnostic services for the population of Northern-Norway, which include DNA diagnostics for some 35 different genetic disorders, as well as cytogenetic analyses. The department provides routine facilities for handling, registration and storage of patient information, and patient material such as blood, fibroblast cells and DNA samples, according to the guidelines of the University Hospital of North-Norway. The laboratory is well equipped for the molecular diagnostics of genetic disorders providing equipment such as DNA extractors, PCR machines and instruments for automated DNA sequencing.

Capacity to contribute to the project: Based on protein sequence data from purified lysosomal alpha-mannosidase, partner 8b cloned and characterised the bovine, the human and the feline LAMAN genes. Partner 8b has determined the pattern of expression in human tissues and resolved the genomic structure of the alphamannosidase genes from man and cattle. So far, partner 8b has identified more than 90 LAMAN mutations of which ~75 are thought to be disease causing (unpublished). Mutant alleles containing missense mutations have been expressed in Cos-cells and studied in detail with regards to enzyme activity, intracellular processing and transport. As the only laboratory in Europe or elsewhere, partner 8b offers genetic testing such as for diagnosis confirmation, carrier analysis and prenatal testing. As for the generation of a relational database, linking genotypes to various phenotypic features (including clinical), partner 8b has already got approval from the Regional Medical Research Ethics Committee and the Norwegian Data Inspectorate.

Members involved: One senior scientist(s) in bioinformatics will be recruited to provide the necessary competence in developing the database design, structure and deployment. (8 pm) Other contributing members of the laboratory: Group leader, Prof. Oivind Nilssen, (4 pm), and Senior scientist, Dr. Hilde Monica F. Riise Stensland, (5 pm) will participate in the molecular diagnostics of alpha-mannosidosis patients, patient and sample record administration and in systematizing the molecular data to be implemented in the database.

TOTAL EXPECTED EFFORT: 17 pm

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