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Human Molecular Genetics, 2002, Vol. 11, No. 26 3299-3308
© 2002 Oxford University Press

Systematic mutagenesis of the functional domains of AIRE reveals their role in intracellular targeting

Chris Ramsey1, Alex Bukrinsky1 and Leena Peltonen1-3,*

1Department of Human Genetics, UCLA School of Medicine, Gonda Center, University of California Los Angeles, Los Angeles, California, USA, 2Department of Human Molecular Genetics, National Public Health Institute, Helsinki, Finland and 3Department of Medical Genetics, University of Helsinki, Finland

Received August 11, 2002; Accepted October 10, 2002

Mutations in the human autoimmune regulator (AIRE ) gene cause a multi-systemic autoimmune syndrome that is known as autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED). To date more than 39 different disease mutations have been identified. They span the entire region of the AIRE gene that encodes a polypeptide with multiple functional domains: an N-terminal homogeneously staining region (HSR), a bipartied nuclear localization signal (NLS), a SAND domain, two PHD fingers and four nuclear receptor targeting motifs. The APECED mutations include insertions, deletions, substitutions and introduction of premature termination codons, while most mutations disrupt one of the functional domains. We have constructed a series of deletion mutants systematically removing one or more functional domain(s) and investigated the stability and sub-cellular compartmentalization of the corresponding polypeptides. Here we show that the first 188 amino acids, containing the HSR domain and the NLS proved necessary for both cytoplasmic filament formation and nuclear targeting. Deletion of the SAND domain and even point mutations in the SAND domain, resulted in the aggregation of the polypeptides in the cytoplasm and interfered with the proper nuclear targeting. The PHD fingers seemed to be necessary for the formation of characteristic dot-like complexes in the nucleus, but their deletion did not interfere with nuclear entry.

* To whom correspondence should be addressed at: Department of Medical Genetics, University of Helsinki and Department of Molecular Medicine, NPHI, Biomediceem, Haartmoninkatu 8 00290 Helsinki, Finland. Tel: 358 947448393; Fax: 358 947448480; Email: leena.peltonen{at}ktl.gi


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