Human Molecular Genetics, Vol 7, 1547-1553, Copyright © 1998 by Oxford University Press
P Bjorses, J Aaltonen, N Horelli-Kuitunen, ML Yaspo and L Peltonen
The molecular background of human autoimmunity is poorly understood.
Although many autoimmune diseases have a genetic basis, the actual disease
appearance results from a complex interplay between genes and environment
and thus these diseases represent typical multifactorial diseases. Even
with molecular tools provided by the Human Genome Project, it still remains
a challenge to identify the predisposing DNA variants behind such
multifactorial traits. Two strategies have been suggested to provide
short-cuts to the dissection of the genetic background of complex
autoimmune diseases: (i) identification of genes in rare human diseases
with a strong autoimmune component or (ii) unravelling loci causing
phenotypes resembling autoimmune diseases in inbred mice strains.
Autoimmune polyendocrinopathy-candidiasis- ectodermal dystrophy (APECED) is
a monogenic autosomal disease with a recessive inheritance pattern,
characterized by multiple autoimmune endocrinopathies, chronic
mucocutaneous candidiasis and ectodermal dystrophies. Since it is the only
known human autoimmune disease inherited in a Mendelian fashion, it
provides an excellent model to analyse the genetic component of human
autoimmunity. The causative gene for APECED was isolated recently by a
traditional positional cloning strategy by two independent groups. The cDNA
for the APECED gene proved to originate from a novel gene, AIRE , which is
expressed prevalently in thymus, pancreas and adrenal cortex. Multiple
mutations in AIRE have been identified in APECED patients. The predicted
proline-rich AIRE polypeptide harbours two PHD-type zinc finger motifs and
contains a putative nuclear targeting signal suggesting its involvement in
the regulation of transcription. In the future, functional analysis of the
AIRE protein both in vitro and in vivo will provide valuable insight not
only into the molecular pathogenesis of APECED but also into the aetiology
of autoimmunity in general.
REVIEWS
Gene defect behind APECED: a new clue to autoimmunity
Department of Human Molecular Genetics, National Public Health Institute, University of Helsinki, Mannerheimintie 166, FIN-00300 Helsinki, Finland.
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