Common Mutations in Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy Patients of Different Origins
Hamish S. Scott,
Maarit Heino,
Pärt Peterson,
Lauréane Mittaz,
Maria D. Lalioti,
Corrado Betterle,
Amnon Cohen,
Marco Seri,
Margherita Lerone,
Giovanni Romeo,
Pekka Collin,
Matti Salo,
Russell Metcalfe,
Anthony Weetman,
Marie-Pierre Papasavvas,
Colette Rossier,
Kentaro Nagamine,
Jun Kudoh,
Nobuyoshi Shimizu,
Kai J. E. Krohn and
Stylianos E. Antonarakis
Laboratory of Human Molecular Genetics (H.S.S., L.M., M.D.L.,
M-P.P., C.R., S.E.A.) Department of Genetics and Microbiology
University of Geneva Medical School and Division of Medical
Genetics (S.E.A.) Cantonal Hospital of Geneva 1211 Geneva 4,
Switzerland
Institute of Medical Technology and University
Hospital (M.H., P.P., P.C., M.S., K.J.E.K.) University of
Tampere 33101 Tampere, Finland
Institute of Semeiotica
Medica (C.B.) University of Padova 35128 Padova, Italy
Pediatric Endocrinology Unit (A.C.) Laboratorio di Genetica
Molecolare (M.S., M.L.) Istituto G. Gaslini University of
Genova Medical School (G.R.) Genova, I-16148, Italy
Division of Clinical Sciences (R.M., A.W.) Northern General
Hospital University of Sheffield Sheffield SS 7AU, United
Kingdom
Department of Molecular Biology (K.N., J.K.,
N.S.) Keio University School of Medicine 35 Shinanomachi,
Shinjuku-ku Tokyo 160, Japan
 |
ABSTRACT
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Autoimmune
polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED; OMIM
*240300, also called APS 1,) is a rare autosomal recessive disorder
that is more frequent in certain isolated populations. It is generally
characterized by two of the three major clinical symptoms that may be
present, Addisons disease and/or hypoparathyroidism and/or chronic
mucocutaneous candidiasis. Patients may also have a number of other
clinical symptoms including chronic gastritis, gonadal failure, and
rarely, autoimmune thyroid disease and insulin-dependent diabetes
mellitus. We and others have recently identified the gene for APECED,
which we termed AIRE (for autoimmune regulator). AIRE is expressed in
thymus, lymph nodes, and fetal liver and encodes a protein containing
motifs suggestive of a transcriptional regulator, including two zinc
finger motifs (PHD finger), a proline-rich region, and three LXXLL
motifs. Six mutations, including R257X, the predominant Finnish APECED
allele, have been defined. R257X was also observed in non-Finnish
APECED patients occurring on different chromosomal haplotypes
suggesting different mutational origins. Here we present mutation
analyses in an extended series of patients, mainly of Northern Italian
origin. We have detected 12 polymorphisms, including one amino acid
substitution, and two additional mutations, R203X and X546C, in
addition to the previously described mutations, R257X,
10961097insCCTG, and a 13-bp deletion (10941106del). R257X was also
the common mutation in the Northern Italian patients (10 of 18
alleles), and 10941106del accounted for 5 of 18 Northern
Italian alleles. Both R257X and 10941106del were both observed in
patients of four different geo-ethnic origins, and both were associated
with multiple different haplotypes using closely flanking polymorphic
markers showing likely multiple mutation events (six and four,
respectively). The identification of common AIRE mutations in different
APECED patient groups will facilitate its genetic diagnosis. In
addition, the polymorphisms presented provide the tools for
investigation of the involvement of AIRE in other autoimmune diseases,
particularly those affecting the endocrine system.
 |
INTRODUCTION
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Autoimmune
polyendocrinopathy-candidiasis-ectodermal dystrophy, also known as
autoimmune polyglandular syndrome type I (APECED; OMIM *240300), is an
autosomal recessive disorder (1). It is characterized by a variable
combination of destructive autoimmune phenomena, principally directed
against the endocrine system, that leads to a failure of the
parathyroid glands, adrenal cortex, gonads, pancreatic ß-cells,
gastric parietal cells, and thyroid gland. Clinical symptoms outside
the endocrine system include chronic mucocutaneous candidiasis,
dystrophy of dental enamel and nails, alopecia, vitiligo, and
keratopathy (2). The disease usually occurs in childhood, but new
tissue-specific symptoms may appear throughout life (2). The incidence
of APECED has been estimated to be approximately 1:25,000 and 1:9,000
in Finns and Iranian Jews, respectively (3, 4), and is also relatively
common in Sardinians. APECED patients develop autoantibodies against
affected organs, including autoantibodies against the steroidogenic
enzymes P450scc, P450c17, and P450c21 in patients with adrenocortical
failure (Addisons disease) (5) and/or gonadal failure (6), glutamic
acid decarboxylase in patients with insulin-dependent diabetes mellitus
(IDDM) (7), and enzymes aromatic L-amino acid decarboxylase
(8) and P450 1A2 (9) in patients with hepatitis.
Based on linkage analysis in Finnish families, the locus for
APECED was mapped to chromosome 21q22.3 between two markers,
D21S49 and D21S171 (3), and linkage
disequilibrium studies further defined the critical region for
APECED to 500 kb between markers D21S1912 and
D21S171. Locus heterogeneity was not revealed by linkage
analysis of non-Finnish families (10). We and others have recently
cloned the gene for APECED, which encodes a 545-amino acid putative
transcription factor (AIRE) with zinc finger (PHD finger) motifs. A
common Finnish mutation, R257X, was shown to be responsible for 82% of
Finnish APECED alleles. R257X was also detected in patients of
different origins on different haplotypes with closely linked
polymorphic markers (11, 12).
Here we present mutation analyses in an extended series of
patients, mainly of Northern Italian origin. We have detected two
common mutations, R257X and a 13-bp deletion (10941106del). As shown
by haplotype analyses, both R257X and 10941106del are likely to have
occurred multiple times by independent mutational events. We also
report two additional mutations, R203X and a mutation in the stop
codon, X546C, and 12 polymorphisms, including one amino acid
substitution. As already suspected from the variable phenotypes of
APECED sibs, genotype-phenotype correlation is not possible, which
indicates that the disease progression is likely to be modified by
other genetic and/or environmental factors.
 |
RESULTS
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Mutation Analysis in APECED Patients
The 14 exons of the APECED gene were individually
PCR-amplified, purified, and sequenced from each of the 15 patients,
including 9 Northern Italians, 2 British, 1 New Zealander, and 3 Finns
(see Materials and Methods). Sequence comparison identified
12 polymorphisms and 2 previously undefined mutations (Fig. 1
and Table 1
). In addition, by sequence, PCR, and
restriction enzyme analyses, R257X in exon 6 and 10941106del in exon
8 of the AIRE gene were detected in 10 of 18 and 5 of 18 independent
Northern Italian alleles, respectively. R257X was also detected in
compound heterozygosity with 10941106del in 1 British, 1 New
Zealander, and 1 Finn. 10941106del was also detected in homozygosity
in 2 Italians and 1 British patient (Fig. 1
and Table 2
).

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Figure 1. Electropherograms Showing the Sequence Surrounding
the Mutations in the APECED Gene
A, Mutation analysis of a Northern Italian APECED family (family A).
The two affected siblings are both compound heterozygotes for the R257X
(paternal origin) and R203X (maternal origin) mutations. The
electropherograms show normal and one patient heterozygous for the
C-to-T transition (underlined) resulting in the
"Arg" to "Stop" nonsense codon at position 203. B, Mutation
analysis of a Northern Italian APECED family (family B). The patients
are homozygous for the four-nucleotide insertion, which most likely results from a replication error due to the normally
occuring two copies of CCTG (underlined). C,
Electropherograms from a normal and homozygous mutant for 10941106del
(the 13-bp deletion, underlined in black in the normal).
The imperfect inverted repeat that may be responsible for the mutations
reoccurence is underlined in red. D, Electropherograms
from a normal and heterozygote mutant for X546C. The mutated nucleotide
is underlined.
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|
Another nonsense mutation resulting from a C
T transition in a CpG
dinucleotide in an arginine codon, R203X in exon 5, was detected in
compound heterozygosity with R257X in a Northern Italian (Fig. 1A
). In
this family, R203X was of maternal origin. In another Northern Italian
family, a 4-bp insertion in exon 8 (CCTG) of the AIRE gene after
position 1096 of the cDNA was detected (Fig. 1B
) (12). The insertion
most likely results from a replication error, as there are two direct
repeats of the inserted nucleotides, CCTG, in the normal sequence. The
insertion presumably results in a frameshift at L323 and premature
truncation of a 371-amino acid protein with 48 C-terminal amino acids
unrelated to the normal 545 AIRE protein. The unaffected sibling of the
twins with this mutation is also a carrier (Fig. 1B
).
A previously described mutation, 10941106del, a deletion of 13
nucleotides (12) also in exon 8, was detected in homozygosity in 2
Northern Italians and 1 British patient (Fig. 1C
) and was also found in
heterozygosity in a British, a New Zealand, and a Finnish patient. The
insertion presumably results in a frameshift at C322, and premature
truncation of a 372-amino acid protein with 50 C-terminal amino acids
unrelated to the normal AIRE protein.
Analysis of two Finnish patients heterozygous for R257X, including VP
(11) revealed a mutation in the stop codon of AIRE, TGA
TGT (X546C)
resulting in the addition of 60 C-terminal amino acids before
termination at an in-frame stop codon in the 3'-untranslated region of
AIRE (Fig. 1D
).
Haplotype Analysis in APECED Families
R257X has previously been described as the common Finnish APECED
allele but the mutation was also observed in APECED patients of various
origins (11, 12). This mutation is a C
T transition of the C residue
of a CpG dinucleotide, and haplotype analysis with the polymorphic
markers D21S1912, and PFKL confirmed that the
R257X mutation is associated with different haplotypes in the
non-Finnish patients. R257X was detected in 10 of 18 Northern Italian
APECED alleles in this study. Due to limited availability of samples
from parents of patients (NIT-A to I, Table 2
), haplotype construction
was performed assuming a founder affect for R257X in the Northern
Italian patients and, therefore, haplotypes were deduced to minimize
ancient implied recombinations. We are uncertain of the
haplotypes only in NIT-C, as the patient is heterozygous for both
markers studied here; however, in all possible allelic combinations,
R257X is associated with a unique haplotype in this patient. In the
patient from family A, where haplotype construction was possible with
immediate family members, and the four homozygotes for R257X, the
mutation is associated with five different haplotypes in Northern
Italians (order, D21S1912, AIRE, PFKL). D21S1912
is located approximately 130 kb from the 5'-end of AIRE (11, 12), and thus this additional association of D21S1912
alleles with R257X could result from an ancient recombination event or
mutation of this dinucleotide marker after the original mutational or
founder effect in Northern Italy. However, the CA repeat polymorphic
marker of PFKL is in the promoter region of the PFKL gene,
which is located approximately only 1.5 kb distal to the stop codon of
AIRE. R257X is associated with three different PFKL alleles
(Tables 2
and 3
). Thus, although
possible, it is unlikely that different haplotypes of R257X and PFKL
are the result of ancient recombination events. Combination of these
results with those previously reported (11, 12) shows R257X to be
associated with nine different haplotypes (Table 3
). Data available
from the intragenic polymorphisms in AIRE in our patient
series are uninformative. There are potentially three to five implied
independent mutational or migrational events that result in the
presence of R257X in Northern Italy. Assuming migrational events could
have mixed Swiss or Finnish R257X alleles in Northern Italy, looking
only at the association of R257X with PFKL alleles, there
have been a minimum of three mutational events.
10941106del had also previously been reported in patients of British,
Dutch, and German origin, all on the same haplotype. Our results
indicate that 10941106del is present on four haplotypes, or a minimum
of two if only PFKL is considered (Tables 2
and 3
). Thus, it is likely
that the 13-bp deletion has also occurred more than once.
 |
DISCUSSION
|
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The recent cloning of the gene for APECED has allowed the
investigation into the molecular basis of the disease in a number of
patients. These studies are pursued to provide clues to the function of
the AIRE protein in autoimmunity and the endocrine system. Six
mutations, including R257X, have previously been reported (11, 12).
Here we report an additional two mutations, one nonsense mutation and
one stop codon mutation. We have shown that R257X is also the common
cause of APECED in Northern Italian patients. Haplotype analyses
indicate a minimum of five independent mutational events worldwide for
this mutation, but the more likely scenario is that there have been a
minimum of nine independent occurrences of R257X. This is not
unprecedented as recurring C
T transition mutations in CpG
dinucleotides, particularly those in arginine codons, are commonly
described mutation events (13, 14, 15). R257X has only been observed with
one haplotype in Finnish patients, and the success of linkage
disequilibrium studies in Finnish families (10) and the frequency of
the disease in Finland point to a single mutational event for the
Finnish R257X.
10941106del is also observed in patients of diverse geo-ethnic
origin and is associated with multiple haplotypes. It is also likely to
be a recurring mutation, perhaps by the formation of hairpin structures
from the imperfect inverted repeat near the ends of the mutation site
(GGCCTGCCTGTCCCCTCCGCTCCGG,
the deletion is in bold and the imperfect inverted repeat is
underlined) as indicated in Fig. 1C
. This is also a known
mutational mechanism (14). We describe the first occurrence of
10941106del in a Finnish patient and another mutation, X546C, in two
Finnish patients. X546C is associated with the same haplotype. The fact
that 10941106del is recurrent and X546C is seen in two patients may
imply that these mutations will account for the remaining undescribed
Finnish APECED alleles with varying haplotypes (10).
A total of eight mutations have now been defined for APECED. It is
notable that all but K83E, and possibly X546C, are null mutations that
would produce no functional protein. Both the 4-bp insertion and 13-bp
deletion described here cause frameshifts in the first of the two PHD
zinc finger domains of AIRE. R257X and R203X are both situated before
the first zinc finger motif. We have also detected 12 polymorphisms, 6
in the coding region, but only one of which causes a conservative amino
acid substitution of a serine at position 278 to an arginine (found in
homozygosity and heterozygosity in control cell lines). S278R is
N-terminal to the zinc finger motifs in the AIRE protein and outside
all recognizable motifs (11, 12).
The 4-bp insertion and 13-bp deletion are in exon 8 of AIRE and are
thus also present in the alternative transcripts we previously named
AIRE2 and AIRE3 (11). However, it is possible that these transcripts
are experimental artifact and not functionally significant as many
mutations fall outside these transcripts and AIRE2 and AIRE3 are not
detectable by Northern blot using specific probes (11).
As expected, due to the slowly developing nature of many
of the symptoms of APECED, the observed differences between Finnish
patients, many of which where known to be homozygous by haplotype
analyses, and variation in phenotypes between APECED siblings (2, 4, 10), genotype-phenotype correlations do not seem to be possible in
APECED. X546C may be expected to produce functional protein, but both
patients had a typical APECED phenotype indistinguishable from that of
R257X homozygotes. This is emphasized by the different disease
progression in the siblings presented in our two Northern Italian
families. In family A, the siblings had a similar disease progression
except that one sibling lacked one of the three major characteristics
of APECED, hypoparathyroidism. In the twins in family B, autoimmune
thyroid disease developed in one patient at 3 yr of age and not until
16 in the other. Genotype-phenotype correlations may only be possible
after long-term follow-up of a large group of patients with division
into subgroups such as human leukocyte antigen (HLA) genotypes.
However, as may be expected from mouse models of autoimmune and
endocrine diseases, environment and genetic background play an
important role as in the mice with rheumatoid arthritis resulting from
crossing a T cell receptor (TCR) transgenic line with the nonobese
diabetic (NOD) strain (16).
The fact that most described APECED mutations in the AIRE
gene are presumably null mutations from many apparently nonrelated
APECED patients may be interpreted in several ways. We may be
investigating a rare disease with founder effects and/or that only null
mutations cause disease and/or the gene contains certain hypermutable
sites accounting for the reoccurrence of R257X and the 13-bp deletion
in patients of several different geo-ethnic origins. Presumably AIRE is
also responsible for a variant of APECED that presents mainly as
hypoparathyroidism in Iranian Jews, with some of the other clinical
symptoms such as candidiasis and kerathopathy present at much lower
frequencies than in Finnish patients (2, 9). With the partially
penetrant nature of many of the symptoms of APECED, the lack of
phenotype-genotype correlation and the fact that mutations in the AIRE
can cause a different clinical course, other mutations in AIRE may
result in other distinct genetic diseases or be contributory to other
polygenic diseases. Different mutations in different domains in the
same gene have been shown to be responsible for disorders with
distinctive phenotypes (e.g. Refs 17, 18, 19, 20). Due to AIREs
pattern of gene expression (thymus, lymph nodes, and fetal liver), AIRE
may be involved in other autoimmune/endocrine diseases such as
autoimmune polyendocrinopathy syndrome type 2, isolated Addisons
disease, or idiopathic hypoparathyroidism (21).
In summary, we have identified two previously undescribed mutations and
12 polymorphisms in the putative transcription factor gene, AIRE,
responsible for APECED. Two of these mutations, R257X and the 13-bp
deletion, occur in patients of different geo-ethnic origin and on
different chromosomal haplotypes, implying the reoccurrence of these
mutations by independent mutational events. These results should
facilitate the genetic diagnosis of APECED and the investigation of the
role of AIRE in other autoimmune-endocrine disorders.
 |
MATERIALS AND METHODS
|
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Patient Selection and DNA Isolation
A total of 15 apparently unrelated patients were studied. Nine
were of North-Italian origin, 2 were from Britain, 1 was from New
Zealand, and 3 were of Finnish origin. No consanguinity was documented
in any of the families. The patients were referred to Tampere
University Central Hospital (Tampere, Finland) or at Department of
Pediatrics, University of Padova (Padova, Italy) or the Pediatric
Department, Gaslini Institute (Genova, Italy) and blood samples were
obtained after informed consent and after approval of the research
projects by the Hospital Ethics Committees. The diagnosis was based on
typical clinical findings and, in some cases, the presence of
autoantibodies against steroidogenic enzymes P450c17 and/or P450scc.
Peripheral blood lymphocytes isolated from patient blood or
lymphoblastoid cell lines from APECED patients were used for extraction
of DNA using standard protocols.
Mutation Analyses
All 14 exons of the AIRE gene (GenBank accession no. AB006684)
were PCR amplified using the PCR primers and conditions shown in Table 4
. In general, PCR amplification was
carried out in a 30-cycle PCR, in which the initial 5-min denaturation
of template DNA at 94 C was followed by a "touch-down" program for
10 cycles: 94 C/20 sec, 65 C/20 sec (-1 C/cycle), 72 C/1 min, and then
20 cycles: 94 C/20 sec, 55 C/20 sec, 72 C/1 min, in a volume of 20 µl
containing 10 mM Tris-HCl, pH 8.3, 50 mM KCl,
0.2 mM of each deoxynucleoside triphosphate (dNTP), 1.5
mM MgCl2, 0.5 µM of each primer,
10% dimethysulfoxide, and 0.5 U of Taq polymerase. For some
exons, presumably due to their GC-rich nature, the use of Pfu
polymerase, and/or 50% deaza-GTP in place of dGTP and a special buffer
(16.6 mM NH4SO4, 67 mM
Tris-HCl, pH 8.8, 6.7 mM MgCl2, 10
mM ß-mercaptoethanol, 1.25 mM of each dNTP)
aided in successful amplification (Table 4
). Exon 9 gave the best
results with the QIAGEN (Chatsworth, CA) Kit Taq Polymerase
with Q-solution and 5% dimethylsulfoxide. PCR products were purified
using Qiaquick PCR purification columns according to manufacturers
instructions, and their nucleotide sequences were determined in both
orientations using all the primers listed with standard dye-terminator
protocols for the ABI377 automated sequencer (ABI Advanced
Biotechnologies, Columbia, MD). The R257X mutation was also analyzed by
TaqI restriction digestions as described (11). Haplotype
analysis for the markers D21S1912 and PFKL was
performed as described (10).
 |
ACKNOWLEDGMENTS
|
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We thank the families with APECED for their collaboration and
donation of samples.
 |
FOOTNOTES
|
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Address requests for reprints to: Hamish S. Scott, Laboratory of Human Molecular Genetics, Department of Genetics and Microbiology, University of Geneva Medical School, 1 rue Michel Servet, 1211 Geneva 4, Switzerland. E-mail: Hamish.Scott{at}medecine.unige.ch
The laboratory of S.E.A. is supported by grants from the Swiss FNRS
31.33965.92 and 3140500.94 and the European Union (EU)/Office
Fédéral de lEducation et de la Science (OFES) CT930015,
funds from the University and Cantonal Hospital of Geneva, and the
Associazione Malattie Rare "Mauro Baschirotto." M.D.L. is a trainee
of the Graduate Program of Molecular and Cellular Biology of the
University of Geneva Medical School. The laboratory of K.J.E.K. was
supported by EU Biomed2 program CA grant (BNH4-CT950729) and by
grants from Tampere University Hospital Medical Research Fund. The
laboratory of N.S. was supported by Funds for Human Genome Sequencing
Project from the Japan Science and Technology Corporation (JST); Grants
in Aid for Scientific Research on Priority Areas and Scientific
Research from the Ministry of Education, Science, Sports and Culture of
Japan; and Fund for "Research for the Future" Program from the
Japan Society for the Promotion of Science (JSPS).
Received for publication December 19, 1997.
Revision received April 6, 1998.
Accepted for publication April 10, 1998.
 |
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