Human Molecular Genetics, 2001, Vol. 10, No. 3 283-290
© 2001 Oxford University Press
Triple A syndrome is caused by mutations in AAAS, a new WD-repeat protein gene
1Children’s Hospital, Technical University Dresden, Fetscherstrasse 74, D-01307 Dresden, Germany, 2Max-Planck-Institute of Molecular Genetics, D-14195 Berlin, Germany, 3Research Institute of Molecular Genetics, Catholic Research Institutes of Medical Sciences, Seoul 137-701, Korea and 4Departments of Endocrinology, St Bartholomew’s and the Royal London School of Medicine and Dentistry, London EC1A 7BE, UK
Received 3 November 2000; Revised and Accepted 23 November 2000.
DDBJ/EMBL/GenBank accession nos AJ297977 and AF226048.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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The triple A syndrome (MIM 231550) is a rare autosomal recessive disorder characterized by adrenal insufficiency, achalasia and alacrima. The frequent association with a variety of neurological features may result in a severely disabling disease. We previously mapped the syndrome to a 6 cM interval on chromosome 12q13 and have now refined the critical region to 0 cM between KRT8 and D12S1651. Overlapping bacterial artificial chromosome (BAC) sequences of a high resolution BAC/P1-derived artificial chromosome (PAC) contig were screened for gene content and a novel gene encoding a 546 amino acid polypeptide was identified. In nine triple A syndrome patients eight different homozygous and compound heterozygous mutations were found in this gene, most of them leading to a truncated protein suggesting loss of function. RNA blotting experiments revealed marked expression in neuroendocrine and gastrointestinal structures, which are predominantly affected in triple A syndrome, supporting the hypothesis that mutations in this triple A syndrome gene (AAAS) are responsible for the disease. The predicted protein belongs to the family of WD repeat-containing proteins which exhibit a high degree of functional diversity including regulation of signal transduction, RNA processing and transcription.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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The triple A syndrome, also known as Allgrove syndrome (MIM 231550), is characterized by the clinical triad of adrenocorticotropic hormone (ACTH)-resistant adrenal failure, achalasia of the cardia and alacrima (1–3). The syndrome is associated with variable and progressive neurological impairment involving the central, peripheral and autonomic nervous systems, suggesting mutations in a pleiotropic-acting gene with developmental and tissue-specific expression (4). Dermatological features such as palmoplantar hyperkeratosis, as well as other signs including short stature, osteoporosis and microcephaly, point to the multisystemic character of the disorder which may severely impair life quality in affected individuals. Using a genome-wide systematic linkage scan we previously mapped the syndrome to a 6 cM interval on human chromosome 12q13 (5). Investigating a total of 47 informative families we have now been able to refine the critical region to a small interval of 0 cM between markers KRT8 and D12S1651 (6). A high-resolution bacterial artificial chromosome/P1-derived artificial chromosome (BAC/PAC) contig in this region was constructed (7), and high throughput genomic sequences (HTGSs) of overlapping BACs were systematically screened for transcribed sequences. Here we report the identification of a novel gene which is mutated in all patients with triple A syndrome investigated. Sequence analysis showed that this novel gene is predicted to encode a protein containing four WD repeats, thus belonging to the family of WD-repeat proteins. We determined the human tissue expression and propose that the gene should be named AAAS (achalasia-addisonianism-alacrima syndrome gene).
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Genetic and physical mapping
In a total of 47 families with triple A syndrome we performed haplotype reconstruction with markers from the triple A critical region which allowed the characterization of six obligate recombination events (Fig. 1A). The centromeric critical breakpoint placed the triple A gene distal to the single nucleotide polymorphism (SNP) HGBASE:SNP000000070 (http://hgbase.interactiva.de ) within KRT8 (Fig. 1B). The critical telomeric breakpoint was in family 8, placing the triple A gene proximal to D12S1651 (Fig. 1C). Additional recombination events inferred from regions of autozygosity in patients from consanguineous families support the refinement of the triple A locus to a genetic interval of 0 cM between KRT8 and D12S1651 (Fig. 1A). There was no evidence for genetic heterogeneity, as in all families the result was compatible with linkage to this region. We constructed a high resolution BAC/PAC-based contig in the triple A critical region (7). The physical map between KRT8 and D12S1651 comprised 42 clones (32 BAC and 10 PAC) with a minimal tiling path consisting of six BAC clones, which span a physical distance of
725 kb. A total of 51 sequence tagged sites (STSs) have been ordered in the contig including 18 expressed sequence tags (ESTs), 16 known genes, 3 polymorphic markers and 14 non-polymorphic STSs.
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Identification of the human AAAS gene
Using GENSCAN and GRAILEXP programs on the six overlapping HTGS BAC clones, several novel genes were predicted. The hypothetical RNAs of these coding segments were subjected to extensive BLAST analyses. One of the predicted mRNA fragments deriving from the HTGS BAC clone RP11-680A11 (GenBank accession no. AC073611) provided significant sequence homology to cDNA clone DKFZp586G1624 (GenBank accession no. AL110160.1) and two full-length cDNA sequences published in GenBank (accession nos AF226048 and AK000833) encoding a transducin-like protein. As these proteins are known to exert regulatory functions in transcription and signal transduction, we considered this gene to be a plausible candidate for triple A syndrome.
The cDNA of 1751 bp exhibited an open reading frame of 1638 bp encoding a protein of 546 amino acids with a calculated molecular mass of 59.6 kDa (Fig. 2). By comparing the cDNA sequence with the HTGS BAC sequence (GenBank accession no. AC073611) the exon–intron structure of the gene was determined. The gene consists of 16 exons and the intron lengths vary between 85 bp and 4575 bp (Table 1). The polyadenylation signal (AATAAA) precedes the poly(A) tail by 21 bp. Protein motif search using PROSITE revealed the existence of WD repeats. Using the WD-repeat consensus sequence (8,9) and BMERC search engine, a total of four WD repeats showing significant similarity to the consensus sequence were identified in this protein (Fig. 2). This suggests that the gene encodes a novel WD-repeat protein. BLAST search revealed no significant homology to any previously identified human WD-repeat protein. A protein database search revealed that AAAS is most closely related to the Drosophila melanogaster CG16892 gene product (GenPept accession no. AAF46484; 30% identity, 45% similarity), Arabidopsis thaliana putative protein (GenPept accession no. CAC00753; 29% identity, 42% similarity) and a vegetative incompatibility protein HET-E-1 from the fungus Podospora anserina (GenPept accession no. AAA85775; 26% identity, 43% similarity). By PROSITE motif search, several sites for glycosylation, myristoylation, casein kinase II phosphorylation and protein kinase C phosphorylation were also identified in AAAS, but their significance remains to be determined. The last three amino acids, Ser-His-Leu, represent a peroxisome-targeting signal 1 (PTS1) (10). It has been shown that PTS1 is important for protein import into peroxisomes and other microbodies (11).
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Tissue expression of human AAAS
To determine the tissue distribution of human AAAS a Clontech multiple tissue expression array was probed with AAAS cDNA (D2). It appears that AAAS shows ubiquitous expression in human tissues. Notably, a particularly abundant expression was observed in the adrenal gland, gastrointestinal structures, pituitary gland, cerebellum and fetal lung (data not shown). ESTs homologous to the AAAS gene were identified in cDNA libraries from whole embryo and diverse adult human tissues (AA330197, Hs 125262), supporting the result that AAAS is an ubiquitously expressed gene.
Mutation analysis in patients with triple A syndrome
We searched for sequence alterations in the entire coding region and exon–intron boundaries of AAAS in nine triple A families including 19 patients. We identified a total of eight different mutations occurring in exons 1, 2, 6, 8, 9, 11 and 15 including three missense mutations (Q15K, H160R and S263P), three nonsense mutations (W84X, R286X and R342X) and two frameshift deletions of 1 and 2 bp (552–553delTT and 1471delC), respectively (Table 2). Selected homozygous or heterozygous sequences are depicted in Figure 3A. Mutations were found in all triple A families either in a homozygous (n = 7 families) or compound heterozygous (n = 2 families) form. The occurrence of homozygous mutations in patients from consanguineous families matches with the autozygosity previously found on the marker level. Interestingly, the 869T
C (S263P) mutation was found in four different families. The two Polish patients from families 6 and 7 were homozygous for this mutation, whereas in families 1 (German origin) and 5 (Polish origin) the mutation was found on one of the disease alleles. In family 1, the second allele bore a missense mutation (125CA, Q15K) and in family 5 the second allele carried the 1 bp deletion (1471delC) resulting in a frameshift after Ser463 with a nonsense sequence of 86 amino acids. In the consanguineous Polish family 2 we found a homozygous TGGTAG transition at the 3' splice junction of exon 2 that causes a change of Trp84 to a stop codon (W84X) predicting a truncated protein of 83 amino acids. In both patients from the consanguineous family 4 from Israel we detected a 2 bp deletion (TT) at the second and third positions of codon 157 in exon 6. This 2 bp deletion (552–553delTT) causes a frameshift after Val156, resulting in a nonsense sequence of 15 residues followed by a premature stop codon. All eight patients from the large and highly consanguineous Métis-Canadian family described by Moore et al. (12) carried a CGATGA transition in exon 9, causing a change from Arg286 to a stop codon (R286X). None of the mutations were found in 50 healthy control individuals.
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Segregation studies were performed by single-strand conformation polymorphism (SSCP) analysis or direct sequencing. In all families the mutations segregated with the disease in that the healthy parents were heterozygotes, affected siblings also bore the mutation and unaffected siblings were either carriers of the disease or healthy homozygotes (Fig. 3B). The results are consistent with the proposed autosomal recessive inheritance (3) and support the hypothesis that the mutations in AAAS are responsible for triple A syndrome.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Patients with triple A syndrome suffer from the clinical triad of adrenal failure, achalasia and alacrima. The autosomal recessive disorder manifests itself within the first decade of life with alacrima being the earliest and most consistent symptom followed by glucocorticoid deficiency and achalasia (4). The frequent association with a variety of neurological disorders, including dysautonomia, in addition to various dermatological and other features such as short stature, facial dysmorphy and osteoporosis, indicates that triple A syndrome is in fact a multisystemic disorder.
Based on the refinement of the triple A critical region to 0 cM on chromosome 12q13 and a positional genomics approach, we identified AAAS, the gene defective in families with triple A syndrome. Sequence analysis established that AAAS protein contains four WD repeats, suggesting that it belongs to the large WD-repeat protein family (8). It has become established that four WD repeats are able to form a typical ß-propeller structure, which is involved in protein–protein interactions (9). Recently, mutations in several novel WD-repeat proteins have been associated with diseases such as Cockayne syndrome, X-linked sensorineural deafness and dactylaplasia (13–15). Despite extensive BLAST searches, no significant homologies could be identified, either to a previously described human WD-repeat protein nor to any other known human protein. A protein database search revealed relevant homologies to the D.melanogaster CG16892 gene product, A.thaliana putative protein and a vegetative incompatibility protein HET-E-1 from the fungus P.anserina. WD-repeat proteins exhibit a high degree of functional diversity in that they are involved in signal transduction, RNA processing, vesicular trafficking, cytoskeleton assembly and cell division control (9). Therefore, it appears difficult to assign a specific function to this novel WD-repeat protein considering the protein sequence alone.
Interestingly, the C-terminal end of the protein consists of the amino acid triplet Ser-His-Leu, which at this position may act as a PTS1 (10). PTS1 is conserved throughout eukaryotic evolution, and it has been demonstrated to function in diverse species including flies, rats, yeast, plants and man (16). The topogenic tripeptide has been shown to direct proteins to and into peroxisomes (17). We therefore presume that AAAS is a protein that may be imported into peroxisomes exerting as yet unknown function(s). Defects of single peroxisomal proteins have been associated with adrenal atrophy, psychomotor retardation, neuronal migrational defects (18,19) and progressive ataxia (20)—symptoms which are also described in individual patients with triple A syndrome (for a review see ref. 4). Further experimental studies are required to test this hypothesis.
The ubiquitous expression of AAAS is in accordance with the multisystemic character of the disorder and the predominant occurrence in the adrenal gland, gastrointestinal and nervous structures is in line with the tissues mainly affected in triple A syndrome.
We have detected homozygous or compound heterozygous mutations in the AAAS gene which segregate with the disease in all triple A families included in the present study. Five mutations cause either a premature stop codon or a frameshift, thus predicting a truncated protein presumably leading to loss of function. The W84X mutation predicts a complete lack and the 552–553delTT and R286X mutations a significant truncation of the WD domain, respectively. Two of three missense mutations are located within the first (H160R) and third (S263P) WD repeat, respectively (Fig. 2). Although only the Ser263 is a conserved residue according to the WD-repeat consensus sequence (9) we assume that both mutations might disrupt the ß-propeller structure of the protein, thus impairing putative protein–protein interactions. The S263P mutation was found in four families. This phenomenon seems to be based on a founder effect rather than a true mutational ‘hot spot’ according to the haplotype analyses and the geographical origin of the families. The nonsense mutations R342X and 1471delC do not alter the WD domain, but result in the loss of the C-terminus of the protein, including the PTS1 sequence. Comparing the severities of the phenotypes of the nine patients, there does not seem to be an obvious genotype–phenotype relationship. The two patients of family 2, bearing the homozygous truncating mutation W84X in exon 2, are not as badly affected as the patients of families 3 and 4, who carry the homozygous H160R and 552–553delTT mutations in exon 6. However, all patients with the S263P mutation in the third WD repeat exhibit a similar severe phenotype with existence of all three main symptoms of the triple A syndrome, mental retardation and progressive peripheral neuropathy. Patients of families 8 and 9 who have an intact WD domain show no significant phenotypic differences to the other patients. Moreover, in view of the considerable phenotypic variation within the same family (4), a strong genotype–phenotype relationship appears to be unlikely. Obviously, this question should be addressed in extended mutation analysis studies which might be important for the understanding of the structure–function relation of the AAAS protein.
In summary, we have identified AAAS, a novel gene encoding a 546 amino acid protein which belongs to the WD-repeat family and which is mutated in all families with triple A syndrome studied to date. Taking into account RNA expression and segregation studies as well as mutation analysis, we believe that defects in AAAS cause the triple A syndrome. The existence of a C-terminal peroxisomal targeting signal in AAAS is strongly suggestive of a protein involved in peroxisomal function. With the functional characterization of the AAAS protein, a greater understanding of neuroendocrine development can be envisaged.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Family material
A total of 47 triple A families from four continents were recruited for the refinement study. A subset of nine families including 19 patients (7 males and 12 females; families 1, 2 and 5–7 were of white European origin, family 3 was of Turkish origin, family was 4 of Arabian origin, family 8 was of Métis-Canadian origin and family 9 was of Moroccan origin), were subjected to SSCP and sequence analysis of the AAAS gene. In seven families (families 2–4 and 6–9), the parents were consanguineous. The diagnosis of triple A syndrome was made on the basis of clinical and biochemical evidence of adrenal insufficiency in combination with a deficiency of tear production in a Schirmer test and signs of achalasia visible in barium contrast radiography. Families 1, 4 and 6–9 were reported previously (2,12,21–23). Blood samples from patients and family members were collected after informed consent. DNA preparation was performed according to standard protocols (24).
Genetic and physical mapping
Microsatellite analysis was performed with fluorescently labeled primers by standard semi-automated methods using an ABI 377 sequencing machine (Perkin Elmer) (5). The order of markers used for the genetic finemapping was based on published human linkage maps (25,26) (http://www.genethon.fr ; http//www.marshmed.org/genetics/ ) and physical mapping data (27). SNP data were extracted from SNP databases (http://hgbase.interactiva.de ; http://www-genome.wi.mit.edu/SNP/ ). The marker order was confirmed by physical mapping using a high resolution chromosome 12q13 clone overlap map (7). Construction of the BAC/PAC contig was based on PCR screening of the CalTech ‘D’ and RPCI-11 human BAC libraries and the RPCI-1,3-5 human male PAC library (Research Genetics). STS content was determined by PCR analysis using all available STSs including markers and ESTs acquired from GeneMap’99.
Databases and database analysis
HTGSs of overlapping BACs from the triple A critical region (7) were analyzed with the use of GENSCAN (28) and GRAILEXP (http://grail.lsd.ornl.gov/grailexp/credits.shtml ) programs. Homology search and exon assembly were performed via BLAST programs at the NCBI server (http://www.ncbi.nlm.nih.gov/ ). PROSITE searches (29) (http://www.expasy.ch/prosite/ ) were performed to identify motifs. The detailed WD-repeat analysis was obtained from the PSA Sequence Analysis Server at the BioMolecular Engineering Research Center of Boston University (http://bmerc-www.bu.edu ).
Mutation screening and segregation analysis
Coding sequences were amplified from patients’ genomic DNA with primers located in flanking introns and untranslated region sequences. Prior to sequencing, PCR products were subjected to SSCP. For SSCP analysis, 10% polyacrylamide gels (Long Ranger; BMA) containing 10% glycerol were run with 1x Tris–borate/EDTA for 16 h at 150 V and 10°C and visualized by silver staining. PCR products were purified using Qiaquick columns (Qiagen) and sequenced on an ABI 377 sequencer using BigDye Terminator Cycle Sequencing kit (PE Biosystems).
Expression analysis
A human multiple tissue northern (MTN) blot (Clontech) was used for northern blot analysis to determine tissue distribution of AAAS transcripts. As a probe, a 606 bp cDNA fragment encompassing nucleotides 1036–1641 of the AAAS cDNA (D2) was radioactively labeled with [32P]dCTP using Prime-IT II (Stratagene). Hybridization with Clontech’s ExpressionHyb solution and stringent washes were performed according to the manufacturer’s protocol. The filter was exposed in a phosphorimager (FUJIFilm BAS-1800; Fuji) and automatically assessed using the VISUAL GRID program (GPC Biotech).
Primer sequences
Primer sequences used for genetic and physical finemapping and amplification of AAAS sequences are available from the authors by request.
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ACKNOWLEDGEMENTS |
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We deeply thank all the families for their participation in this study. We greatly acknowledge the contributions by Christopher Cowell (Parramatta, Australia), Heather Dean (Winnipeg, Canada), Maria Ginalska-Malinowska (Warsaw, Poland), Claudine Heinrichs (Brussels, Belgium), Klaus Hübschmann (Potsdam, Germany), Arpad von Moers (Berlin, Germany) and Avraham Zeharia (Petah-Tikva, Israel) for the collection and clinical evaluation of triple A patients. The excellent technical assistance of Cornelia Hilscher and Heike Petzold is kindly acknowledged. We thank Patricia Ruiz for her encouraging discussions. We are grateful for the provision of clones by the Resource Center of the German Human Genome Project (RZPD, Berlin). This work was supported by grants from the Deutsche Forschungsgemeinschaft (We 1693/3-1,3-2) to A.H. and from the Korean Research Foundation to S.K.Y. (1998-010-158).
NOTE ADDED IN PROOF
After submission of this paper, Tullio-Pelet et al. reported the independent identification of the AAAS gene and mutations therein in patients with triple A syndrome [Tullio-Pelet et al. (2000) Nature Genet., 26, 332–335].
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FOOTNOTES |
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+ To whom correspondence should be addressed. Tel: +49 351 458 2926; Fax: +49 351 458 4334; Email: angela.huebner@mailbox.tu-dresden.de
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REFERENCES |
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R. W. Orrell and A. J.L. Clark ALADIN, but where's the Genie? Neurology, March 26, 2002; 58(6): 847 - 848. [Full Text] [PDF]
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F. Sandrini, C. Farmakidis, L. S. Kirschner, S.-M. Wu, A. Tullio-Pelet, S. Lyonnet, D. L. Metzger, C. J. Bourdony, D. Tiosano, W.-Y. Chan, et al. Spectrum of Mutations of the AAAS Gene in Allgrove Syndrome: Lack of Mutations in Six Kindreds with Isolated Resistance to Corticotropin J. Clin. Endocrinol. Metab., November 1, 2001; 86(11): 5433 - 5437. [Abstract] [Full Text] [PDF]
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