Triple A syndrome is caused by mutations in AAAS, a new WD-repeat protein gene.

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.

[1]  H J Dean,et al.  Linkage of the gene for the triple A syndrome to chromosome 12q13 near the type II keratin gene cluster. , 1996, Human molecular genetics.

[2]  Amos Bairoch,et al.  The PROSITE database, its status in 1999 , 1999, Nucleic Acids Res..

[3]  D. Valle,et al.  Peroxisome biogenesis disorders: genetics and cell biology. , 2000, Trends in genetics : TIG.

[4]  R. Couch,et al.  Allgrove syndrome: an autosomal recessive syndrome of ACTH insensitivity, achalasia and alacrima , 1991, Clinical endocrinology.

[5]  A. Huebner,et al.  Triple a Syndrome—Clinical Aspects and Molecular Genetics , 2000, Endocrine research.

[6]  H. Tabak,et al.  Peroxisomal protein import is conserved between yeast, plants, insects and mammals. , 1990, The EMBO journal.

[7]  Amos Bairoch,et al.  The PROSITE database, its status in 2002 , 2002, Nucleic Acids Res..

[8]  Klaus Hübschmann,et al.  Achalasie, Alakrimie und Cortisolmangel - das Allgrove Syndrom , 1995 .

[9]  D B Grant,et al.  Neurological and adrenal dysfunction in the adrenal insufficiency/alacrima/achalasia (3A) syndrome. , 1993, Archives of disease in childhood.

[10]  L Kruglyak,et al.  An STS-Based Map of the Human Genome , 1995, Science.

[11]  A. Clark,et al.  ACTH resistance syndromes. , 1999, Journal of pediatric endocrinology & metabolism : JPEM.

[12]  M. de Hoop,et al.  Import of proteins into peroxisomes and other microbodies. , 1992, The Biochemical journal.

[13]  E. Friedberg,et al.  The Cockayne syndrome group A gene encodes a WD repeat protein that interacts with CSB protein and a subunit of RNA polymerase II TFIIH , 1995, Cell.

[14]  G. Clayden,et al.  FAMILIAL GLUCOCORTICOID DEFICIENCY WITH ACHALASIA OF THE CARDIA AND DEFICIENT TEAR PRODUCTION , 1978, The Lancet.

[15]  C. Tsigos,et al.  Familial adrenocorticotropin unresponsiveness associated with alacrima and achalasia: biochemical and molecular studies in two siblings with clinical heterogeneity. , 1995, European journal of pediatrics.

[16]  F Roels,et al.  Pseudo-Zellweger syndrome: deficiencies in several peroxisomal oxidative activities. , 1986, The Journal of pediatrics.

[17]  T. Lerman-Sagie,et al.  Periventricular Brain Heterotopias in a Child With Adrenocortical Insufficiency, Achalasia, Alacrima, and Neurologic Abnormalities (Allgrove Syndrome) , 1999, Journal of child neurology.

[18]  G. Borsani,et al.  X-linked late-onset sensorineural deafness caused by a deletion involving OA1 and a novel gene containing WD-40 repeats. , 1999, American journal of human genetics.

[19]  Cécile Fizames,et al.  A comprehensive genetic map of the human genome based on 5,264 microsatellites , 1996, Nature.

[20]  Amos Bairoch,et al.  The PROSITE database, its status in 1997 , 1997, Nucleic Acids Res..

[21]  K. Montgomery,et al.  A second-generation YAC contig map of human chromosome 12. , 1995, Nature.

[22]  Shirley A. Miller,et al.  A simple salting out procedure for extracting DNA from human nucleated cells. , 1988, Nucleic acids research.

[23]  B. Birren,et al.  A novel member of the F-box/WD40 gene family, encoding dactylin, is disrupted in the mouse dactylaplasia mutant , 1999, Nature Genetics.

[24]  Temple F. Smith,et al.  The ancient regulatory-protein family of WD-repeat proteins , 1994, Nature.

[25]  A Weber,et al.  Adrenocorticotropin insensitivity syndromes. , 1998, Endocrine reviews.

[26]  R Kucherlapati,et al.  High-resolution transcript map of the region spanning D12S1629 and D12S312 at chromosome 12q13: triple A syndrome-linked region. , 2000, Genome research.

[27]  S Subramani,et al.  Identification of Peroxisomal Targeting Signals Located at the Carboxy Terminus of Four Peroxisomal Proteins Materials and Methods Reagents , 1988 .

[28]  S. Karlin,et al.  Prediction of complete gene structures in human genomic DNA. , 1997, Journal of molecular biology.

[29]  A. Moser,et al.  Peroxisomal bifunctional enzyme deficiency. , 1989, The Journal of clinical investigation.

[30]  Temple F. Smith,et al.  The WD repeat: a common architecture for diverse functions. , 1999, Trends in biochemical sciences.