Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0014848 (achalasia)
 2,804 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Triple A syndrome (Allgrove syndrome, MIM No. 231550) is a rare autosomal recessive disorder characterised by ACTH-resistant adrenal insufficiency, achalasia of the cardia, and alacrimia. The triple A gene has been previously mapped to chromosome 12q13 in a maximum interval of 6 cM between loci D12S1629 and D12S312. Using linkage analysis in 12 triple A families, mostly originating from North Africa, we confirm that the disease locus maps to the 12q13 region (Zmax = 10.89 at theta = 0 for D12S1604) and suggest that triple A is a genetically homogeneous disorder. Recombination events as well as homozygosity for polymorphic markers enabled us to reduce the genetic interval to a 3.9 cM region. Moreover, total linkage disequilibrium was found at the D12S1604 locus between a rare allele and the mutant chromosomes in North African patients. Analysis of markers at five contiguous loci showed that most of the triple A chromosomes are derived from a single founder chromosome. As all markers are located in a 0 cM genetic interval and only allele 5 at the D12S1604 locus was conserved in mutant chromosomes, we speculate that the triple A mutation is due to an ancient Arabian founder effect that occurred before migration to North Africa. Since we also found linkage disequilibrium at D12S1604 in two patients from Southern Europe (France and Spain), the founder effect might well extend to other Mediterranean countries. Taking advantage of a YAC contig encompassing the triple A minimal physical region, the triple A gene was mapped to a 1.7 Mb DNA fragment accessible to gene cloning.
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PMID:Linkage disequilibrium in inbred North African families allows fine genetic and physical mapping of triple A syndrome. 1095 24

Triple-A syndrome (MIM 231550; also known as Allgrove syndrome) is an autosomal recessive disorder characterized by adrenocorticotropin hormone (ACTH)-resistant adrenal insufficiency, achalasia of the oesophageal cardia and alacrima. Whereas several lines of evidence indicate that triple-A syndrome results from the abnormal development of the autonomic nervous system, late-onset progressive neurological symptoms (including cerebellar ataxia, peripheral neuropathy and mild dementia) suggest that the central nervous system may be involved in the disease as well. Using fine-mapping based on linkage disequilibrium in North African inbred families, we identified a short ancestral haplotype on chromosome 12q13 (<1 cM), sequenced a BAC contig encompassing the triple-A minimal region and identified a novel gene (AAAS) encoding a protein of 547 amino acids that is mutant in affected individuals. We found five homozygous truncating mutations in unrelated patients and ascribed the founder effect in North African families to a single splice-donor site mutation that occurred more than 2,400 years ago. The predicted product of AAAS, ALADIN (for alacrima-achalasia-adrenal insufficiency neurologic disorder), belongs to the WD-repeat family of regulatory proteins, indicating a new disease mechanism involved in triple-A syndrome. The expression of the gene in both neuroendocrine and cerebral structures points to a role in the normal development of the peripheral and central nervous systems.
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PMID:Mutant WD-repeat protein in triple-A syndrome. 1106 74

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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PMID:Triple A syndrome is caused by mutations in AAAS, a new WD-repeat protein gene. 1115 47

The triple A syndrome or Allgrove syndrome (MIM*231550) is characterized by adrenocorticotropic hormone (ACTH) resistant Adrenal insufficiency, Achalasia of the cardia and Alacrima. In addition to the main features, patients frequently suffer from neurological disturbances. Dermatological abnormalities such as palmoplantar hyperkeratosis as well as other signs like short stature, microcephaly and osteoporosis point to the multisystemic character of the disorder. The molecular defect of the autosomal recessively inherited triple A syndrome is not known. We initially performed a systematic genome linkage scan in eight triple A families and were able to map the syndrome to a 6 cM interval on human chromosome 12q13 near the type II keratin gene cluster. A refinement of the triple A critical region was achieved by detailed haplotype analysis in a further 37 families from different ethnic backgrounds. There was no indication of genetic heterogeneity. The achalasia-alacrima (AA) syndrome which has been defined as a distinct clinical entity (MIM 200440) is most likely a variant of the triple A syndrome as shown by haplotype analysis in three AA families. We constructed a high-resolution BAC/PAC-based transcript map of the region which will greatly facilitate the identification of the triple A syndrome gene. The considerable intra- and interfamilial variability of the severity of the disorder implies a variable expression of an impaired pleiotropically acting gene.
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PMID:Triple A syndrome--clinical aspects and molecular genetics. 1119 51

Familial glucocorticoid deficiency due to corticotropin (ACTH) resistance consists of two distinct genetic syndromes that are both inherited as autosomal recessive traits: isolated ACTH resistance (iACTHR), which may be caused by inactivating mutations of the ACTH receptor (the MC2R gene) or mutations in an as yet unknown gene(s), and Allgrove syndrome (AS). The latter is also known as triple-A syndrome (MIM 231550). In three large cohorts of AS kindreds, the disease has been mapped to chromosome 12; most recently, mutations in the AAAS gene on 12q13 were found in these AS families. AAAS codes for the WD-repeat containing ALADIN (for alacrima-achalasia-adrenal insufficiency-neurologic disorder) protein. We investigated families with iACTHR (n = 4) and AS (n = 6) and a Bedouin family with ACTHR and a known defect of the TSH receptor. Four AS families were of mixed extraction from Puerto Rico (PR); most of the remaining six families were Caucasian families from North America (NA). Sequencing analysis found no MC2R genetic defects in any of the kindreds. No iACTHR kindreds, but all of AS families, had AAAS mutations. The previously reported IVS14+1G-->A splice donor mutation was found in all PR families, apparently due to a founder effect; one NA kindred was heterozygous for this mutation. In the latter family, long-range PCR failed to identify a deletion or other rearrangements of the AAAS gene. No other heterozygote or transmitting parent had any phenotype that could be considered part of AS. The IVS14+1G-->A mutation results in a premature termination of the predicted protein; although it was present in all PR families (in the homozygote state in three of them), there was substantial clinical variation between them. One PR family also carried a novel splice donor mutation of the AAAS gene in exon 11, IVS11+1G-->A; the proband was a compound heterozygote. A novel point mutation, 43C-->A(Gln15Lys), in exon 1 of the AAAS gene was identified in the homozygote state in a Canadian AS kindred with a milder AS phenotype. The predicted amino acid substitution in this family is located in a sequence that may participate in the preservation of stability of ALADIN beta-strands, whereas the splicing mutation in exon 11 may interfere with the formation of WD repeats in this molecule. We conclude that 1) AAAS does not appear to be frequently mutated in families with iACTHR; 2) AAAS is mutated in AS families from PR (that had previously been mapped to 12q13) and NA; and, 3) there is significant clinical variability between patients with the same AAAS defect.
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PMID:Spectrum of mutations of the AAAS gene in Allgrove syndrome: lack of mutations in six kindreds with isolated resistance to corticotropin. 1170 18

Triple-A syndrome (MIM 231550; also known as Allgrove syndrome) is an autosomal recessive disorder characterized by adrenocorticotropin hormone (ACTH)-resistant adrenal insufficiency, achalasia of the oesophageal cardia and alacrima. Much initial molecular analysis supported that Triple-A syndrome was caused by mutations in AAAS, a WD-repeat protein gene. Here we report cloning and characterization of a novel splice variant of human AAAS, which we named AAAS-v2, which is located on the human chromosome 12p13. The cDNA is 1703 bp, encoding a 513-amino acid polypeptide, which contains three WD40 domains, one less than the original which we called AAAS-v1 (Gen Bank: NM_015665.3). RT-PCR analysis in our work revealed that AAAS-v2 and AAAS-v1 were ubiquitously detected in human multiple tissue cDNA (MTC) panels (CLONTECH).
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PMID:Molecular cloning and characterization of AAAS-V2, a novel splice variant of human AAAS. 1602 85