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 (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

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 (3A) syndrome, a rare autosomal recessive disorder, is characterized by adrenocorticotropic hormone-resistant adrenal insufficiency, achalasia of the cardia, alacrima, and variable autonomic and neurologic dysfunction. The gene responsible, AAAS, recently has been identified. We describe the neurologic phenotype of the first adult case of 3A syndrome presenting bulbospinal amyotrophy as the prominent sign in association with a homozygous nonsense mutation identified in the AAAS gene.
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PMID:Progressive bulbospinal amyotrophy in triple A syndrome with AAAS gene mutation. 1247 93

Triple A syndrome, also known as Allgrove syndrome, is a rare autosomal recessive disorder characterized by adrenal insufficiency, achalasia and alacrima. It has recently been reported that this syndrome is caused by mutations in the AAAS gene. In the present study, we analyzed the AAAS gene in a Japanese patient with triple A syndrome. The patient was a Japanese girl previously reported by Hirose et al. (J Jpn Pediatr Soc 102: 912-915, 1998). The parents of the patient were first cousins. The patient was confirmed to have alacrima and isolated glucocorticoid deficiency at the age of 2 years. She later developed achalasia of the cardia, and was diagnosed as having triple A syndrome. The AAAS gene was amplified by the PCR method, and the PCR products were directly sequenced. The patient was homozygous for a novel nonsense mutation Q237X, changing codon 237 encoding Gln (CAA) to a stop codon (TAA). The parents were heterozygous for the Q237X mutation. The AAAS gene encodes a protein of 546 amino acids, ALADIN. The Q237X mutation is predicted to result in a truncated and presumably non-functioning ALADIN protein, thus causing the clinically manifest syndrome in the patient. To our knowledge, this is the first report on AAAS gene mutations in Japan.
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PMID:Analysis of the AAAS gene in a Japanese patient with triple A syndrome. 1200 50

Triple A (Allgrove) syndrome is characterized by achalasia, alacrima, adrenal abnormalities and a progressive neurological syndrome. Affected individuals have between two and four of these relatively common clinical problems; hence the diagnosis is often difficult in all but the classical presentation. The inheritance is autosomal recessive, and most cases of triple A have no family history. Using genetic linkage analysis in a small number of families, a locus on chromosome 12q13 was identified. The triple A gene was identified recently at this locus and called ALADIN (alacrima, achalasia, adrenal insufficiency neurologic disorder). Mutations in this gene were reported in families from North Africa and Europe. The majority of mutations were homozygous. We have identified 20 families with between two and four of the clinical features associated with the triple A syndrome. Sequencing of the triple A gene revealed five families that had a total of nine compound heterozygous mutations, and one Portuguese family (previously published) had two homozygous mutations; these changes were spread throughout the triple A gene in exons 1, 2, 7, 8, 10, 11, 12, 13 and 16, and the poly(A) tract. Those bearing mutations had the classical triple A syndrome of achalasia, alacrima, adrenal abnormalities and a progressive neurological syndrome. We identified a spectrum of associated neurological abnormalities in these cases, including pupil and cranial nerve abnormalities, frequent optic atrophy, autonomic neuropathy and upper and lower motor neurone signs including distal motor neuropathy and amyotrophy with severe selective ulnar nerve involvement. In these families, we have made genotype-phenotype correlations. Mutations in the triple A gene are thus an important cause of this clinically heterogeneous syndrome, and sequencing represents an important diagnostic investigation. Identifying further mutations and defining their phenotype along with functional protein analysis will help to characterize this neuroendocrine gene.
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PMID:Clinical and genetic characterization of families with triple A (Allgrove) syndrome. 1242 95

Allgrove syndrome (triple A syndrome) is an autosomal recessive disorder characterised by adrenocortical insufficiency, achalasia and alacrima. Patients also suffer from diverse neurological disorders. Allgrove syndrome is caused by mutations in the AAAS gene located at chromosome 12q13, which encodes for a tryptophan-aspartic acid (WD) repeat protein (aladin). The exact function of this protein is still not known.
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PMID:[From gene to disease; adrenocortical insufficiency, achalasia and disrupted tear secretion: Allgrove syndrome]. 1266 22

The triple A syndrome (MIM*231550) is a rare autosomal recessive disorder characterized by adrenocorticotropic hormone (ACTH) resistant adrenal failure, achalasia, alacrima and a variety of neurological and dermatological features. Adrenal insufficiency usually presents in the first decade of life, however in some patients it may occur later in life or may even lack completely. Recently, we and others identified a novel gene on chromosome 12q13, designated AAAS (Achalasia-Addisonianism-Alacrima-Syndrome gene) which is mutated in patients with triple A syndrome. We investigated n=84 families including 111 patients with clinically suggested triple A syndrome and identified homozygous or compound heterozygous AAAS mutations in 78 families. Genotype/phenotype analyses revealed a highly variable occurrence, age of onset and severity of all clinical symptoms between patients with the same AAAS mutation. The obvious lack of a genotype/phenotype relationship is suggestive of modifying genes/factors which need to be determined. The AAAS protein function is unknown. With four WD repeats it belongs to the family of WD repeat-containing proteins which may exhibit a high degree of functional diversity. The subcellular localization of the protein and the determination of its putative binding partners will shed light on the role of the AAAS protein for the development and function of the adrenal gland and other neuroendocrine structures.
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PMID:New insights into the molecular basis of the triple A syndrome. 1253 Jun 89

Triple A syndrome is a rare, autosomal recessive disorder characterized by alacrima, achalasia, and adrenal insufficiency. Previous studies have shown that the triple A gene (AAAS) maps to chromosomal band 12q13. Mutations in the AAAS gene have been identified in triple A syndrome patients; however, the function of this gene is still obscure. We used classical and high-resolution chromosome analyses along with chromosome painting and DNA sequencing to study patients with triple A syndrome. We observed abnormalities in the heterochromatic region of chromosome 9 that included chromatid breaks, chromosome breaks, whole chromosome arm loss, and marker chromosomes, which occurred at unusually high frequencies in affected patients and heterozygotes. Our study raises the possibility of an association between chromosomal fragility in band 9q12 and triple A syndrome. Further investigation is necessary to understand the biologic basis of this finding in the context of triple A syndrome.
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PMID:Chromosomal fragility in patients with triple A syndrome. 1254 37

Allgrove's or "4 A" syndrome is a rare autosomal recessive condition with alacrima, achalasia, autonomic disturbance, and ACTH insensitivity among other features. Recent studies have identified mutations in the AAAS, a candidate gene on chromosome 12q13 in such patients. Manifestations in adult patients are rarely reported. The syndrome usually presents during the first decade of life with dysphagia or severe (occasionally fatal) hypoglycaemic or hypotensive attacks, related to adrenocortical insufficiency. Onset of adrenal insufficiency or other features may be delayed to adulthood. In contrast with paediatric patients, adult patients with Allgrove's syndrome may present with multisystem neurological disease; the childhood history of achalasia or alacrima may be overlooked. The authors describe two families with two affected siblings and a further unrelated patient with typical clinical features of Allgrove's syndrome, who exhibit signs of multisystem neurological disease including hyperreflexia, muscle wasting, dysarthria, ataxia, optic atrophy, and intellectual impairment. None of the cases have developed adrenal insufficiency but all have progressive neurological disability. Autonomic dysfunction was a significant cause of morbidity in two cases. The three index cases represent the longest described follow up of Allgrove's syndrome into adulthood. It is speculated that they represent a subgroup of patients who follow an often undiagnosed chronic neurological course. Recognition of the syndrome presenting in adult life permits treatment of unrecognised autonomic dysfunction, adrenal insufficiency and dysphagia, and appropriate genetic advice.
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PMID:Allgrove or 4 "A" syndrome: an autosomal recessive syndrome causing multisystem neurological disease. 1270 Mar 13


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