Linkage disequilibrium in inbred North African families allows fine genetic and physical mapping of triple A syndrome

Abstract

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 (Z max = 10.89 at Θ = 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. European Journal of Human Genetics (2000) 8, 613-620.

Allgrove’s Syndrome: Two Case Reports and Review of Literature

“…However, the apparently normal ACTH receptor gene in affected children suggests that the etiology of AS is probably heterogeneous (14). Here, we highlighted the importance of hypoglycaemia, hyperpigmentation and alacrima as some clues in the diagnosis of Allgrove's syndrome.…”

“…In these kindreds, genetic analysis did not suggest the presence of microdeletions. Searching for gene responsible for AS, a variety of genes were excluded in the 0.5-cM interval between polymorphic markers D12S361 and D12S368 (13,14). The gene coding for the neuronal sodium channel SCN8A had been previously mapped to a clone containing D12S368 (16), placing it at the AS locus.…”

“…Absence of peristalsis within the body of the oesophagus is detected by a defect in relaxation of the gastro-oesophageal sphincter and a dilatation in the proximal oesophagus. Achalasia may sometimes be a part of AS and displays autosomal recessive inheritance disorder (2,8,14). Esophagography of the patient showed a narrowing in the cardio-oesophageal junction and a dilatation of the oesophagus proximal to the junction (19).…”

Tunisia: Communities and Community Genetics

“…Other syndromes are commonly seen, e.g. the Meckel syndrome, the Seckel syndrome, the Robinow syndrome, the Schwartz-Jampel syndrome, and triple A syndrome [49,50,51]. New entities are proposed, too [52].…”

Mice Lacking the Nuclear Pore Complex Protein ALADIN Show Female Infertility but Fail To Develop a Phenotype Resembling Human Triple A Syndrome

“…The involvement of other organ systems demonstrated by palmoplantar hyperkeratosis, scoliosis, osteoporosis, caries, and parodontosis, as well as short stature, point to the multisystemic character of the disorder (3,11,16). The disease was linked to chromosome 12q13 (8,12,19,25), and the causative gene, AAAS, was identified. AAAS encodes a 546-amino-acid protein designated ALADIN (for "alacrima-achalasia-adrenal insufficiency neurologic disorder") (9,20).…”