New Insights Into the Molecular Basis of the Triple a Syndrome

Abstract

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.

The nuclear pore complex protein ALADIN is mislocalized in triple A syndrome

“…An interesting aspect of triple A syndrome is the high degree of variability in severity and age of onset, seen even between patients with the same mutation and similar genetic backgrounds (7,11). Clearly, other factors also are involved in triple A syndrome, and recent reports suggest that there may be another causative gene (11).…”

“…Clearly, other factors also are involved in triple A syndrome, and recent reports suggest that there may be another causative gene (11). These additional factors may be involved in nucleocytoplasmic transport or in signaling pathways that act through ALADIN at NPCs.…”

“…There is no obvious correlation between different ALADIN mutations and disease phenotype. Patients with the same mutation, even patients within the same family, frequently display a high degree of variability in the clinical severity and age of onset of their symptoms (7,11). This indicates that other factors play an important role in the pathogenesis of triple A syndrome.…”

A Novel <i>AAAS</i> Gene Mutation (p.R194X) in a Patient with Triple A Syndrome

“…The etiology of delayed puberty in triple A syndrome remains unclear. In view of the marked expression of AAAS in the pituitary gland [20], the delayed and slowly advancing puberty in our patient could be an indication for a progressive impairment of pituitary function in triple A syndrome, so that testosterone replacement could be considered. According to present knowledge, patients with isolated adrenal insufficiency usually develop puberty at the right time, but fail to develop adrenarche [21,22].…”

The Adrenal

“…The molecular basis of triple A syndrome has recently been elucidated and shown to be due to mutations in the WD-motif protein ALADIN (AAAS) , which likely plays a role in downstream receptor signalling [17, 18, 19]. Associated features of triple A syndrome include subtle neurological and dermatological signs (e.g.…”